Dedication

The authors dedicate this book to George, Ahmad, Giovanna, Nicos, Meigui, Sumitra, Christine,
Minh-Quan, Hamid, Pranee, Eduard, Karim, and all other patients with thalassaemia, who are not
with us any more but whose will and determination to live have inspired researchers and health
professionals across the world to promote scientific knowledge and quality care.

It is our fervent hope that this book will serve not only as a manual for promoting clinical
management, but also as a tool for improving communication and collaboration amongst all of
those, patients, parents, health professionals and others who are striving towards the same goal,
the establishment of effective control of thalassaemia and the promotion of equal access to
quality health care for every patient with Thalassaemia.

1
EED
DIITTOORRSS AANNDD AAUUTTHHOORRSS::
Maarriiaa--D
M Doom
meenniiccaa CCaappppeelllliinnii,, M
MDD – Professor, Centro Anemie Congenite, Ospedale Maggiore
Policlinico IRCCS, University of Milan, Italy

Allaann CCoohheenn,, M
A MDD – Professor of Paediatrics, University of Pennsylvania, School of Medicine, USA
AAnnddrroouullllaa EElleefftthheerriioouu,, PPhh..DD.. – Ex-Director of the Virus Reference Laboratory, Ministry of Health
Cyprus, Executive Director - Thalassaemia International Federation

AAnnttoonniioo PPiiggaa,, M
MDD – Professor, Dipartimento di Scienze Pediatriche e dell’Adolescenza, Universita
degli Studi di Torino, Italy

JJo
ohhnn PPoorrtteerr,, M
MDD – Professor, Department of Haematology, University College, London, UK
AAllii TTaahheerr,, M
MDD – Professor Medicine - Hematology & Oncology, Department of Internal Medicine,
American University of Beirut Medical Center, Beirut Lebanon

AUUTTHHOORRSS OOFF CCHHAAPPTTEERRSS::

A
Athanasios Aessopos, MD - Professor of Cardiology, First Department of Internal Medicine,
University of Athens - "Laiko" General Hospital, Athens, Greece

Emanuel Angelucci, MD - Professor of Haematology, U.O. Ematologia Ospedale Oncologico

"Armando Businco", Cagliari, Italy

Michael Antoniou, Ph.D. - Division of Medical & Molecular Genetics, GKT School of Medicine, Guy's
Hospital, London, UK

Ratna Chatterjee, MD – Consultant/Senior Lecturer in Reproductive Health, University College

London, London, UK

Demetrios Farmakis, MD - First Department of Internal Medicine, University of Athens - "Laiko"

General Hospital, Athens, Greece.

Susan Perrine, MD - Director of Haemoglobinopathy/Thalassaemia Research Unit, Professor of

Paediatrics – Medicine Pharmacology and Experimental Therapeutics Boston, Boston University
School of Medicine, Boston, Massachusetts, USA

Vicenzo De Sanctis, MD- Professor of Paediatric Endocrinology, Divisione Pediatrica Azienda,

Ospedaliera – Archispedale S. Anna, Ferrara, Italy

Malcolm John Walker, MD - Consultant Cardiology – Hatter Institute, Cecil Fleming House,
University College London Hospital, London, UK

COO--OORRDDIINNAATTIINNGG EEDDIITTOORR::
C

Androulla Eleftheriou, B.Sc., M.Sc., Ph.D., Dipl.MBA

2
COONNTTRRIIBBUUTTOORRSS::
C

Constantina Politis, MD – Associate Professor, Director of the 3rd Reg. Blood Transfusion Centre,
'George Gennimatas' General Hospital, Athens, Greece

Ala Sharara, MD – Professor, Director of Division of Gastroenterology- American University of

Beirut Medical CenterEndoscopy Unit, Beirut, Lebanon

Nicos Skordis, MD - Consultant of Paediatric Endocrinology, Department of Paediatrics,

Thalassaemia Centre, Makarios III Hospital, Ministry of Health Cyprus, Nicosia, Cyprus.

Ersi Voskaridou, MD - Director of the Thalassaemia Unit and WHO Collaborating Centre, Geniko
Laiko Nosokomio Athinon, Greece

ACCKKNNOOW
A WLLEEDDGGEEM
MEENNTTSS::
The Thalassaemia International Federation would like to express its most sincere appreciation and
Drr.. HHeelleenn PPeerrrryy – Editor, DDrr M
gratitude to D Miicchhaaeell AAnnggaassttiinniioottiiss - Thalassaemia International
Federation, Medical Advisor and D Drr.. M
Maatthheeooss DDeem meettrriiaaddeess – Thalassaemia International
Federation, Projects’ Coordinator for their invaluable contribution to the completion of the
book.

3
Contents

Foreword 6

Introduction 9

CHAPTER 1 12
Genetic Basis and Pathophysiology

CHAPTER 2 18
Blood Transfusion Therapy in ‚-Thalassaemia Major

CHAPTER 3 31
Iron Overload

CHAPTER 4 64
Endocrine Complications In Thalassaemia Major

CHAPTER 5 70
Management of Fertility and Pregnancy in ß-thalassemia

CHAPTER 6 79
Diagnosis and Management of Osteoporosis in ‚-thalasaemia

CHAPTER 7 83
The Management of Cardiac Complications in Thalassaemia Major

CHAPTER 8 92
The Liver in Thalassaemia

CHAPTER 9 106
Infections in Thalassaemia Major

CHAPTER 10 116
Splenectomy in ‚-thalassaemia

CHAPTER 11 121
Thalassaemia Intermedia and HbE

4
CHAPTER 12 132
Stem Cell Transplantation

CHAPTER 13 136
Alternative Approaches to the Treatment of Thalassaemia

CHAPTER 14 139
Gene Therapy: Current Status and Future Prospects

CHAPTER 15 142
Psychological Support in Thalassaemia

CHAPTER 16 149
General Health Care and Lifestyle in Thalassaemia

CHAPTER 17 155
Organisation and Programming of a Thalassaemia Centre

CHAPTER 18 159
Outline of Diagnostic Dilemmas in Thalassaemia

References 170

Index 196

About thalassaemia 202

5
Foreword

The fight against thalassaemia has entered new and exciting territory, with major advances
dramatically improving patient care. At the forefront of that fight, the Thalassaemia International
Federation (TIF) remains true to its goal: to secure equal access to quality healthcare for every
patient with thalassaemia around the world. This book is a key tool in achieving that goal.

Written by some of the world’s leading authorities on haemoglobin disorders, this fully updated
second edition of Guidelines for the Clinical Management of Thalassaemia provides medical
professionals with a clear, comprehensive guide to the optimal treatment of thalassaemia, based
on scientific evidence, clinical studies and observations. The information provided here has been
meticulously compiled by experts fully aware of the many different circumstances in which medical
personnel strive to treat patients with thalassaemia. As such, it sets out to provide a full guide to
the treatment to which every patient everywhere is entitled, including access to sufficient
quantities of safe blood and iron chelation therapy, as well as offering a comprehensive
assessment of groundbreaking advances in chelation therapy, other treatment options and the
long-awaited final cure, including stem cell transplantation and gene therapy.

With the support of member associations, dedicated scientists and healthcare workers, patients,
families and friends, TIF focuses on three categories of projects, each contributing to the overall
goal of reaching its objectives and achieving its mission:

TIF projects aim to promote and support:

ñ Awareness about thalassaemia, its prevention and its medical and other care;

ñ Research focused on the continuous improvement of medical care and on realising a total cure
for thalassaemia, and;

ñ Dissemination of the knowledge, experience and expertise of countries with successful control
programmes to countries in need.

TIF’s activities in achieving the above include:

1. The establishment of new and promotion of existing national patient organisations;

2. The development of a collaborative network of national and international

ñ thalassaemia and other disease-specific patient organisations;
ñ medical and scientific communities involved in the field;
ñ research institutes and medical centres of excellence;
ñ health-related organisations, and;
ñ pharmaceutical industries

3. The coordination of or participation in national, regional and international projects contributing

to worldwide improvements in:
ñ Epidemiology

6
ñ Medical and other care
ñ Social integration and quality of life
ñ Extending knowledge of the disease, its prevention and treatment to policy makers, health
professionals, patients and parents, and the community at large
ñ Securing the rights of every patient for equal access to quality medical care, and
ñ The safety and adequacy of blood

4. The establishment of programmes for the continuous education of health professionals,

patients and parents, and the community, including:
ñ Organisation of local, national, regional European and international workshops, conferences,
seminars and meetings.
ñ The preparation, publication, translation and free distribution of educational and awareness-
raising material.

The recent launch of a unique e-MSc in Haemoglobinopathies, offered by University College

London (UCL) and part-funded by TIF, is just one example of the scope and ambition of TIF’s
educational programme.

TIF’s achievements are the result of voluntary, dedicated work by

scientists and medical professionals from around the world, without
which TIF’s educational programme, one of its most important tools
for the dissemination of knowledge and experience, would never have
achieved the level of success it currently enjoys.
The authors and all other contributors that have made this book possible deserve particular
recognition for their work. The first edition of this book served for many years as the reference
text for the treatment of thalassaemia. We are confident that this second edition will make a
similar if not greater contribution to efforts to spread existing knowledge and the advances
achieved in the last seven years in the field of the clinical management of thalassaemia. Special
acknowledgement is also due to a number of other specialists, including Antonio Cao, Vilma
Gabutti, Renzo Galanello, Giuseppe Masera, Bernadette Modell, Annuziata di Palma, Calogero Vullo
and Beatrix Wonke, who led the way in the early, difficult years, when knowledge on this subject
was very limited. They are amongst the pioneers in the promotion of the clinical management of
thalassaemia and in the setting out of standards of care to which every patient is entitled.

The first edition of the Guidelines for the Clinical Management of Thalassaemia, published in 2000,
was the first of its kind to be produced at a time when specialists, patients and parents considered
its preparation essential, in view of the rapid achievements in the treatment of thalassaemia. This
new, fully updated, second edition is a timely response to the many further advances that have
been made since then.

This new edition of Guidelines for the Clinical Management of Thalassaemia offers an invaluable tool
to medical staff involved in the treatment of thalassaemia. National governments, thalassaemia

7
centres and individual health personnel caring for patients with thalassaemia are strongly
encouraged to follow the recommendations of the panel of experts, as presented here.

At the same time, it is extremely important that the prevention of

thalassaemia receives similar attention.
While outside the scope of this book, the prevention of thalassaemia remains a crucial objective for
TIF. Unless new births of affected children are prevented or minimized, even the best updated
treatment programmes will eventually collapse, unable to provide for an ever-increasing number of
patients. In this context, the development of national prevention programmes is at the heart of
TIF’s activities. TIF, based on its long-time experience, can offer considerable support to countries,
including detailed advice on the structure of, and challenges to implementing, such programmes.

On behalf of the Board of Directors of TIF I would like to once again extend our deepest gratitude
to the experts who have dedicated work, time and effort to producing this updated second edition
of Guidelines to the Clinical Management of Thalassaemia. Last but by no means least, I would like
to express our most sincere appreciation to the Non-Communicable Diseases Genetics Department
of the World Health Organisation (WHO), with which TIF has been collaborating on an official basis
since 1996, and whose support and guidance in promoting our mission have been multi-faceted
and invaluable.

Panos Englezos
TIF President

8
Introduction

Haemoglobin (Hb) disorders are hereditary, genetic diseases consisting mainly of sickle cell
disease and the thalassaemias, which account for a great proportion of births affected by a
genetic disease.

The thalassaemias are a heterogeneous group of the haemoglobin disorders in which the
production of normal haemoglobin is partly or completely suppressed as a result of the
defective synthesis of one or more globin chains. Several types of thalassaemia have been
described and named according to the affected globin-chain, the most common types of clinical
importance being ·-, ‚‰- and ·-thalassaemia.

Haemoglobin disorders are thought to have originated in countries

where malaria was or is endemic—areas to which it was for many
years believed such disorders were confined.
Sub-Saharan Africa accounts for more than 70% of births affected by sickle cell disorders every
year, with the remainder occurring at various rates (from low to high) in other parts of the
world. Thalassaemia, including HbE, is more prevalent in the Mediterranean basin, the Middle
East, Southern and Eastern Asia, the South Pacific and South China, with reported carrier rates
ranging from 2% to 25%.

Although reliable data are still lacking for many regions of the world, recent data indicate that
about 7% of the world’s population is a carrier of a haemoglobin disorder, and that 300,000-
500,000 children are born each year with the severe homozygous states of these diseases.
(World Bank 2006, report of a joint WHO-March of Dime meeting 2006)

It is now well recognised that Hb disorders are not confined to any particular region, occurring
widely across the world and constituting a global public health problem. Hb disorders have
spread through the migration of populations from endemic areas to countries where their
prevalence in indigenous populations had been extremely low. Such countries include the USA,
Canada, Australia, South America, the United Kingdom and France, where migration occurred up
to a century ago and where large ethnic minority groups are now entering their fourth and even
fifth generation.

More recent migration movements from highly endemic countries have been to Northern and
Western Europe, where the prevalence of Hb disorders in the indigenous population is very low,
including Germany, Belgium, the Netherlands and, more recently, Scandinavia.

These changes have challenged health professionals and policy-makers throughout the region in
providing equitable access to quality services for the prevention and treatment of Hb disorders.
In some regions, such as Scandinavia, to which there is currently large-scale migration, the
proportion of births in ‘at-risk groups’ is predictive of the future genetic make-up of the
population, as has been the case in some of the countries mentioned above, where large scale
migration from affected countries had occurred much earlier.

9
Carrier prevalence will clearly continue to rise in Northern and Western Europe, even in the
absence of further migration, as a result of reproduction and inter-community marriages, and
Hb disorders are likely to become the leading recessive disorder throughout the region, posing a
serious public health problem. Clearly, the earlier classification of endemic and non-endemic
countries for Hb disorders is no longer relevant. However, effectively addressing the control of
these disorders in these countries will require considerable work, financial backing and certainly
political commitment. The main difficulty is that the populations of these countries are not
homogeneous, as was the case in the Mediterranean countries where the earliest control
programmes were successfully established. Some countries in Europe, such as the United
Kingdom and France, have already accumulated considerable experience and knowledge in the
most cost-effective and practical ways of intervention to address this highly important public
health problem.

Recognition of the problem in Northern and Western Europe has raised concerns and stirred up
interest amongst national and EU health policy-makers who, in addition to and complementary
to the work of World Health Organisation (WHO), which was traditionally involved in the
promotion of control programmes for Hb disorders, have already taken significant steps in the
context of their agenda on rare diseases.

Unlike affected countries of the developing world, these countries already have strong health
care infrastructure and systems in place, and the resources and quality health services required.
The European countries need to address ethnic minorities, which are widely scattered
geographically, and to raise strong health professional and patient/parent awareness—tasks that
are essential in the promotion of effective control programmes.

Recent improvements in the resources and health care structures of Eastern European countries
such as Bulgaria and Romania have contributed to a greater recognition of the importance of
developing and implementing control systems for Hb disorders occurring in the indigenous
population, which in some regions can reach very high carrier levels.

Southern European countries with Hb disorders occurring in the indigenous population, albeit at
considerably lower prevalence rates, include Portugal and Spain—countries that are, however,
able to respond effectively to public health requirements and to adopt effective policies.

Low prevalence European countries where haemoglobinopathies have not yet penetrated to a
significant degree through migration include Poland, Hungary and the Czech Republic, although
these, along with Spain and Portugal, constitute potential targets for increasing migration.

Albania is a separate example, having higher prevalence rates of Hb disorders than the rest of
the Balkan countries in the indigenous population with carriers and affected individuals widely
scattered across the country. Although appropriate services are still largely underdeveloped,
significant progress has been achieved during the last few years, especially in the area of clinical
management. Unfortunately data on the epidemiology and status of control programmes in
Russia remains scanty.

10
In lower and middle-income countries on the other side of the world, where haemoglobin
disorders are most prevalent in the indigenous population, 50-80% of children with sickle cell
disease and a significant number of children with ‚-thalassaemia die each year—undiagnosed or
misdiagnosed, sub-optimally treated or not treated at all.

There is an urgent need to bridge this wide gap until every patient in every part of the world has
equal access to quality medical care. An essential means of doing so is through global
collaboration on Hb disorders, enabling all countries to benefit from each other’s experience.
Health authorities need to recognise Hb disorders as a significant threat to public health—one
that deserves the development and implementation of national policies for treatment and
prevention. The instruments required to support such policies include:

ñ Standards and guidelines for laboratory services

ñ National guidelines for the management of thalassaemia
ñ Epidemiological information and surveillance
ñ Establishment of an educational programme for health
professionals, patients, parents and the community
It is evident that all countries would benefit from the sharing of experience and expertise. The
difficulties encountered in service development for haemoglobin disorders apply equally to many
other inherited disorders. Professionals and support groups alike would benefit from forming
wider partnerships with similar groups representing other disorders.

It is hoped that this book will offer valuablel information to all medical professionals involved in
the treatment of patients with thalassaemia. It includes updated information on new approaches
for more effective, safe and less laborious treatment, and an overview of the progress achieved
to date towards a total cure for thalassaemia, using methods such as gene therapy and stem cell
transplantation.

Until the final goal of a complete cure for thalassaemia is found, it is the obligation of national
health authorities and health professionals to provide, and the right of patients to receive, the
most complete and up-to-date systems of treatment available. We hope that these guidelines,
which constitute the authors’ consensus on the most effective treatment of ‚-thalassaemia
major, will prove an indispensable tool for health professionals involved in this field.

Androulla Eleftheriou, B.Sc., M.Sc., Ph.D., Dipl.MBA

TIF Executive Director
Coordinating Editor

11
Genetic Basis and
Pathophysiology
Haemoglobin Types
Oxygen is transported from the lungs to the
tissues by a highly specialised protein
molecule, haemoglobin, which is located in
the red cells of the blood. Each red blood
cell contains approximately 300 million
molecules of this protein, totalling about 30
picograms in weight per cell. Each molecule
of haemoglobin is formed by two pairs of
identical sub-units, the globin chains, which
are named with letters of the Greek alphabet
and belong to two groups: the ·-globin
cluster, comprising the ˙- and ·-globin
chains, and the ‚-globin cluster, comprising
the globin chains Â, Á, ‚ and ‰. The globin
chains appear sequentially during ontogeny
and, after pairing, form the following four
major types of haemoglobin:
a) “embryonic” haemoglobins, which are
detectable from the 3rd to the 10th
week of gestation and represent ˙2Â2,
·2Â2 and ˙2Á2 tetramers;
b) “fetal” haemoglobin (HbF ·2Á2), which
constitutes the predominant oxygen
carrier during pregnancy ;
c) “adult” haemoglobin (HbA ·2‚2), which
replaces HbF shortly after birth, and;
d) a minor adult component, HbA2 (·2‰2).
Under normal conditions, the red cells of the
adult human contain approximately 98% HbA,
2.0% HbA2 and traces of HbF.
Globin Genes and
Globin Synthesis
The globin chains have an extremely precise
structure, ensuring their prompt loading with
oxygen in the lung alveoli and its controlled
gradual delivery into the tissues. The precise
12
structure of the globin chains is coded by
genes contained in the DNA of chromosomes
16 (the · gene cluster) and 11 (the ‚ gene
cluster). Flanking the structural genes, i.e. in
front (on the 5’ side of the DNA sequence,
“upstream”) and following them (on the 3’
side of the DNA sequence, “downstream”), lie
several nucleotide sequences which have a
“regulatory” role, i.e. they determine which
gene is to be turned on and which off, as
well as how efficient its expression will be. In
adult life, most of the globin synthesis occurs
in the erythroblasts in the bone marrow.
Haemoglobin must have the correct
structure and be trimmed in such a way that
the number of ·-chains precisely matches
that of the ‚-chains. When the above
conditions are not met, the result is a
complete or partial defect in one or both
“allelic” globin genes.
The Thalassaemias:
Definitions and
Worldwide
Distribution
The term “thalassaemia” refers
to a group of blood diseases
characterised by decreased
synthesis of one of the two
types of polypeptide chains (·
or ‚) that form the normal adult
human haemoglobin molecule
(HbA, ·2‚2), resulting in
decreased filling of the red cells
with haemoglobin, and anaemia.
Depending on which of the genes the defect
occurs and the corresponding effect on the
 production of globin chains, ·-thalassaemia
or ‚-thalassaemia results. The present book
mainly addresses the latter group of
thalassaemias, which are now recognised to
occur widely across the world well beyond
the countries where these were originally
thought to be endemic i.e. countries around
the Mediterranean Basin, the Middle East,
Trans-Caucasus and India for ‚- and the Far
East for ·-thalassaemia (see Figure 1).
‚-Thalassaemia
Ph en o ty pi c h eter o gen ei ty
As a rule, heterozygous carriers of ‚-
thalassaemia (one affected allele), display a
low mean cellular haemoglobin (MCH), low
mean cell volume (MCV), mild morphological
CELL TYPE
SITE OF
ERYTHROPOIESIS
PERCENTAGE
OF TOTAL
GLOBIN
SYNTHESIS
Figure 1: Globin synthesis at various stages of embryonic and fetal development
13
alterations of their red cells, an increased
level of HbA2, and a low ‚/·- globin chain
ratio on biosynthesis, which is occasionally
associated with low normal or slightly
subnormal haemoglobin levels. Under normal
circumstances, the thalassaemia trait is not
related to any significant clinical effects,
mainly because the activity of the normal ‚
gene on the allelic chromosome makes
enough stable globin. In contrast, inheritance
of two defective ‚-globin genes results in a
wide spectrum of clinical conditions, ranging
from transfusion dependence (thalassaemia
major) to mild or moderate anaemia
(thalassaemia intermedia). Molecular studies
may reveal a large array of abnormalities
underlying the above phenotypes and may
assist in their identification.

Pathophysiology of
‚-thalassaemia
Advances in the management of thalassaemia
were achieved only after the pathophysiology
of the disease was elucidated and clearly
understood by the scientific and medical
community involved in the field. Figure 2
PATHOPHYSIOLOGY OF ‚-THALASSAEMIA MAJOR
Figure 2: Effects of excess production of free ·-globin chains
14
below outlines the pathophysiology of ‚-
thalassaemia and describes the chain of
events following globin chain imbalance and
the accumulation of excess ·-chains – that is,
ineffective erythropoiesis leading to anaemia,
bone marrow expansion, skeletal deformities
and increased GI iron absorption.
The degree of globin chain imbalance is
determined by the nature of the mutation of
the ‚-gene. ‚o refers to the complete
absence of production of ‚-globin on the
affected allele. ‚+ refers to alleles with some
residual production of ‚-globin (around 10%).
In ‚++ the reduction in ‚-globin production is
very mild. More than 200 thalassaemic
mutations have been reported to date.
Table 1 includes the common types of
‚-thalassaemia mutations according to ethnic
distribution and severity. A more
comprehensive list of ‚ mutations can be
found on the internet at
http://globin.cse.psu.edu/globin/html/huisman .

Population ‚ - g e n e M u t a ti o n S e ve r i ty

Indian -619 del ‚Ô

Mediterranean -101 ‚++
Black -88 ‚++
Mediterranean; African -87 ‚++
Japanese -31 ‚++
African -29 ‚++
Southeast Asian -28 ‚++
Black -26 ‚++
Mediterranean; Asian Indian IVS1-nt1 ‚o
Mediterranean; Asian Indian IVS1-nt5 ‚o
Mediterranean πøS1-nt6 ‚+/++
Mediterranean IVS1-nt110 ‚+
Chinese IVS2-nt654 ‚+
Mediterranean IVS2-nt745 ‚+
Mediterranean codon 39 ‚o
Mediterranean codon 5 ‚o
Mediterranean; African-American codon 6 ‚o
Southeast Asian codons 41/42 ‚o
African-American AATAAA to AACAAA ‚++
Mediterranean AATAAA to AATGAA ‚++
Mediterranean Hb Knossos ‚++
Southeast Asian HbE ‚++

Table 1: Common types of ‚-thalassaemia, their severity and ethnic distribution

15

Beta structural
haemoglobin variants
relevant to
thalassaemia
management
Haemoglobin E disorder is the most common
structural variant resembling thalassaemia
desorders (see relevant Chapter 11:
Thalassaemia Intermedia).
HbE results from a mutation (G➔A) at codon
26 of the ‚-globin gene causing the
substitution of lysine for glutamic acid – a
mutation that results in a qualitative and
quantitative ‚-globin gene defect since it is
related to the activation of a cryptic splice
site at codon 24-25, leading to an alternative
splicing pathway. The overall result is the
production of reduced amounts of the
variant haemoglobin (HbE).
HbE is the most common abnormal
haemoglobin in South East Asia, with a carrier
frequency of more than 50% in some
regions. It is also prevalent in parts of the
Indian subcontinent, including Bangladesh.
Heterozygotes for HbE are clinically normal
and manifest with 25-30% of HbE on
electrophoresis and with only minimal
changes in red blood cell indices.
Homozygotes for HbE are clinically silent and
may be only mildly anaemic. On microscopic
examination, the peripheral blood smear
demonstrates microcytosis with 20-80% of
target red cells, while Hb electrophoresis
shows 85-95% of HbE and 5-10% of HbF.
HbE/‚-thalassaemia constitutes the most
common combination of ‚-thalassaemia with
a structural variant, most prevalent in South
East Asia. The related clinical manifestations
16
are variable in severity— ranging from those
characterising thalassaemia intermedia to
those described for severe transfusion-
dependent thalassaemia major. The reasons
for this variability have only partially been
defined, since patients with seemingly
identical genotypes present with clinical
manifestations very different in severity.
Hb Lepore is another structural
‚ variant resulting from a fusion
of the ‰ and ‚ globin genes.
The homozygous state of Hb
Lepore can result in moderate
to severe transfusion-
dependent ‚-thalassaemia
syndromes.
HHaaeem
mo
oggllo
obbiinn SS ddiissoorrddeerrss: HbS, the most
common haemoglobin variant in the world,
results from a substitution of valine for
glutamic acid at position 6 of the ‚-globin
chain. The interaction of ‚-thalassaemia with
HbS results in a syndrome that most closely
resembles the sickling disorders, which
typically do not require lifelong transfusions
and are not consequently associated with
iron overload. As for thalassaemia, Guidelines
for the management of sickle cell disorders
have been formulated in recent years and a
useful web-site for more information is:
http://www.nhlbi.nih.gov/health/prof/blood/
sickle/sick-mt.htm.
·-thalassaemia
·-thalassaemias are inherited disorders
characterised by reduced or suppressed
production of ·-globin chains. The human ·-
globin genes are duplicated and located in
the telomeric end of the short arm of
chromosome 16. ·-thalassaemia is caused
most commonly by deletions of large DNA crisis, mainly in response to oxidant drugs
fragments that involve one or both ·-globin and infections.
genes.
Silent carrier state: The presence of a single Other relevant structural variants include Hb
·-globin gene deletion results in the silent Constant Spring, characterised by ineffective
carrier state occurring widely across the synthesis of a-globin chains, resulting from a
world. defect on the relevant gene that causes their
elongation. This mutation is found primarily
·-thalassaemia trait is in Asia and its co-inheritance with the
characterised by the presence deletion of two ·-genes results in a severe
form of HbH disease.
of two residual functional a-
genes and is not related to any Hb Bart’s hydrops fetalis, the most severe
serious clinical or laboratory clinical manifestation of ·-thalassaemia, is
findings: generally associated with the absence of all
four ·-globin genes and death in utero.
Miilldd aannaaeem
M miiaa aanndd m
miiccrrooccyyttoossiiss.. Absence of ·-globin genes in the “cis”
position on the same chromosome (·Ô-
Deletions or abnormalities of three globin
thalassaemia) is common in South East Asia,
genes result in HbH disease, usually
while it is rare in the Mediterranean area and
characterised by a moderate haemolytic
even rarer in Africa.
anaemia, splenomegaly and acute haemolytic

With permition from the Source: March of Dimes: Global Report 2006

17
Blood Transfusion Therapy in
‚-Thalassaemia Major
Goals of Blood
Transfusion Therapy
Appropriate goals of transfusion therapy and
optimal safety of transfused blood are the
key concepts in the protocol for routine
administration of red blood cells to patients
with thalassaemia. The major goals are:
ñ Maintenance of red cell viability and
function during storage, to ensure
sufficient transport of oxygen;
ñ Use of donor erythrocytes with a normal
recovery and half-life in the recipient;
ñ Achievement of appropriate haemoglobin
level, and;
ñ Avoidance of adverse reactions, including
transmission of infectious agents.
Quality and Adequacy
of Blood
To safeguard the health of the
transfusion recipient, including
patients with thalassaemia,
blood should be obtained from
carefully selected regular
voluntary, non-remunerated
donors and should be collected,
processed, stored and
distributed, in the context of
dedicated, quality assured
national blood transfusion
centres.
Nationally developed legislation-based on EU,
Council of Europe, North American, World
Health Organisation (WHO) or other
international directives, recommendations or
18
relevant laws and taking into account
national needs, resources and prevalence of
infectious agents, should safeguard the
quality of blood transfusion services. Blood
donation practices, donor selection (e.g.,
through questionnaire) and product
screening constitute some of the most
important strategies that contribute to the
safety and adequacy of blood. For more
information on EU directives visit:
http://europa.eu.int and http://europa.eu.int
/consus/health/index_en.html.
On recommendations of the Council of
Europe visit http://www.coe.int, while on
WHO guidelines and American Standards visit
www.who.int/bloodsafety/gcbs/structure/en/
and http://www.aabb.org/content,
respectively. Other sites are also available
should the reader require to obtain more
information.
Transfusion Therapy
in Thalassaemia
This chapter will address five of the most
common questions related to the transfusion
therapy of patients with thalassaemia major:
(i) When to initiate transfusion therapy and
whom to transfuse;
(ii) How blood is processed for effective
and safe transfusion therapy in
thalassaemia major;
(iii) Is there an optimal haemoglobin (Hb)
level for effective transfusion;
(iv) Do transfusion requirements affect the
success of iron chelation therapy;
(v) What are the most serious transfusion
related (TR) reactions (common and less
frequent);
FFoorr ddeecciiddiinngg wwhhoom
m ttoo ttrraannssffuussee, the
following should be included in the Recommended blood
investigations: product
(i) Confirmed laboratory diagnosis of Patients with ‚-thalassaemia
thalassaemia major;
(ii) Laboratory criteria:
major should receive
Hb < 7g/dl on 2 occasions, > 2 weeks leucoreduced packed red blood
apart (excluding all other contributory cells with a minimum
causes such as infections) or haemoglobin content of 40g.
(iii) Laboratory and clinical criteria,
including: Reduction to 1 X 106 or less leucocytes per
- Hb > 7g/dl with: unit (mean counts as low as 0.05 x 106 are
- Facial changes achievable) (Council of Europe, RE 2006) is
- Poor growth considered the critical threshold for
- Fractures, and eliminating adverse reactions attributed to
- Extramedullary haematopoiesis contaminating white cells (see Table 1,
below) and for preventing platelet
alloimmunisation.

REEAACCTTIIOONNSS
R CAAUUSSAATTIIVVEE AAGGEENNTTSS
C

Febrile non-haemolytic transfusion HLA-antibodies in patients, cytokines

reactions (FNHTR) produced by donor leucocytes
HLA- alloimmunisation of recipients HLA antigens on donor leucocytes
Transfusion-transmitted infections Cell-associated infectious agents
Graft-versus-Host-Disease (GVHD) Donor T-lymphocytes

[Morell A, ZLB Central Laboratory Swiss Red Cross, Bern Switzerland, 2000.
Pathogen inactivation of labile blood products]

Table 1: Contaminating Leucocytes as pathogens: Some adverse effects of Leucocytes in labile blood products.

19
Meetthhooddss ffoorr lleeuuccoorreedduuccttiioonn iinncclluuddee::
M immunoglobulin A (IgA) deficiency, in which
ñ P
Prre
e--ssttoorraaggee ffiillttrraattiioonn of whole blood is
the preferred method for leucoreduction.
The delay in filtration (4-8 hours) may
allow some phagocytosis of bacteria (e.g.
Yersinia enterocolitica) (Buchholz, 1992).
This method of leucocyte removal offers
high efficiency filtration and provides
consistently low residual leucocytes in the
processed red cells and high red cell
recovery. Packed red cells are obtained
by centrifugation of the leucoreduced
whole blood.
ñ P
Prre
e--ttrraannssffuussiioonn, laboratory filtration
refers to the filtration at the blood bank
laboratory of packed red cells, prepared
from donor whole blood.
ñ B eddssiiddee ffiillttrraattiioonn refers to the packed red
Be
cell unit which is filtered at the bedside,
at the time of transfusion. This method,
although equally sensitive to those above,
may not allow optimal quality control
because the techniques used for bedside
filtration may be highly variable.
Blood products for
special patient
populations
Waasshheedd rreedd cceellllss may be beneficial for
W RReedd cceellllss oobbttaaiinneedd bbyy ddoonnoorr
patients with thalassaemia who have
repeated severe allergic transfusion
reactions. Saline washing of the donor
product removes plasma proteins that
constitute the target of antibodies in the
recipient. Other clinical states that may
require washed red cell products include
20
the recipient’s preformed antibody to IgA
may result in an anaphylactic reaction.
Washing usually does not result in adequate
leucocyte reduction and should not be used
as a substitute for leucoreduction. Instead,
washing should be used in conjunction with
filtration. In addition, washing of red cell
units may remove some erythrocytes from
the transfusion product, and it is therefore
valuable to monitor post-transfusion
haemoglobin levels to ensure attainment of
the targeted Hb level.
F r oz e n ( o r c ry o p r e s e rv e d ) re d c e l l s
Frozen (or cryopreserved) red cells is
the component derived from whole blood in
which red cells are frozen, preferably within 7
days of collection, using a cryopreservant
and stored at -60oC to -80oC or below, based
on the method used. These are used to
maintain a supply of rare donor units for
certain patients who have unusual red cell
antibodies or who are missing common red
cell antigens. The Council of Europe is
promoting an international network of rare
blood donor units and may be contacted as
follows:
CCoouunncciill ooff EEuurrooppee –– PPooiinntt II
FF6677007755 SSttrraassbboouurrgg CCeeddeexx
FFrraannccee
TTeell:: + +3 33 33 38 8884 4112 2000 00 0
FFaaxx:: + +333 33 38 8884 4112 27 78 81 1
EEm maaiill:: ppooiinntt__ii@
@cco
oee..ffrr
IInntteerrnneett:: wwwwww..ccooee..ffrr//iinnddeexx..aasspp
aapphheerreessiiss:: This method whereby two units
of red cells are collected from the same
donor for transfusion of one patient is
associated with reduction of donor exposures
and consequently to a decreased risk (i) of
transmission of infections, and (ii) of
developing alloimmunisation and other
transfusion related complications.
N e oc y t e or y o u n g r e d c e l l t r a n s f u s i o n
may modestly reduce blood requirements
(Spanos, 1996). However, patients are
exposed to a higher number of donors, with
a consequent increase in cost, risk of
transmission of infections, and risk of
developing alloantibodies.
Storage of donor red
cell units
The anticoagulant preservative solutions used
in blood collection (see Table 2a) have been
developed to prevent coagulation and to
permit storage of red cells for a certain
period of time. All of these solutions contain
sodium citrate, citric acid and glucose, some
of them may also contain adenine, guanosine
and phosphate (e.g., CPD-A).
When red cell concentrates are prepared, a
considerable part of the glucose and adenine
is removed with the plasma. If not
compensated for in other ways, sufficient
viability of the red cells can only be
maintained if the cells are not over-
concentrated. Normal CPD-adenine red cell
concentrate should therefore not have a
haematocrit (Hct) above 0.70 on average
(CoE Re 2006). Newly developed additive
solutions, however, allow maintenance of red
cell viability even if more than 90% of the
plasma is removed, as they contain
considerably higher levels of the necessary
nutrients (see Table 2b). The use of glucose
and adenine is necessary for the
maintenance of red blood cell post-
transfusion viability, phosphate may be used
to enhance glycolysis, and other substances
(e.g.; mannitol, citrate) may be used to
prevent in vitro haemolysis. Sodium chloride
or di-sodium phosphate may be used to give
21
the additive solution a suitable osmotic
strength. Thus the introduction of additives
such as AS-1, AS-3, AS-5 (see Table 2b) has
permitted considerably longer storage of red
cells for up to 42 days.
The maximum duration of
storage (expiry date) as noted
on each unit varies with the
type of preparation
(concentration of cells, formula
of anticoagulant, use of additive
suspension fluid, etc) and
should be determined for each
type on the basis of achieving a
mean 24 hours post-transfusion
survival of no less than 75% of
the transfused red cells.
The haemoglobin oxygen release function
(which is extremely important in thalassaemia
major) is impaired during storage due to
progressive loss of 2, 3-biphosphoglycerate
(2, 3-BPG, previously known as 2, 3-
diphosphoglycerate, DPG). Although, the
storage time of whole blood in CPDA-1 for
example is 35 days (CoE Re 2006), after 10
days of storage all 2, 3 – BPG is lost (CoE Re
2006). In the case of additives such as the
ones mentioned above (see Table 2b),
although storage times up to 42 days are
advocated and high levels of ATP are
maintained up to the 28th day of storage, 2,
3-BPG and P50 values may not be fully
maintained even for this length of time. In
addition, information about the red cell half-
life in the recipient after prolonged storage
of donor blood is limited. Taking into
consideration all the above and in view of the
fact that in thalassaemia major, decreased
recovery and a shortened red cell half-life
may increase transfusion requirements and
as a consequence the rate of transfusional
iron loading. the current practice is to use
red cells stored in additive solutions for less
than two weeks, and in CPD-A for even less
days – as fresh as possible. In patients with
cardiac disease and in small children,
particular attention should be paid to the
increased volume resulting from additive
solutions. In general, for all patients, the
lower haematocrit of red cell units containing
newer additive solutions should be taken into
consideration when calculating the annual
rate of transfusional iron loading (see Tables
2a & 2b).

AC
A CD
D--AA CP
CPD
D CP
C P22D
D CP
C PD
DAA--11
Trisodium citrate 22.00 26.30 26.30 26.30
Citric acid 8.0 3.27 3.27 3.27
Dextrose 24.50 25.50 51.10 31.90
Monobasic sodium phosphate 2.22 2.22 2.22
Adenine 0.275

[Source: Brecker M, ed Technical Manul, 14TH ed Bethesda, MD: American Association of Blood
Banks, 2003: 162]

Table 2a: Content of anticoagulant-preservative solutions (g/L)

ASS--11 ((AAd
A dsso
oll)) ASS--33 ((N
A Nuuttrriicceellll)) ASS--55 ((O
A Oppttiisso
oll))
Dextrose 2,200 1,100 900
Adenine 27 30 30
Monobasic sodium phosphate 0 276 0
Mannitol 750 0 525
Sodium Chloride 154.00 70.00 15.00
Sodium Citrate 0 588 0
Citric acid 0 42 0

[Source: Brecker M, ed Technical Manul, 14TH ed Bethesda, MD: American Association of Blood
Banks, 2003: 183]
Table 2b:Content of additive solutions (mg/100mL)

22
Compatibility testing
Development of one or more specific red cell
antibodies (alloimmunisation) is a common
complication of chronic transfusion therapy
(Spanos, 1990; Singer, 2000). Thus it is
important to monitor patients carefully for
the development of new antibodies and to
eliminate donors with the corresponding
antigens. Anti-E, anti-C and anti-Kell
alloantibodies are the most common.
However, 5-10% of patients present with
alloantibodies against rare erythrocyte
antigens or with warm or cold antibodies of
unidentified specificity.
It is recommended that:
ñ Before embarking on
transfusion therapy, patients
should have extended red cell
antigen typing that includes
at least C, c, E, e and Kell, in
order to help identify and
characterise antibodies in
case of later immunisation;
ñ All patients with thalassaemia
should be transfused with
ABO and Rh(D) compatible
blood.
In addition, the use of blood that is also
matched for the C, E and Kell antigens is
highly recommended in order to avoid
alloimmunisation against these antigens.
Some centres use even more extended
antigen matching.
23
ñ Before each transfusion it is
necessary to perform a full
crossmatch and screen for
new antibodies.
If new antibodies appear, they must be
identified so that in future blood lacking
the corresponding antigen(s) can be
used. A complete and detailed record of
antigen typing, red cell antibodies and
transfusion reactions should be
maintained for each patient, and should
be readily available when and if the
patient is transfused at a different centre.
Transfusion of blood from first-degree
relatives should be avoided because of
the risk of developing antibodies that
might adversely affect the outcome of a
later stem cell transplant.
Transfusion
programmes
The recommended treatment
for thalassaemia major involves
lifelong regular blood
transfusions, usually
administered every two to five
weeks, to maintain the pre-
transfusion haemoglobin level
above 9-10.5 g/dl.
This transfusion regimen promotes normal
growth, allows normal physical activities,
adequately suppresses bone marrow activity
in most patients, and minimises transfusional
iron accumulation (Cazzola, 1995 and 1997).
A higher target pre-transfusion haemoglobin
level of 11-12 g/dl may be appropriate for
patients with heart disease or other medical
conditions and for those patients who do not (Michail-Merianou, 1987; Spanos, 1990; see
achieve adequate suppression of bone Table 3). Presence of alloantibodies and
marrow activity at the lower haemoglobin autoantibodies (see below) may severely
level. Although shorter intervals between compromise transfusion therapy in patients
transfusions may reduce overall blood with thalassaemia intermedia, for example,
requirements, the choice of interval must who receive their first transfusions in
take into account other factors such as the adolescence or later.
patient’s work/school schedule and other
lifestyle issues. Recommendations regarding the volume of
transfused red cells are complicated by the
The decision to initiate lifelong transfusion use of different anticoagulant-preservatives
therapy should be based on a definitive and additive solutions. For CPD-A units with a
diagnosis of ‚-homozygous thalassaemia. This haematocrit of approximately 75%, the
diagnosis should take into account the volume per transfusion is usually 10-15
molecular defect, the severity of anaemia on ml/kg, administered over 3-4 hours. Units
repeated measurements, the level of with additive solutions may have lower
ineffective erythropoiesis, and clinical criteria haematocrits in the range of 60-70%, and
such as failure to thrive or bone changes. consequently larger volumes with a higher
The initiation of regular transfusion therapy haematocrit level are needed to administer
for severe thalassaemia usually occurs in the the same red cell mass (see Table 4). For
first two years of life. Some patients with most patients, it is usually easier to avoid
milder forms of thalassaemia who only need these differences in red cell concentration by
sporadic transfusions in the first two decades ordering a certain number of units (e.g. one
of life may later need regular transfusions or two) rather than a particular volume of
because of a falling haemoglobin level or the blood. Younger children may require a
development of serious complications (see fraction of a unit to avoid under- or over-
Chapter 11: Thalassaemia Intermedia and transfusion. Patients with cardiac failure or
HbE). The risk of alloimmunisation appears to very low initial haemoglobin levels should
be greater in patients who begin transfusion receive smaller amounts of red cells at slower
therapy after the first few years of life rates of infusion.

Aggee aatt FFiirrsstt TTrraannssffuussiioonn AAllllooiim

A mm
muunniissaattiioonn RRaattee
< 1 year old 7.7%
> 1 year old 27.9% [Machail-Merianou et al, 1987]

Aggee aatt FFiirrsstt TTrraannssffuussiioonn AAllllooiim

A mm
muunniissaattiioonn RRaattee
< 3 years old 20.9%
> 3 years old 47.5% [Spanos et al, 1990]

Table 3: Age and alloimmunisation in Thalassaemia

24
 Haaeem
H maattooccrriitt ooff DDoonnoorr RReedd CCeellllss
50% 60% 75% 80%
TTaarrggeett 1 g/dl 4.2 ml/kg 3.5 ml/kg 2.8 ml/kg 2.6 ml/kg
IInnccrreeaassee iinn
Haaeem
H moogglloobbiinn 2 g/dl 8.4 ml/kg 7.0 ml/kg 5.6 ml/kg 5.2 ml/kg
LLeevveell 3 g/dl 12.6 ml/kg 10.5 ml/kg 8.4 ml/kg 7.8 ml/kg
4 g/dl 16.8 ml/kg 14.0 ml/kg 11.2 ml/kg 10.4 ml/kg

As an example, to raise the haemoglobin level by 4g/dl in a patient weighing 40kg and
receiving AS-1 blood with a haematocrit of 60% would require 560ml. This calculation
assumes a blood volume of 70ml/kg of body weight.

Table 4: Guidelines for choosing how much blood to transfuse

The post-transfusion Hb should A careful record of transfused

not be greater than 14-15g/dl blood should be maintained for
and should be monitored each patient, including the
occasionally to allow assessment volume or weight of the
of the rate of fall in the administered units, the
haemoglobin level between haematocrit of the units or the
transfusions in evaluating the average haematocrit of units
effects of changes in the with similar anticoagulant-
transfusion regimen, the degree preservative solutions, and the
of hypersplenism, or patient’s weight. With this
unexplained changes in information, it is possible to
response to transfusion. calculate the annual blood
requirements as volume of
Although erythrocytapheresis, or automated
red cell exchange, has been shown to reduce
transfused blood and pure red
net blood requirements and thus the rate of cells (haematocrit 100%) per kg
transfusional iron loading (Berdoukas, 1986; of body weight.
Friedman, 2003], its use may be limited due
to a two- to three-fold increase in donor The latter (RBC at 100% ht) when multiplied
blood utilisation, increased (i) costs, (ii) risk of with 1.08, the estimated amount of iron per
transmission of infections and (iii) ml of RBC (see Chapter 3: Iron Load and Iron
development of alloimmunisation. Chelation) yields an approximate value for

25
the amount of transfusional iron that the
patient receives per kilogram of body weight
in a year. Figure 1 shows a detailed example
of how the daily rate of iron loading
(mg/kg/day) is calculated and Table 5 shows
the relationship between the annual
transfusion requirements and the daily rate
of iron loading at two common haematocrits
for donor blood. The rate of transfusional
iron loading may be very important in
choosing the appropriate dose of an iron
chelator. For example, the recommended
dose of the chelator deferasirox is based in
part on the daily or annual rate of
transfusional iron loading.

Patient weight: 40kg

Transfusion amount and schedule: 600ml every 4 weeks.
Average haematocrit of transfused red cells: 60%

Annual blood requirement: 13 transfusions x 600ml/40kg = 195ml/kg

Annual pure red cell requirement: 195ml/kg/yr x 60% (average haematocrit) = 117ml/kg/yr

Annual transfusional iron loading:

117ml/kg/yr of pure red cells x 1.08mg iron per ml pure red cells = 126mg iron
Daily transfusional iron loading: 126mg iron/yr/365 days = 0.34mg/kg

Figure 1: Calculation of annual blood requirements and transfusional iron loading.

AAnnnnuuaall BBlloooodd AAnnnnuuaall BBlloooodd VVoolluum mee ooff DDaaiillyy IIrroonn

RReeqquuiirreem
meenntt RReeqquuiirreem
meenntt PPuurree RRBBCCss//kkgg LLooaaddiinngg
((HHaaeem
maatto
occrriitt 6
600%%)) ((HHaaeem
maatto
occrriitt 7
755%%)) ((HHaaeem
maatto
occrriitt 1
10000%%))

100 – 150 ml/kg 80 – 120 ml/kg 60 – 90 ml/kg 0.18 – 0.27 mg/kg

150 – 200 ml/kg 120 – 160 ml/kg 90 – 120 ml/kg 0.27 – 0.36 mg/kg
200 – 250 ml/kg 160 – 200 ml/kg 120 – 150 ml/kg 0.36 – 0.44 mg/kg
250 – 300 ml/kg 200 – 240 ml/kg 150 – 180 ml/kg 0.44 – 0.53 mg/kg

Table 5: Relationship between annual blood requirements and rate of daily iron loading.

26
Knowing the annual transfusion
requirements is also valuable in
identifying changes that may
constitute important evidence
of hypersplenism or accelerated
destruction of donor red cells.
Specific guidelines for consideration of
splenectomy in the presence of increasing
transfusion requirements are difficult to
establish because of a lack of information on
the haematocrit levels of the transfused
blood in earlier recommendations and
uncertainty with regard to long-term
consequences of splenectomy, including
sepsis and thrombosis. Moreover, the
decision to proceed to splenectomy must
take into consideration the individual
patient’s ability to control iron stores at a
given level of transfusional iron loading.
Nevertheless, as the annual transfusion
requirements rise above 200ml/kg/yr of pure
red cells, splenectomy should be considered
as a potential strategy to reduce the rate of
iron loading.
ACCUUTTEE
A FFR
REEQQUUEENNCCYY
Haemolytic (Intravascular) 1/25,000
Anaphylactic 1/50,000
Febrile non-haemolytic 1/100
Allergic (Urticarial) 1/100
TR Acute Lung Injury 1/10,000
Table 6: Broad categorisation of immune-mediated transfusion related (TR) reactions and reported
frequencies
27
Adverse reactions
Blood transfusion exposes the
patient to a variety of risks.
Thus, it is vital to continue to
improve blood safety and to
find ways of reducing
transfusion requirements and
the number of donor exposures.
Adverse events (see Table 6) associated with
transfusion include:
ñ N
No onnhhaaeem moollyyttiicc ffeebbrriillee ttrraannssffuussiioonn
rreeaaccttiioonnss:: These were common in past
decades, but have been dramatically
reduced by leucoreduction, especially
pre-storage leucoreduction, which sharply
reduces cytokine accumulation and
leucocyte alloimmunisation. In the
absence of effective leucoreduction,
patients experiencing such reactions
should be given antipyretics before their
transfusions. Since fever may accompany
a haemolytic transfusion reaction or the
administration of a unit with bacterial
DEELLAAYYEEDD
D FFR
REEQQUUEENNCCYY
Alloimmune 1/100
Haemolytic (Extravascular) 1/ 2,500
Graft Vs Host Disease Rare
 contamination, these causes should
always be considered in a patient who
develops fever during administration of
red cells.
ñ A
Alllle
errggiicc rreeaaccttiioonnss are usually due to
plasma proteins and range from mild to
severe. Milder reactions include urticaria,
itching and flushing, and they are
generally mediated by IgE. More severe
reactions, such as stridor, bronchospasm,
hypotension or other symptoms of
anaphylaxis may occur, especially in
patients with IgA deficiency and anti-IgA
antibodies. Occasional mild allergic
reactions often can be prevented by the
use of antihistamines or corticosteroids
before transfusion. Recurrent allergic
reactions can be markedly reduced by
washing the red cells to remove the
plasma. Patients with IgA deficiency and
severe allergic reactions may require
blood from IgA -deficient donors.
ñ A
Accu
uttee hhaaeem
moollyyttiicc rreeaaccttiioonnss begin within
minutes or sometimes hours of beginning
a transfusion and are characterised by the
abrupt onset of fever, chills, lower back
pain, dyspnea, hemoglobinuria and shock.
These unusual reactions most commonly
arise from errors in patient identification
or blood typing and compatibility testing.
The risk of receiving the wrong blood is
greater for a patient with thalassaemia
who travels to another centre or is
admitted to a hospital not familiar with
his/her case and medical history.
Haemolytic reactions in these patients
can still be avoided by (1) the use of
optimal methods for identifying the
patients and labelling of the sample when
blood is obtained for crossmatch, (2)
proper linkage of the sample to the
donor unit in the blood bank, (3)
28
adherence to standard protocols for
screening for antibodies and carrying out
the necessary full crossmatching of donor
units and (4) use of multiple patient
identifiers before transfusing the blood.
In many transfusion units, two staff
members check the identification of the
unit and the recipient prior to beginning
the transfusion.
If signs and symptoms suggest an acute
haemolytic reaction, the transfusion
should be stopped immediately and
intravenous fluids should be administered
to maintain intravascular volume.
Diuretics may help to preserve renal
function. Disseminated intravascular
coagulation (DIC) may require additional
measures such as heparin. The
identification of the patient and the
donor unit should be re-checked. The
blood bank should also be alerted to the
possibility of an undetected alloantibody.
ñ D
Deellaayyeedd ttrraannssffuussiioonn rreeaaccttiioonnss usually
occur 5-14 days after transfusion and are
characterised by unexpected levels of
anaemia, as well as malaise and jaundice.
These reactions may be due to an
alloantibody that was not detectable at
the time of transfusion or to the
development of a new antibody. A
sample should be sent to the blood bank
to investigate the presence of a new
antibody and to repeat cross-matching of
the last administered unit(s).
ñ A
Auuttooiim
mmmuunnee hhaaeem
moollyyttiicc aannaaeem
miiaa is a very
serious complication of transfusion
therapy that usually but not always
occurs in patients with alloantibodies.
Even red cells from seemingly compatible
units (i.e., those units that do not contain
the antigen to which there is a known
alloantibody) may demonstrate markedly
 shortened survival, and the haemoglobin complication of transfusion.
concentration may fall well below the Immunosuppressed patients are at
usual pre-transfusion level. Destruction particular risk, but TI-GVHD may also
both of the donor’s and the recipient’s occur in immunocompetent recipients of
red cells occurs. The serologic evaluation red cells from a haploidentical donor such
by the blood bank usually shows an as a family member. TI-GVHD usually
antibody that reacts with a wide range of occurs within 1-4 weeks of transfusion
test cells and fails to show specificity for and is characterised by fever, rash, liver
a particular antigen. Steroids, dysfunction, diarrhoea and pancytopenia
immunosuppressive drugs and due to bone marrow failure. To reduce
intravenous immunoglobulin are used for the risk of TI-GVHD, donated blood from a
the clinical management of this situation, family member should be avoided or if
although they may give little benefit. used should always be irradiated before
Some patients have also been treated transfusion. Leucodepletion alone is
with rituximab, but the effectiveness of inadequate for the prevention of this
its use in this situation is presently not complication.
well defined. Autoimmune haemolytic
anaemia occurs more frequently in ñ TTrraan
nssffuussiioonn--aassssoocciiaatteedd cciirrccuullaattoorryy
patients who begin transfusion therapy oovveerrllooaadd may occur in the presence of
later in life (Rebulla, 1991), and should be recognised or unrecognised cardiac
carefully considered before instituting dysfunction, or when the rate of
transfusion therapy for teenagers and transfusion is inappropriately fast. Signs
adults with thalassaemia intermedia. and symptoms include dyspnoea and
tachycardia, and the chest radiograph
ñ TTrraannssffuussiioonn--rreellaatteedd aaccuuttee lluunngg iinnjjuurryy shows the classic findings of pulmonary
((TTRRAALLII)) is a potentially severe oedema. Treatment focuses on volume
complication that is usually caused by reduction and cardiac support, as
specific anti-neutrophil or anti-HLA required.
antibodies (Swanson, 2006). This
complication is characterised by ñ TTrraan
nssm
miissssiioonn ooff iinnffeeccttiioouuss aaggeennttss
dyspnoea, tachycardia, fever and including viruses, bacteria and parasites,
hypotension during or within six hours of are a major risk in blood transfusion (see
transfusion. Hypoxemia is present and the Chapter 9: Infections in Thalassaemia
chest radiograph shows bilateral infiltrates Major). Even in countries where residual
typical of pulmonary oedema although risk of transmission through blood of
there is no reason to suspect volume clinically significant pathogens (HIV, HBV,
overload. Management includes oxygen, HCV and Syphilis) has been reduced to
administration of steroids and diuretics, minimal levels, problems continue to exist
and, when needed, assisted ventilation. or emerge because:

ñ TTrraan nssffuussiioonn--iinndduucceedd ggrraafftt vveerrssuuss hhoosstt − A limited range of known pathogens

ddiisseeaassee ((TTII--GGVVHHDD)) is caused by viable is targeted in mandatory donor
lymphocytes in units of transfused red screening (excludes HPV B-19, HCMV,
cell. It is a rare but often fatal EBV, HAV, Yersinia enterolitica,
parasites, e.g., malaria);

29
 − Transmission of viruses still occurs
(window period, sensitivity threshold
of tests);
− The clinical significance of newly
identified infectious agents (HGV,
GBV-C, TTV, SEN-V, HSV6,7,8) is not
yet completely clarified and donors
are not screened for these agents;
− Newly emerging infectious agents
(WNV, SARS, Avian Flu, prions),
constitute serious threats, and;
− Absence of widely accepted tests for
bacteria (endogenous and exogenous)
and for parasitic protozoa associated,
for example, with Chaga’s disease,
toxoplasmosis and babesiosis.
In many regions of the developing world,
where thalassaemia is most prevalent,
continued transmission of hepatitis B,
hepatitis C and HIV underscores the
importance of promoting the quality of
national blood transfusion services, including
voluntary blood donations, careful donor
selection and screening, and public health
services’ provision of necessary
immunisation.

SSu
ummm
maarryy RReeccoom
mmmeennddaattiioonnss::
ñ Careful donor selection and screening – voluntary, regular non-remunerated blood
donation.
ñ Confirm diagnosis of thalassaemia major.
ñ Before initiation of transfusion therapy, confirm laboratory and clinical criteria.
ñ Before first transfusion, extended red cell antigen typing of patients at least for C, E
and Kell.
ñ At each transfusion, give ABO, Rh(D) compatible blood. Matching for C, E and Kell
antigen is recommended.
ñ Before each transfusion, full cross-match and screen for new antibodies.
ñ Keep record of red cell antibodies, transfusion reactions and annual transfusion
requirements for each patient.
ñ Use leucoreduced packed red cells. Pre-storage filtration is recommended, but blood
bank pre-transfusion or bedside filtrations are acceptable alternatives.
ñ Washed red cells for patients who have severe allergic reactions.
ñ Use red cells stored in CPD-A, as fresh as possible (less than one week old) and in
additive solutions for less than 2 weeks.
ñ Transfuse every 2-5 weeks, maintaining pre-transfusion Hb above 9-10.5 g/dl, but
higher levels (11-12 g/dl) may be necessary for patients with heart complications.
ñ Keep post-transfusion Hb not higher than 14-15 g/dl.

30
Iron Overload
IIr
roon
noovve
errlload occurs when iron intake is
increased over a sustained period of time,
either as a result of red blood cell
transfusions or increased absorption of iron
through the gastrointestinal tract (GI). Both
of these occur in thalassaemia, with blood
transfusion therapy being the major cause of
iron overload in thalassaemia major and
increased GI iron absorption being more
important in thalassaemia intermedia.
In the absence of any
mechanism of the human body
to excrete excess iron, chelation
therapy is essential and
constitutes the second
important arm, besides
transfusion therapy, of the
clinical management of these
patients.
The Rate of Iron
Loading
B l o o d t ra n s fu s i o n :
Knowledge of the rate of iron loading from
transfusion to as high a level of accuracy as
possible will contribute significantly to the
formulation of chelation therapy appropriate
for each patient. Simple calculations, such as
those described in the Blood Transfusion
Chapter of this book, can provide the
treating physician with this information.
In case organisational or other
difficulties do not allow such
estimations, a rough
approximation can be made
31
based on the assumption that
200 mg of iron is contained in
each donor unit.
Thus, irrespective of whether the blood used
is packed, semi-packed or diluted in additive
solution, if the whole unit is given, this will
approximate to 200 mg of iron intake.
According to the recommended transfusion
scheme for thalassaemia major, the
equivalent of 100–200 ml of pure RBC per kg
per year are transfused (equivalent to 116-
232 mg of iron per kg body weight per year
or 0.32-0.64 mg/kg/day). Regular blood
transfusion therapy therefore increases iron
stores to many times the norm unless
chelation treatment is given.
IIncreased gas tro-intest inal absorpt ion
o f i r on :
o
Normal intestinal iron absorption is about 1-2
mg/day. In patients with thalassaemia who
do not receive any transfusion, iron
absorption increases several-fold.
It has been estimated that iron
absorption exceeds iron loss
when expansion of red cell
precursors in the bone marrow
exceeds five times that of
healthy individuals.
Transfusion regimens aimed at keeping the
pre-transfusion haemoglobin above 9 g/dl
have been shown to prevent such expansion
(Cazzola 1997). In individuals who are poorly
transfused, absorption rises to 3-5 mg/day or
more representing an additional loading of
1-2 grams of iron loading per year.
 Paattiieenntt’’ss wweeiigghhtt
P 200 kkgg
2 355 kkgg
3 500 kkgg
5 655 kkgg
6
Pure red cell volume (ml) 2,000-4,000 3,500-7,000 5,000-10,000 6,500-13,000
transfused yearly
(if 100-200 ml/kg/yr)
Yearly iron loading from 2.3-4.6 4.1-8.2 5.8 -11.6 7.5 -15.1
transfusion (g)
Daily iron loading from 4.7 -9.5 11.1-22.2 15.9-31.8 20.6-41.5
transfusion (mg)

Table 1: Examples of increase in iron stores from transfusion in the absence of chelation

Figure 1: A simplified scheme of iron turnover in healthy adults is shown above in bold arrows. The broken line
indicates the effect of transfusion on iron turnover, with an increased daily delivery of haem iron to
macrophages which leads to increased iron release rates from macrophages, saturation of transferrin
and the appearance of Non-Transferrin-Bound Iron (NTBI) in blood. This in turn causes increased iron
uptake by the liver and other parenchyma, such as the heart and endocrine glands.
(Adapted from Porter JB. Hematol Oncol Clin North Am. 2005;19:1-6)

(atoms or molecules with unpaired

Toxicity from Iron
Overload
Meecchhaanniissm
M m ooff iirroonn ttooxxiicciittyy
Iron is highly reactive, easily alternating
between two states – iron III and iron II – in a
process which results in the gain and loss of
electrons, generating harmful free radicals
electrons). These can damage lipid
membranes, organelles and DNA causing cell
death and the generation of fibrosis. In
health, iron is ‘kept safe’ by binding to
molecules such as transferrin, but in iron
overload their capacity to bind iron is
exceeded both within cells and in the plasma
compartment. The resulting ‘free iron’
damages many tissues in the body and is
fatal unless treated by iron chelation therapy.

32
Coom
C mpplliiccaattiioonnss ooff iirroonn oovveerrllooaadd
Untreated transfusional iron overload in
thalassaemia major is fatal in the second
decade of life, usually as a result of cardiac
complications (Zurlo 1989). Iron overload also
causes pituitary damage, leading to
hypogonadism and poor growth. Endocrine
complications, namely diabetes,
hypothyroidism and hypoparathyroidism, are
also seen. Liver disease with fibrosis and
eventually cirrhosis, particularly if
concomitant chronic hepatitis is present, is
also a serious complication. (These
complications are described in greater detail
in the relevant chapters of this book.)
Monitoring of Iron
Overload
Monitoring closely and assessing as accurately
as possible iron overload is essential in
establishing effective iron chelation regimes,
such as those mentioned in this chapter,
tailored to the individual patient’s specific
needs. However, some general principles of
monitoring iron overload apply to all
treatments:
SSe
erruum
m ffeerrrriittiinn
This is a relatively easy test to perform, well
established, generally correlating with body
iron stores and prognostically relevant in
thalassaemia major. Up to a value of about
3,000 Ìg/L serum ferritin is secreted in an
iron-free form from macrophages, but above
this value increasing proportions of iron-
laden ferritin ‘leaks’ from hepatocytes
(Worwood, 1984; Davis, 2004). Day-to-day
variations are particularly marked: high
degrees of iron loading, inflammation,
hepatitis and/or liver damage may falsely
33
increase serum ferritin, while vitamin C
deficiency may depress it. A sudden and
unexpected rise in ferritin level should
prompt a search for hepatitis, other
infections or inflammatory conditions. In
thalassaemia intermedia, serum ferritin tends
to underestimate the degree of iron
overloading (Pootrakul 1981; Galanello,
1994). Therefore although there is a broad
correlation between serum ferritin level and
liver iron, the prediction of iron loading from
serum ferritin can be unreliable (Olivieri
1995). Importantly, however, at least five
studies have shown an association between
the control of serum ferritin and prognosis
(Gabutti V and Piga A. 1996; Olivieri, N. et al
1994; Telfer PT, et al. 2000; Davis BA, et al.
2004; Borgna-Pignatti et al. 2004). Studies
have identified a significantly lower risk of
cardiac disease and death in at least two-
thirds of cases where serum ferritin levels
have been maintained below 2,500 Ìg/L
(with desferrioxamine) over a period of a
decade or more (Olivieri, 1994). Observations
with larger patient numbers show that
maintenance of an even lower serum ferritin
of 1,000 Ìg/L may be associated with
additional advantages (Borgna-Pignatti et al,
2004) (see Table 2).
LLiivve
err iirroonn ccoonncceennttrraattiioonn ((LLIICC))
Liver iron concentration is now regarded as
the reference standard for estimating body
iron loading and has been shown accurately
to predict total body iron stores (Angelucci,
2000), using the formula:
TToottaall bbooddyy iirroonn ssttoorreess iinn m
mgg//kkgg =
= 1100..66 xx tthhee
LLIICC ((iinn m
mgg//gg ddrryy wwtt))
Normal LIC values are up to 1.8 mg/g dry wt,
with levels of up to 7 mg/g dry wt seen in
some non-thalassaemic populations without
apparent adverse effects (see Figure 2).
Several studies link high Liver Iron Content Telfer, 2000), liver fibrosis progression
(LIC) (above 15-20 mg/g dry wt) to (Angelucci, 1997) or liver function
worsening prognosis (Brittenham, 1994; abnormalities (Jensen, 2003).

TTaab
bllee 22:: M
Meeaassuurriinngg aanndd iinntteerrpprreettiinngg sseerruum
m ffeerrrriittiinn
Addvvaannttaaggeess
A Diissaaddvvaannttaaggeess
D

ñ Easy to assess ñ Indirect measurement of iron burden

ñ Inexpensive ñ Fluctuates in response to inflammation,
ñ Repeat measures are useful for monitoring abnormal liver function, metabolic
chelation therapy deficiencies
ñ Positive correlation with morbidity and ñ Serial measurement required
mortality

LLIIV
VEERR IIRROONN AANNDD RRIISSKK FFRROOM
M IIRROONN OOVVEERRLLOOAADD

Figure 2: Liver risk and iron overload (Olivieri & Brittenham, 1997)

34
LIC determination should be considered, by
the treating physicians for those patients
whose serum ferritin levels deviate from
expected trends (i.e. those with suspected
co-existing hepatitis, or patients on chelation
regimens with variable or uncertain
responses), as this may reduce the risk of
giving either inadequate or excessive doses
of chelation therapy. Since the relationship
of serum ferritin to iron overload and iron
balance has not yet been established,
assessment of LIC may be particularly useful
when new chelating regimes are being used.
Measurement of LIC can be done by chemical
determination on a liver biopsy sample
(fresh, fixed or from dewaxing of paraffin-
embedded material)(see Table3) or by non-
invasive methods such as magnetic
biosusceptometry (SQUID) (Brittenham 1994)
or magnetic resonance imaging (MRI)(see
Table 4). Biopsy is an invasive procedure, but
in experienced hands has a low complication
rate (Angelucci 1997). Inadequate sample
size (<1 mg/g dry weight, 4 mg wet wt or
about a 2.5 cm core length) or uneven
distribution of iron, particularly in the
presence of cirrhosis (Villeneuve 1996), may
give misleading results.
TTaab
bllee 33:: M
Meeaassu
urriin
ngg LLIIC
Ad
A dvvaan
nttaag
geess
ñ Direct measurement of LIC
ñ Validated reference standard
ñ Quantitative, specific, and sensitive
ñ Allows for measurement of non-heme
storage iron
ñ Provides information on liver
histology/pathology
ñ Positive correlation with morbidity and
mortality
35
LIC can also be measured accurately using a
method known as SQUID (supercoducting
quantum interference device). However, only
four such machines are currently available
worldwide: they are expensive to purchase
and maintain, and require dedicated trained
staff. Liver iron measured by SQUID has the
advantage of possessing a wide linear range
but each SQUID machine has to be
individually calibrated.
LIC can also now be measured using MRI
techniques, previously limited to a relatively
narrow linear range. One recently described
approach, is the R2 or Ferriscan technique
which appears to have acceptable linearity
and reproducibility over the range of clinical
interest (St Pierre TG, et al, 2005). The
technique demonstrates an average
sensitivity of >85% and specificity of >92%
up to an LIC of 15 mg/g dry wt, and has
been registered in the EU and US. For
calibration, the MRI machine must use a
Phantom supplied by the company, while the
data acquired is sent via internet for analysis
by dedicated Ferriscan software (payment
per scan analysed). A particular advantage of
this technique is that it can be applied with
little training, at any centre with a reasonably
up-to-date MRI machine (see Table 4).
Cbbyy lliivveerr b
biio
oppssyy
Diissaad
D dvvaan
nttaag
geess
ñ Invasive, painful procedure associated with
potentially serious complications
ñ Risk of sampling error, especially in
patients with cirrhosis
ñ Requires skilled physicians and
standardized laboratory techniques
Heeaarrtt ffuunnccttiioonn
H myocardial T2* to <20 ms (implying
Regular monitoring of left ventricular
ejection fraction (LVEF) has allowed
identification of a group of patients with
poor prognosis at high risk of subsequent
heart failure and death who responded well
to intensification of desferrioxamine (Davis et
al, 2004). Patients with a fall in ejection
fraction below reference values for the
method used have a 35-fold increased risk of
cardiac failure and death, with a median
interval to progression of 3.5 years allowing
time for intensification of chelation
treatment. Left ventricular function can be
quantified using MRI, MUGA or
echocardiography. The first two methods
have advantages over echocardiography in
that they are less operator-dependent and
therefore more easily adapted to longitudinal
monitoring.
Myyo
M occaarrddiiaall iirroonn eessttiim
maattiioonn ((TT22** oorr
ootthheerr m
meeaassuurreess))
Estimation of myocardial iron using MRI is
becoming increasingly available but requires
expertise in its use and standardisation.
The T2* value in tissues shortens as the iron
concentration increases. A shortening of
TTaab
bllee 44:: M
MRRII aasssseessssm
Addvvaannttaaggeess
A Diissaaddvvaannttaaggeess
ñ Assesses iron content throughout
the liver
ñ Potentially widely available
ñ Pathological status of liver and heart
can be assessed in parallel
Liver iron levels can be assessed using a technique known as R2 (spin echo) MRI, which is a
validated and standardised method for measuring LIC
MRRII=Magnetic Resonance Imaging
M
36
increased myocardial iron) is associated with
an increased chance of decreased LV
function (Anderson et al, 2001). For example,
patients with T2* values >20 ms have a very
low chance of decreased LVEF. T2* values of
10-20 ms indicate up to a 10% chance of
decreased LVEF; 8-10 ms indicates an 18%
chance; 6 ms indicates a 38% chance; and
T2* values of just 4 ms indicate a 70% chance
of decreased LVEF (Westwood et al, 2005). In
centres where such methodology is available,
the T2* value may identify patients at high
risk of developing a fall in LVEF before it
occurs permitting a more informed choice
regarding patients whose chelation
treatment should be intensified.
The ability to estimate heart iron offers an
additional way to stratify risk, opening up a
new diagnostic window. However, factors
affecting the risk of developing heart failure
from myocardial iron overload are complex,
while T2* measures storage iron – not in
itself directly toxic to cells. Factors that may
increase the availability of labile intracellular
iron to cause intracellular damage such as
myocarditis, or lack of continuous exposure
to intracellular chelation, may influence the
meenntt ooff LLIICC
D
ñ Indirect measurement of LIC
ñ Requires MRI imager with dedicated
imaging method
risk posed by excess heart iron, and explain of which can redox cycle. One
why only a proportion of people with short way of measuring the NTBI
T2* values show abnormal heart function at
any moment in time. Prospective data on the
fraction that is labile and can
relationship between myocardial T2* and
redox cycle is the labile plasma
survival are still required. However, the iron’ assay (LPI assay). However,
relationship between short T2* values although the measurement of
(<10ms) and the risk of heart dysfunction is NTBI (or LPI) has proved a useful
clear (see Table 5). tool for examining how
chelators interact with plasma
Urriinnaarryy iirroonn eessttiim
U maattiioonn iron pools, its value as a guide
Measurement of the urinary iron excretion to routine treatment or
can assist in assessing the effect on iron prognosis has yet to be
excretion of desferrioxamine (about half of demonstrated.
total iron excreted in urine) or deferiprone
(over 80% of iron excreted in urine). Otthheerr m
O maarrkkeerrss ooff ooxxiiddaattiivvee ddaam
maaggee
However, the inherent variability in daily iron A wide variety of markers for oxidative
excretion necessitates repeated damage have been investigated.
determinations. Faecal iron excretion Malondialdehyde (MDA) is increased in iron
contributes an additional, but variable (30- overload, while a wide range of antioxidants
100%) to the amount of urinary iron are depleted.
excretion, depending on the level of iron
stores, the dose of desferrioxamine and the There has been interest in the
level of haemoglobin (Pippard 1982).
use of antioxidants or naturally
PPllaassm
maa nnoonn--ttrraannssffeerrrriinn bboouunndd iirroonn occurring products that contain
antioxidant properties, such as
((NNTTBBII)) Curcumin. However, until
In iron overload, transferrin, the normal
carrier of iron in plasma becomes saturated
controlled data are available
leaving iron unbound i.e. Non-Transferrin
caution is advised in the use of
Bound Iron (or NTBI). these, as the effects of
NTBI is cleared by different cells than antioxidants in the presence of
transferrin iron, and is mainly responsible for iron can be unpredictable due
the abnormal pattern of iron distribution in to redox cycling of iron
transfusional iron overload. Because these between the iron (II) and iron
forms of iron rapidly reappear once iron (III) states.
chelators are cleared from the blood, experts
suggest that the optimal treatment is 24- Otthheerr m
O maarrkkeerrss ooff oorrggaann ddyyssffuunnccttiioonn..
hour chelation (Porter, 1996). These are discussed more fully in other
chapters. However, iron overloaded patients
NTBI consists of several chemical should be monitored for evidence of
entities, only some of which are hypoganadotrophic hypogonadism (growth
readily chelatable and only some and sexual development and biochemical

37
markers of HH), diabetes mellitus (yearly GTT), Iron appears to be removed
hypothyroidism and hypoparathyroidism. more quickly from some tissues,
such as the liver, than others –
Treatment of Iron for example, the heart.
Overload Increasing the dose of chelators given in an
attempt to speed up iron removal runs the

Gooaallss ooff iirroonn cchheellaattiioonn tthheerraappyy

G
risk of increasing the toxicity of an iron
chelator, by chelating the iron needed for
The primary goal of chelation normal tissue metabolism. The twin goals of
therapy is to maintain safe levels iron chelation in iron overloaded patients is
of body iron at all times. therefore to decrease tissue iron to safe
Unfortunately, once iron levels, while simultaneously making the iron
overload has accumulated, as safe as possible by binding the toxic iron
removal of storage iron is slow pools responsible for causing tissue damage.
and inefficient, because only a Iron is constantly being turned over, either as
a result of the breakdown of red cells in
small proportion of body iron is macrophages or the breakdown of ferritin
available for chelation at any within cells. These same fractions are redox-
given time. active and potentially harmful; the plasma
component of this iron (NTBI) is mainly
Consequently, when an iron chelator is given,
responsible for the iron loading of tissues.
only a small proportion of the drug binds
As mentioned above, NTBI appears within
iron, before it is excreted or metabolised.
minutes of a chelator being cleared from the
Once a patient is iron overloaded, it may take
body. Thus, in order to achieve the second
months or years to reduce body storage iron
goal of chelation – the minimisation of toxic
to safe levels, even with the most intensive
(labile) iron pools – 24-hour chelation
treatment. Chelation must therefore begin
coverage is the ideal. Once low levels of iron
soon after (2-3 years) the initiation of
have been achieved, it is more appropriate to
transfusion therapy.
reduce the dose of chelator than to interrupt
or decrease the frequency of chelation.

TTaab
bllee 55:: M
MRRII aasssseessssm
meenntt ooff ccaarrddiiaacc iirroonn
Addvvaannttaaggeess
A Diissaaddvvaannttaaggeess
D
ñ Rapidly assesses iron content in ñ Indirect measurement of cardiac iron
the septum of heart ñ Requires MRI imager with dedicated
ñ Iron levels can be quantified reproducibly imaging method
ñ Functional parameters can be examined ñ Technically demanding
concurrently ñ Methodology remains to be standardized
ñ Pathological status of liver and heart and validated
can be assessed in parallel
Cardiac iron levels can be rapidly and effectively assessed using a technique know as T2* (gra-
dient echo) MRI, which is becoming the new standard method

MRRII=Magnetic Resonance Imaging

M

38

Desferrioxamine
(Desferal® or
deferoxamine)
Desferrioxamine has been in clinical use since
the 1970s and widely used as subcutaneous
infusions since about 1980. Provided that
treatment is 1) begun within 2-3 years of
beginning transfusion therapy, 2)
administered regularly and 3) administered in
adequate doses, desferrioxamine has a well-
established impact on survival and on cardiac
and other complications of iron overload
described above (Brittenham, 1994; Piga,
1996; Borgna-Pignatti, 2004).
The main disadvantages of the
treatment are that it is costly
and that it must be
administered parenterally.
M
Me ecchhaanniissm
m ooff aaccttiioonn aanndd
pphhaarrm
maaccoollooggyy
Due to its molecular size, desferrioxamine is
poorly absorbed from the gut. The higher
the dose, the higher the proportion of iron
excreted in the faeces rather than the urine.
Iron excreted in the urine is derived from the
breakdown of red cells in macrophages,
whereas faecal iron is derived from iron
chelated within the liver (Hershko, 1979;
Pippard, 1982). Desferrioxamine has a short
plasma half-life (initial half-life 0.3h), being
eliminated rapidly in urine and bile. The
process of iron chelation ceases soon after
an infusion of desferrioxamine is complete.
The efficiency of desferrioxamine (measured
in terms of percent of dose excreted in the
iron bound form) administered at standard 8-
12 hour intervals 5-7 days a week is
39
approximately 14%. Iron excretion with
desferrioxamine increases with dose, with
body iron stores and with the addition of
vitamin C.
EEvviiddeennccee ffoorr tthhee eeffffeeccttiivveenneessss ooff
ddeessffeerrrriiooxxaam
miinnee
EEffffeeccttss oonn sseerruum
m ffeerrrriittiinn
Clinical experience over a period of three
decades indicates that ferritin can be
controlled with desferrioxamine
monotherapy, and that maintaining serum
ferritin <2500 Ìg/L with this drug is closely
linked to protection from heart disease and
to improved survival (Olivieri, 1994).
However, the results of a formal
prospective study on the dose
required to stabilise or decrease
serum ferritin in large
populations have only recently
become available.
The study – a prospective evaluation of
changes in ferritin levels and LIC as a function
of dose in 290 thalassaemia major patients
(Cappellini, 2006) – demonstrated that a
mean daily dose of 42 mg/kg resulted in a
small decrease in serum ferritin of 364 Ìg/L
at one year, whereas a mean daily dose of 51
mg/kg resulted in an average ferritin
decrease of approximately 1,000 Ìg/L over
one year. Therefore, if the serum ferritin is
>2,500 Ìg/l, a mean daily dose of at least 50
mg/kg/day is recommended (except in
children – see below).
EEffffe
eccttss oonn lliivveerr iirroonn
Administered at least 5 times a week and in
sufficient doses, desferrioxamine is effective
in controlling liver iron and hence total body
iron stores (Brittenham, 1994). The
relationship between dose and change in LIC
was not examined systematically until
recently (Cappellini, 2006), in a study
establishing that a mean dose of 37 mg/kg
stabilised LIC for patients with baseline LIC
values of between 3 and 7 mg/g dry wt. For
patients with LIC values between 7 and 14
mg/g dry wt, a mean dose of 42 mg/kg
resulted in a small decrease of 1.9 mg/kg dry
wt. In patients with LIC values >14 mg/g dry
wt, a mean dose of 51 mg/kg resulted in LIC
decreases of an average of 6.4 mg/g dry wt.
Thus a dose of 50 mg/kg at least 5 days a
week is recommended if a significant
decrease in LIC optimal levels (see above) is
required. It should be emphasised that these
are average changes and that the dose
required may increase or decrease depending
on transfusion requirement (Cohen, 2005).
EEffffe
eccttss oonn hheeaarrtt ffuunnccttiioonn
Subcutaneous therapy has long been known
to improve asymptomatic cardiac disease
(Freeman, 1983, 1989; Wolfe, 1985; Aldouri
et al, 1990). Since the introduction of
desferrioxamine, the incidence of iron-
induced heart disease has fallen progressively
in cohorts of patients – with a key factor
being the age of starting treatment
(Brittenhan, 1994; Borgna-Pignatti, 2004).
Symptomatic heart disease can be reversed
by high dose intravenous treatment (Marcus,
1984; Cohen, 1989). The same results can be
obtained with excellent long-term prognosis
with lower doses (50-60 mg/kg/day – see
below) and consequently less drug toxicity
using continuous dosing (Davis, 2000 and
2004). Continuous intravenous doses of 50-
60 mg/kg/day typically normalised LVEF in a
period of three months (Anderson LJ, et al.,
2004), significantly before liver or heart iron
stores had been normalised. However, if
advanced heart failure has developed before
treatment is intensified, the chances of
successful rescue are decreased.
40
Early intervention for decreased LV function
is therefore recommended (Davis, 2004).
EEffffe
eccttss oonn hheeaarrtt iirroonn ((TT22**))
Treatment with continuous
intravenous desferrioxamine has
been shown to improve
myocardial iron, even in the
most overloaded hearts, with
average myocardial T2* values of <6 ms
(Anderson et al, 2004). The average rate of
improvement at this level of iron loading of
the heart is about 3 ms/year in severely
overloaded hearts: if improvement is linear it
would take several years to normalise the T2*
to >20 ms (Porter 2002).
In patients with baseline T2* values of
between 8-20 ms, subcutaneous treatment
at relatively low doses of 35 mg/kg showed
an average improvement in T2* of 1.8 ms
over one year (Pennell 2006). At a slightly
higher dose of 40-50 mg/kg, five days a
week, patients showed an improvement of 3
ms over one year (Porter et al, 2005).
Improvement in cardiac T2*, even at low,
intermittent doses, has been confirmed by
two prospective randomised studies (Pennell,
2006; Tanner, 2007).
EEffffe
eccttss oonn m
moorrbbiiddiittyy
Regular subcutaneous therapy started before
the age of 10 years reduces the incidence of
hypogonadism (Bronspiegel-Weintrob, 1990),
as well as other endocrine disturbances,
including diabetes mellitus (Brittenham,
1994; Olivieri, 1994; Borga-Pignatti, 2004)
(See Table 6).
EEffffeeccttss oonn ssuurrvviivvaall aanndd ccoom
mpplliiccaattiioonnss demonstrated by the improving survival in
ooff iirroonn oovveerrllooaadd patients born between the 1960s and the
present day (see Figure 3). Note that only
As mentioned previously, desferrioxamine
was first used to treat iron overload in patients born after 1980 will have started
thalassaemia in the 1970s but was only treatment at an early age, and that age of
widely used by infusion after 1980. The starting treatment is a key factor in outcome
benefits of its regular use are clearly (Borgna-Pignatti, 2004; Brittenham et al,
1994; Davis et al, 2004).

Biirrtthh 11997700––7744**
B Biirrtthh 11998800––8844††
B

Death at 20 years 5% 1%
Hypogonadism 64.5% 14.3%
Diabetes 15.5% 0.8%
Hypothyroidism 17.7% 4.9%

* IM, DFO introduced in 1975

† SC, DFO introduced in 1980
In 1995, 121 patients switched to DFP (censored at the time)

Table 6: Decreasing complications in cohorts born after desferrioxamine was already available.
Survival probability

Age (years)

Figure 3: Increasing probability of survival (% alive at ages shown) with desferrioxamine therapy for
thalassaemia, mainly as a result of decreased cardiac iron toxicity, in patient cohorts born
between 1960-64 and 1995-97 (Borgna-Pignatti, 2004)

41
Desferrioxamine needs to be
taken at least five times a week
in order to optimise survival
(Piga, 1996). Fatal complications
from iron overload are also
decreased if body iron (as
measured by liver iron) is kept
below certain levels
(Brittenham, 1994) (see below).
Unwanted effects of
desferrioxamine
Local skin reactions, such as itching,
erythema, induration and mild to moderate
discomfort are common and may be due to
inadequate dilution of desferrioxamine.
Ulceration at the site of a recent infusion
results from an intradermal infusion of
desferrioxamine and should be addressed by
deeper placement of the needle in
subsequent infusions.
Infection with Yersinia enterocolitica is an
important risk associated with
desferrioxamine treatment (described in
detail in the Chapter 9: Infections in
Thalassaemia Major). Such an infection may
be difficult to diagnose. However, where
there is reasonable clinical suspicion of
infection, with Yersinia enterolitica treatment
with desferrioxamine should be temporarily
discontinued. Infection should be considered
in any patient with a febrile illness, especially
when associated with abdominal pain,
diarrhoea or joint pains, and should be
treated as a medical emergency.
Desferrioxamine can usually be reintroduced
once symptoms have subsided and a full
course of antibiotics completed. Other
42
infections such as Klebsiella may also be
exacerbated by continued treatment with
desferrioxamine.
It is therefore recommended to cease
administration of desferrioxamine in anyone
with an unexplained fever, until the cause
has been identified and effective antibiotic
treatment begun. The decision as to when to
recommence treatment with desferrioxamine
requires clinical judgement and a careful
balancing of the potential risks and benefits.
For example, a patient with high cardiac iron
or poor heart function may be at high risk if
desferrioxamine is withheld during a septic
episode, outweighing the risks of infection
once antibiotics have been commenced.
Severe allergy to desferrioxamine is a rare
event and can be treated by careful
desensitisation, carried out under close
medical supervision (Bosquet, 1983; Miller,
1981). Desensitisation is usually successful
but may need to be repeated. If
unsuccessful, an alternative chelator, such as
Deferiprone or Deferasirox (see below), may
be considered.
Dose-related
complications
Administration of excessive dosage of
desferrioxamine may cause the following
complications in patients who are not heavily
iron loaded:
ñ H e a r i n g p ro b l e m s :
Hearing problems: High frequency
sensory neural loss, tinnitus and deafness
may occur when desferrioxamine is given
in high doses, particularly to young
children whose iron burden is low
(Olivieri, 1986), and when the therapeutic
 index is exceeded (>0.025) (Porter,
1989). Minor sensory neural deficit has
been reversible in some cases, but
significant hearing loss is usually
permanent. It is therefore advisable to
monitor audiometry yearly, bearing in
mind that audiometric changes due to
excessive desferrioxamine are usually
symmetrical; asymmetry suggests other
pathology.
ñ E ff e c t s o n t h e e y e :
Effects on the eye: These were first
noted when very high doses (>100
mg/kg/day) were given (Davies, 1991).
Symptoms may include night-blindness,
impaired colour vision, impaired visual
fields and reduced visual acuity. Severe
cases may show signs of retinitis
pigmentosa on fundoscopy, whereas
milder cases are only demonstrable with
electroretinography. The main risk factor
appears to be high dose (Olivieri, 1986)
but complications are also more likely in
patients who have diabetes (Arden, 1984)
or those receiving concomitant
phenothiazine treatment (Blake, 1985).
Treatment with desferrioxamine should
be temporarily suspended in patients who
develop complications, to be
reintroduced at lower doses once
investigations indicate resolution of the
problem.
ñ G ro w t h re t a r d a t i o n:
Growth retardation: This may occur if
desferrioxamine is administered at too
high a dose. Another risk factor is a
young age of starting treatment (<3yrs)
(De Virgillis, 1988; Piga, 1988). Growth
velocity resumes rapidly when the dose is
reduced to <40 mg/kg day, while it does
not respond to hormonal treatment. It is
therefore recommended that doses do
not exceed 40 mg/kg until growth has
ceased. Regular monitoring of growth is
43
essential in all children (see Chapter 4:
Endocrine Complications).
ñ S ke l e t a l c h a n g e s :
Skeletal changes: These are more
common in cases of excessive dosage of
desferrioxamine where patients have a
low level of iron loading (De Virgillis,
1988; Olivieri, 1992; Gabutti, 1996).
Rickets-like bony lesions and genu valgum
may be seen in association with
metaphyseal changes, particularly in the
vertebrae, giving a disproportionately
short trunk. Radiographic features include
vertebral demineralisation and flatness of
vertebral bodies. Patients should be
regularly observed for such changes, as
they are irreversible.
ñ R ar e c o m p li c a t io n s :
Rare complications: Renal impairment
and interstitial pneumonitis have been
reported at very high doses of 10
mg/kg/h or more. In patients without
iron overload, desferrioxamine has
induced reversible coma when used with
a phenothiazine derivative (Blake, 1985).
Rapid intravenous injection, as may occur
during flushing of a line containing
desferrioxamine, must be avoided.
Recommended
standard therapy
SSttaan
nddaarrdd ddoossee aanndd ffrreeqquueennccyy
The standard recommended
method is slow subcutaneous
infusion over 8-12 hours of a
10% desferrioxamine solution,
using an infusion pump.
In general, average doses should not exceed
40 mg/kg until growth has ceased. The
standard dose is 20-40 mg/kg for children,
and up to 50-60 mg/kg for adults, as an 8- Liver iron concentration (by biopsy, SQUID or
12-hour subcutaneous infusion for a MRI) has recently been advocated as a more
minimum of 6 nights a week. To achieve reliable alternative to serum ferritin (see
negative iron balance in patients with below). To avoid wasting a costly drug such
average transfusion requirements, a dose of as desferrioxamine, the dose can be adjusted
50 mg/kg/day at least 5 days a week is to the nearest whole vial (500 mg or 2 g),
required (Capellini, 2006). It is important that alternating dose volumes between the higher
patients with high degrees of iron loading or and lower number of vials to achieve the
at increased risk of cardiac complications desired mean daily dose.
receive adequate doses.
W
Wh heenn ttoo ssttaarrtt ddeessffeerrrriiooxxaam
miinnee
UUssee ooff ddeessffeerrrriiooxxaam
miinnee bbyy tthheerraappyy
ssuubbccuuttaanneeoouuss bboolluuss In thalassaemia major, this should start as
If an infusion pump is not available or if 10- soon as transfusions have deposited enough
hour infusions are not tolerated, bolus iron to cause tissue damage. This has not
subcutaneous treatment may be considered been formally determined, but current
if the patient is not at high risk of heart practice is to start after the first 10-20
disease. A randomised study has shown that transfusions or when the ferritin level rises
serum ferritin and liver iron can be controlled above 1,000Ìg/l. If chelation therapy begins
equally effectively by giving an equivalent before 3 years of age, particularly careful
total dose (45 mg/kg x 5 per week) either as monitoring of growth and bone development
two subcutaneous ‘boluses’ or as a nightly is advised, along with reduced
10-hour subcutaneous infusion (Yarali, 2006). desferrioxamine dosage. In thalassaemia
intermedia, the rate of iron loading is highly
Doossee aaddjjuussttm
D meenntt variable and the relationship between serum
At low ferritin levels, the dose of ferritin and body iron can be different from
desferrioxamine may need to be reduced and that seen in thalassaemia major. If possible,
desferrioxamine-related toxicities monitored an estimation of liver iron is advisable before
particularly carefully. Dose reductions can be starting treatment to see whether iron has
made using the therapeutic index (see Figure exceeded safe levels (see Figure 4).
4) (Porter, 1989):
Use of vitamin C:
Use of vitamin C: Vitamin C increases iron
Figure 4: Therapeutic Index excretion by increasing the availability of
chelatable iron, but if given in excessive
Therapeutic index = doses may increase the toxicity of iron. It is
me
m eaan
nddaaiillyy d
doossee ((m
mgg//kkgg))** // ffeerrrriittiinn ((ÌÌgg//ll)) recommended not to give more than 2-3
The aim is to keep the index < 0.025 at all mg/kg/day as supplements, taken at the time
times of the desferrioxamine infusion so that
**m meeaann ddaaiillyy ddoossee = = ((aaccttuuaall ddoossee rreecceeiivveedd oonn eeaacchh liberated iron is rapidly chelated. Where a
iinnffuussiioonn xx ddoosseess ppeerr ddaayy//77)) patient has just started on desferrioxamine
and it has been decided to administer
Although a valuable tool in protecting the vitamin C, the vitamin supplement should
patient from excess chelator, this index is not not be given until after several weeks’
a substitute for careful clinical monitoring. treatment.

44
DDeessffeerrrriiooxxaam
miinnee uussee dduurriinngg
pprreeggnnaannccyy:: This is discussed in detail in the
relevant Chapter 5: Management of Fertility
and Pregnancy in ‚-thalassaemia), but
Desferrioxamine is not generally
recommended unless the risk of cardiac
disease in the mother without chelation
treatment is high.
Practical issues with
subcutaneous
infusion
Because regular use of desferrioxamine is
critical to a good outcome, every effort
should be made with each individual to help
him or her to find the most convenient way
to infuse the drug.
Figure 5: Rotation of infusion sites
45
SSttrre
ennggtthh ooff iinnffuussiioonn
The manufacturers of desferrioxamine
recommend that each 500 mg vial of the
drug is dissolved in at least 5 ml of water,
giving a 10% solution. Concentrations in
excess of this may increase the risk of local
reactions at the site of infusion.
SSiitte
e ooff iinnffuussiioonn
Care must be taken to avoid inserting
needles near important vessels, nerves or
organs. The abdomen is generally the best
place. However because of local reactions
such as erythema, swelling and induration, it
is often necessary to ‘rotate’ the sites used
for injection (see Figure 5). Some patients
find that the skin over the deltoid or the
lateral aspect of the thigh provides useful
additional or alternative sites.
Figure 6: Insertion of needles for desferrioxamine
infusion
TTyyp
pee ooff nneeeeddllee
The best needle to use will depend on the
individual. Many patients are happy with
butterfly needles of 25 gauge or smaller,
which are inserted at an angle of about 45
degrees to the skin surface. The needle tip
should move freely when the needle is
waggled. Other patients prefer needles that
are inserted vertically through the skin and
are fixed with an adhesive tape attached to
the needle (see Figure 6). Patient preference
is highly variable and clinicians should explore
the best type of needle for each patient in
order to maximise compliance.
TTyyp
pee ooff iinnffuusseerr
There are many types of infusers now
available. Newer devices, including balloon
pumps, are smaller, lighter, and quieter than
their predecessors. For patients who find
dissolving, mixing and drawing up
desferrioxamine a problem, pre-filled syringes
or balloons may be useful. Some pumps are
designed to monitor compliance.
LLo
occaall rreeaaccttiioonnss
Persistent local reactions may be reduced by
varying the injection sites, lowering the
strength of infusion or, in severe cases, by
adding 5-10 mg of hydrocortisone to the
infusion mixture.
SSu
uppppoorrttiinngg ccoom
mpplliiaannccee
It is clear that compliance with
therapy determines prognosis.
However, desferrioxamine treatment is
troublesome and time-consuming, and can
be painful. Practical approaches to
maximising compliance by decreasing local
reactions and providing the most convenient
pump system have been discussed above.
Especially important, however, is support
from family and the health care team.
46
Compliance requires a sustained and secure
relationship between doctor, patient and
parents, and regular discussion and support
are keys to maximising compliance. The
reasons for poor compliance are varied. In
some cases, parents cannot sanction the
daily “ordeal” of chelation therapy for their
child. In others, compliance may only
become a problem when a child reaches
adolescence. Sometimes a previously good
complier may become less compliant when
other life events or stresses become a
burden (see Chapter 15: Psychosocial
Support). Helping a patient to take control or
‘self-manage’ is often a useful approach of
long-term benefit (see TIF’s book on
‘Compliance to Iron Chelation Therapy with
Desferrioxamine’).
Moonniittoorriinngg ccoom
mpplliiaannccee
M
There is no perfect way to measure
compliance. One successful approach may be
to give patients a calendar, in which each
infusion of desferrioxamine is noted down
during the treatment. Some pumps can log
usage. Another approach has been to keep a
record of empty vials returned to the
provider of the desferrioxamine.
RReessccuuee tthheerraappyy wwiitthh ccoonnttiinnuuoouuss
iinnffuussiioonnss
In high risk cases, continuous infusion of
desferrioxamine is potentially more beneficial
than periodic infusions because it reduces
the exposure to toxic free iron (NTBI), which
returns to pre-treatment levels within
minutes of stopping a continuous
intravenous infusion (Porter, 1996). The
route of administration is not critical,
provided that as close to 24-hour exposure
to chelation is achieved. Intensification of
treatment through continuous, 24-hour
intravenous administration of
desferrioxamine via an implanted intravenous
delivery system (e.g. Port-a-cath) (Davis,
2000) or subcutaneously (Davis, 2004) has
been shown to normalise heart function,
reverse heart failure, improve myocardial T2*
(Anderson, 2002) and lead to long-term
survival, provided treatment is maintained. In
non-high risk cases, options such as
encouraging the patient to improve
compliance or an increase in dose should be
explored before moving to 24-hour
treatment.
Coonnssiiddeerraattiioonn ffoorr iinntteennssiivvee tthheerraappyy
C but preferably not the duration of treatment
Intensification should be considered in the
following cases:
SSu
uggggeesstteedd ddoossiinngg
A dose of at least 50 mg/kg/day and not
exceeding 60 mg/kg/day is recommended as
a 24-hour infusion (Davis, 2000 and 2004).
Higher doses have been used by some
clinicians however DFO is not licensed at
these doses and the risk of retinopathy
increases. Addition of vitamin C is
recommended only when acute heart
dysfunction has settled, which usually occurs
by three months of continuous treatment
(Anderson, 2004). As ferritin falls, the dose
can be reduced, in line with the therapeutic
index (see above).

ñ severe iron overload Maan

M naaggeem meenntt ooff iinn--ddwweelllliinngg
- persistently very high ferritin values*
- liver iron > 15 mg/g dry weight *
iinnttrraavveennoouuss lliinneess
Infection and thrombosis of the catheter
may occur. Careful aseptic procedures must
ñ significant cardiac disease^: be followed in order to prevent possible
- significant cardiac dysrhythmias infection by Staphylococcus epidermidis and
- evidence of failing left ventricular aureus, which when established are difficult
function to eradicate and often removal of the
- evidence of very severe heart iron infusion system becomes necessary. The risk
loading (T2*<6 ms) of thrombosis and infection is likely to be
greater in centres that do not have regular
ñ prior to pregnancy or bone marrow experience in the use of long-term in-
transplantation, when rapid reversal of dwelling lines. Use of prophylactic
iron loading may be desirable anticoagulation is advised as line-thrombosis
* If the only abnormalities are high ferritin or LIC, it would is relatively common in thalassaemia major
be usual to try to increase the dosing (for example, to 50- (Davis, 2000). As development of a
60 mg/kg) or the duration or the frequency of thrombosis can occur at the tip of the
subcutaneous infusions. catheter, it is advisable, if possible to avoid
placing the tip in the right atrium.
When cardiac disease is present,
24-hour intensive therapy is IInnttrraavveennoouuss ddeessffeerrrriiooxxaam
miinnee wwiitthh
necessary and simple bblloooodd ttrraannssffuussiioonn
increments in conventional 8- This has been used as a supplement to
12-hour dosing are not conventional therapy (e.g. 1 g over 4 hours
piggy-backed into the infusion line), but its
recommended. contribution to iron balance is very limited.
Special attention must be given to avoiding

47
accidental boluses due to desferrioxamine
collecting in the dead space of the infusion
line. Co-administration of desferrioxamine
and blood can lead to errors in interpreting
side effects such as acute fever, rashes,
anaphylaxis and hypotension during blood
transfusion. Desferrioxamine should never be
added directly into the blood unit.
Deferiprone
(Ferriprox®, Kelfer®,
L1)
Deferiprone is an orally absorbed iron
chelator that began clinical trials in the UK in
the 1980. It was first licensed for use in
thalassaemia in India, followed by the
European Union and other countries outside
the US and Canada, in the late 1990s.
Phhaarrm
P maaccoollooggyy
Three molecules of deferiprone are required
to bind one iron atom, and the efficiency of
iron binding decreases with falling
concentrations of iron or of chelator. The
drug is rapidly metabolised and inactivated in
the liver by glucuronidation of one of its iron
binding sites (Kotoghiorghes, 1998). At
currently used doses, about 6% of the drug
binds iron before it is excreted or
metabolised (6% efficiency) (Aydinok, 2005).
Unlike desferrioxamine, iron excretion is
almost exclusively in the urine.
EEvviiddeennccee ooff eeffffeeccttiivveenneessss ooff
ddeeffeerriipprroonnee
There are considerable accumulated
publications about the effects of
deferiprone. Most of these have not been
randomised controlled trials, making
comparison with desferrioxamine difficult.
48
However, ten small, randomised controlled
trials are now underway, involving a
combined total of nearly 400 patients.
EEffffe
eccttss oonn sseerruum
m ffeerrrriittiinn
Four prospective randomised trials compare
the effects of deferiprone on serum ferritin
at baseline and at follow-up (Maggio, 2002;
Gomber, 2004; Pennell, 2005; Ha, 2006).
Pooled analysis shows a statistically significant
decrease in serum ferritin at six months in
favour of desferrioxamine (Gomber, 2004;
Ha, 2006), with no difference between the
two drugs at 12 months (Maggio, 2002;
Pennell, 2006). There are numerous non-
randomised cohort studies demonstrating a
lowering of serum ferritin at doses of 75
mg/kg/day administered in three doses. The
effect on serum ferritin at this dose appears
greater at higher baseline ferritin values. In
these studies significant decreases in serum
ferritin are seen in patients with baseline
values above 2,500 Ìg/L (Al-Refaie et al.,
1992; Agarwal, 1992; Oliveiri, 1995) but not
with values below 2,500 Ìg/L (Olivieri,1995;
Hoffbrand,1998; Cohen, 2000).
EEffffe
eccttss oonn lliivveerr iirroonn
Four trials that measure change in liver iron
concentration (LIC) from baseline after a
period of treatment with deferiprone
compared with desferrioxamine are available
(Olivieri, 1997; Maggio, 2002; Pennell, 2005;
Ha, 2006). One study showed increases in LIC
at 33 months of 5 mg/g dry wt with
deferiprone (n=18) and 1 mg/g dry wt with
desferrioxamine (n=18) (Olivieri, 1997). A
second study showed an average decrease in
LIC at 30 months with both deferiprone
(n=21) and desferrioxamine (n=15) (Maggio,
2002). A third study found decreases in LIC at
one year of 0.93 mg/g dry wt with
deferiprone (n=27) and 1.54 mg/g dry wt
with desferrioxamine (n=30) (Pennell, 2005).
Another study reported decreases in LIC at six
months with both deferiprone (6.6 mg/g dry
wt, n=6) and desferrioxamine (2.9mg/g dry
wt, n= 7) (Ha, 2006). In a non-randomised
prospective study, using Deferiprone, LIC
increased from baseline by 28% at two years
and by 68% at three years of treatment
(Fischer, 2003). In other studies where only
single biopsies were performed after several
years of Deferiprone treatment, LIC has been
found to be above 15 mg/g dry wt in
variable proportions of patients: 11% (Del
Vecchio et al, 2000), 18% (Tondhury, 1998)
and 58% (Hoffbrand et al, 1998).
EEffffe
eccttss oonn hheeaarrtt ffuunnccttiioonn
One prospective one-year study found that in
patients with normal left ventricular ejection
fraction, deferiprone given at high doses (92
mg/kg) improved heart function (Pennell,
2006). In another randomised study over one
year, no difference in LVEF or other
measures of LV function was seen with either
deferiprone at 75 mg/kg/day or
desferrioxamine (Maggio, 2002). A
prospective study of the effects of
deferiprone monotherapy on patients with
abnormal LVEF or symptomatic heart disease
has not been reported.
EEffffe
eccttss oonn hheeaarrtt iirroonn
The effect of deferiprone monotherapy on
heart iron has been reported in two
prospective studies. One study found
significant improvement in T2* after one year
at 92 mg/kg of deferiprone daily. Patients
with starting T2* values of between 8 and 20
ms showed an average increase from 13 ms
to 16.5 ms in the deferiprone group, and
13.3 to 14.4 ms in the desferrioxamine group
(Pennell, 2006). In another randomised
study, of deferiprone and desferrioxamine
administered at standard doses over one
year, no change in heart iron estimated by T2
49
was reported for either drug (Maggio, 2002).
A recent study using a new technique
multislice, multiecho T2* demonstrated
improved T2* values in the Deferiprone
group compared to the Desferrioxamine
group (Pepe, 2006).
EEffffeeccttss oonn ssuurrvviivvaall aanndd ccoom
mpplliiccaattiioonnss
ooff ccaarrddiiaacc ddiisseeaassee
In six randomised prospective comparisons
with desferrioxamine, mortality was not
reported as an outcome measure while in a
seventh, one death reported in the
Deferiprone arm, but not in the
Desferrioxamine arm was considered as due
to cardiac complications (Ha, 2006). In a
retrospective cohort analysis of patients
treated with deferiprone or desferrioxamine,
no deaths were reported (n=157) in the
Deferiprone arm in contrast to the
desferrioxamine-treated patients (Borgna-
Pignatti, 2006), although some caution was
expressed by the authors with regard to the
interpretation of these results. In this analysis
the author noted that there were no cardiac
events in 750 patient years of exposure to
Deferiprone in more than 150 patients.
Coom
C mpplliiaannccee wwiitthh ddeeffeerriipprroonnee
One study comparing compliance with
deferiprone and desferrioxamine found rates
of 95% and 72% respectively (Olivieri, 1990),
while another found 94% and 93%
respectively (Pennell, 2005).
Two important points to be taken into
consideration are (i) compliance with any
treatment tends to be higher in studies than
in routine use, and (ii) although compliance
with oral treatment is expected to be better,
it cannot be taken for granted requiring, as
in the use of Desferrioxamine, constant
supervision and patient support.
Unwanted effects
with deferiprone
NNeeuuttrrooppeenniiaa,, aaggrraannuullooccyyttoossiiss aanndd
tthhrroom
mbbooccyyttooppeenniiaa
The most serious and potentially fatal adverse
effect of deferiprone is agranulocytosis
(absolute neutrophil count, or ANC*,
<500/mm3). The condition may occur with
thrombocytopenia, but also isolated
thrombocytopenia has occasionally been
reported. Onset of agranulocytosis is variable,
from a few months to nine years. In a
prospective trial where weekly neutrophil
counts were undertaken and where
deferiprone was discontinued when the ANC
was <1,500/mm3, agranulocytosis developed
in 0.2/100 patient years and milder forms of
neutropenia (ANC 500-1500/mm3) occurred
in about 2.8/100 patient years (Cohen, 2000
and 2002). Recently, 46 cases of
agranulocytosis, were reported, in Europe
with nine related deaths (Swedish Orphan,
safety alert, 2006). Five of these cases were
in patients who had been prescribed the
drug for an unspecified ‘off label’ indication,
and several were not receiving weekly blood
count monitoring. Swedish Orphan has
subsequently issued the following
recommendations on the use of deferiprone:
ANC* should be monitored
every week or more frequently
if there are signs of infection;
concomitant treatment that
could affect the white cell
count should be avoided; if
severe neutropenia or
agranulocytosis develop, the
drug should be stopped and not
* ANC: absolute neutrophil count
50
reintroduced, and the use of GM
CSF should be considered in the
case of agranulocytosis; off-
label use of the drug should be
avoided.
Gaassttrrooiinntteessttiinnaall ssyym
G mppttoom
mss
Nausea and change in appetite (loss or gain)
occur in 3-24% of patients (Ceci 2002; Cohen
et al, 2000).
EEffffe
eccttss oonn lliivveerr
Variable fluctuation in liver enzymes has been
reported. About a quarter of patients show
ALT fluctuation of twice the normal upper
limit (Cohen, 2000). One prospective
randomised study showed no significant end-
of-study changes in liver enzymes with
deferiprone or desferrioxamine (Pennel,
2006). An observational report about the
frequency of fibrosis after treatment for
three or more years has led to conflicting
interpretations (Olivieri, 1998; Tondury, 2001;
Hoffbrand, 1998; Wanlass, 2000). A relevant
prospective randomised study investigating
the progression to fibrosis, using Deferiprone
for one year, showed no difference as
compared with Desferrioxamine, over the
same period and no difference in baseline
and end-of-treatment liver function tests
(Maggio, 2002).
Arrtthhrrooppaatthhyy
A
The frequency of arthropathy varies greatly
between studies, from as low as 4.5% at one
year (Cohen, 2000) to 15% after four years
(Cohen, 2004) in a predominantly European
patient group, and as high as 33-40% in a
study of patients in India (Agarwal et al,
1992; Choudhry et al, 2004). It is not yet
clear whether these differences reflect
environmental or genetic differences, or
differences in iron overload between
populations at the start of treatment.
Symptoms range from mild non-progressive
arthropathy, typically in the knees,
controllable with non-steroidal anti-
inflammatory drugs to (more rarely) severe
erosive arthropathy that may progress even
after treatment is stopped. Cases involving
other joints, such as wrists, ankles and
elbows, and avascular necrosis of the hips,
have also been described.
Treatment should be stopped
where joint symptoms continue
despite a reduction in
deferiprone dose and are not
controlled by non-steroidal anti-
inflammatory drugs.
Neeuurroollooggiiccaall eeffffeeccttss
N treatment withdrawal.
Neurological complications are very rare and
have been typically associated with
unintentional overdosing. Rare neurological
effects have included cognitive effects,
nystagmus, walking disorders, ataxia, dystonia
and impaired psychomotor skills. These
effects appear to improve on cessation of
treatment.
EEffffe
eccttss oonn eeyyee aanndd eeaarr
There have been isolated reports of loss of
vision (central scotoma). One study reported
continued audiometric deterioration after
switching from desferrioxamine to
deferiprone (Chiodo, 1997). It is therefore
advisable to monitor for CNS, audiometric
and visual function in patients on regimes
containing deferiprone.
Otthheerr eeffffeeccttss
O
Zinc deficiency during deferiprone therapy
has also been observed in some patients,
especially those with diabetes.
51
As a result of the various
unwanted effects, 20-30% of
patients are unable to sustain
long-term treatment with
deferiprone (Hoffbrand, 1998).
FFrreeqquueennccyy ooff aaddvveerrssee eevveennttss
ccoom
mppaarreedd wwiitthh ddeessffeerrrriiooxxaam
miinnee
Adverse effects have been reported in four
randomised studies comparing deferiprone
with desferrioxamine. One trial has reported
data that allows comparison of the
probability of an adverse event with
deferiprone and desferrioxamine (Maggio,
2002), establishing a statistically significant
two-fold difference between deferiprone
(34%) and desferrioxamine (15%), but no
difference between temporary or permanent
Prreeggnnaannccyy
P
Deferiprone is teratogenic in animals and
must never be given to patients attempting
to conceive. Until more is known, potentially
fertile sexually active women and men taking
deferiprone must use contraception.
Deferiprone should not be used in pregnant
women.
RReeccoom mm meennddeedd ttrreeaattm
meenntt rreeggiim
meennss
wwiitthh ddeeffeerriipprroonnee
According to the official European licensing
Agency (EMEA*), Deferiprone could be used
as a second line drug, for removing iron in
patients who are unable to use
Desferrioxamine or in whom DFO therapy has
proven ineffective.
SSttaan
nddaarrdd ddoossiinngg aanndd ffrreeqquueennccyy
The daily dose of deferiprone that has been
evaluated most thoroughly is 75 mg/kg/day,
given in three doses. In the EU, the drug is
* EMEA: European Agency for the Evaluation of Medicinal
Products
licensed for doses up to 100mg/kg/day but
evidence for the safety of this dose is
limited. The standard dose of 75mg/kg/day
administered in three separate doses is
therefore recommended.
Doossee eessccaallaattiioonn wwiitthh ddeeffeerriipprroonnee..
D
Doses of 100mg/kg/day have been given in
at least one prospective study (Pennell,
2006), with no increase in side-effects
reported. High dose monotherapy with
deferiprone has not yet been prospectively
evaluated for safety and effectiveness for
patients with abnormal heart function, and in
this context monotherapy is not
recommended for this group of patients.
Aggee ooff ccoom
A mmmeenncceem
meenntt
Although there have been some
retrospective reports of its use in children,
the safety and efficacy of this drug has not
been formally evaluated in children under 10
years of age.
Ussee ooff vviittaam
U miinn CC
The effect of vitamin C on iron excretion
with deferiprone is not clear and is thus not
recommended.
SSaaffe
ettyy m
moonniittoorriinngg
Weekly blood counts are necessary
throughout treatment so that a falling white
cell count can be detected early and
treatment stopped before overwhelming
sepsis develops. If severe neutropenia or
agranulocytosis develops, re-challenge is
contra-indicated. Recent reports of eight
deaths from agranulocytosis in patients
treated in Europe, cited above, only
emphasise the importance of scrupulous
monitoring of the blood count throughout
treatment.
52
Combined
Desferrioxamine and
Deferiprone
A variety of regimens involving combinations
of deferiprone and desferrioxamine have
been used by clinicians, either in the context
of a formal trial or on an ad hoc basis, usually
when monotherapy with desferrioxamine or
deferiprone has failed to control iron
overload or its effects.
Phhaarrm
P maaccoollooggyy
In principle, chelators can be given at the
same time as each other (simultaneously) or
following one another (sequentially). There is
considerable variation in the way in which
sequential treatment can and has been
administered. Some investigators have used
the term ‘alternating therapy’ to describe the
use of two drugs administered on alternate
days, reserving the term ‘sequential therapy’
for when desferrioxamine is given at night
and deferiprone during the day. In practice
regimes may involve a component of
‘sequential’ and ‘alternating’ therapy, such as
when desferrioxamine is given three times a
week (alternate nights) and deferiprone
every day. Most regimes have tended to give
deferiprone daily, at standard doses,
combined with varying frequency and dosing
of desferrioxamine.
The pharmacology of combinations of
chelators may be fundamentally different
depending on whether the drugs are present
in cells or plasma at the same time. By giving
desferrioxamine at night and deferiprone by
day (sequentially), 24-hour exposure to iron
chelation can be achieved (similar to that
achieved with 24-hour desferrioxamine
infusion or once daily deferasirox. (For more
on deferasirox (Exjade), see below). This has
the theoretical advantage of 24-hour
protection from labile (redox active) iron
(Cabantchik, 2005). If the drugs are given at
the same time (simultaneously), they may
interact in a process that involves the
‘shuttling’ of iron, which may lead to
additional chelation of iron from cells or
plasma and so improved iron removal.
However, there is also a possibility of
chelation from metalloenzymes, leading to
increased drug-related toxicity.
In short, the simultaneous use of these drugs
has not been tested formally in large enough
patient groups to allow firm, evidence-based
recommendations about efficacy and safety.
However, data from several prospective
studies indicate that sequential (or
alternating) use of these chelators can be
used to achieve control of iron overload and
improvement in heart iron measurements.
Evidence of efficacy
of combined
treatments
EEffffeeccttss ooff sseeqquueennttiiaall uussee oonn sseerruum
m on liver iron of combined treatment
ffeerrrriittiinn
Four randomised studies have compared
levels of serum ferritin in patients using
combined treatments with those under other
treatment regimes. One study (Mourad et al,
2003) found the decrease in serum ferritin
achieved with five days of desferrioxamine
monotherapy (n=11) to be similar to that
achieved with two nights of desferrioxamine
plus seven days of deferiprone at 75 mg/kg
(n=14). Another randomised study, involving
53
30 patients and three different treatments
(Gomber et al, 2004), found that the
decrease in serum ferritin was greatest with
five nights of desferrioxamine, albeit not
significantly different from that achieved
with a combined treatment of
desferrioxamine two nights a week plus
deferiprone seven days a week. A third
randomised study, involving 60 patients
(Galanello, 2006), found no difference in the
level of decrease in serum ferritin in patients
randomised to combined treatment (two
days desferrioxamine at 33 mg/kg + seven
days deferiprone at 75 mg/kg) or to
desferrioxamine five nights a week at 33
mg/kg.
Taken together, these studies suggest that
serum ferritin can be controlled with a
relatively small dose of desferrioxamine given
twice a week, when combined with
deferiprone at standard doses (75
mg/kg/day). In a more recent randomised
study of 65 patients (Tanner, 2007), serum
ferritin was decreased more by combined
treatment (desferrioxamine five days a week
plus deferiprone seven days a week) than
with standard desferrioxamine monotherapy
(40 mg/kg five times a week).
EEffffe
eccttss ooff sseeqquueennttiiaall uussee oonn lliivveerr iirroonn
One randomised study, assessing the effects
compared to desferrioxamine monotherapy
(n=60), found LIC of <7 mg/g dry wt at
baseline – a figure maintained, on average, in
both arms of the study (Galanello, 2006).
Another prospective randomised study,
comparing the effect of desferrioxamine
monotherapy administered subcutaneously
five times a week with that of deferiprone
administered daily at 75 mg/kg daily or
deferiprone at 75 mg/kg daily, plus twice-
weekly desferrioxamine, found that the
decrease in liver iron was highest in the were compared with patients on standard
desferrioxamine monotherapy group and desferrioxamine five times a week (Tanner,
lowest in the deferiprone monotherapy 2007). T2* improved in both groups but was
group, with sequential combination significantly greater (6 ms) with combined
treatment showing an intermediate effect treatment than with desferrioxamine
(Aydinok, 2005). A further randomised study, monotherapy (3 ms). In an observational
comparing deferiprone plus desferrioxamine study, the T2 of the heart improved with
five times a week with desferrioxamine combined therapy (Kattamis, 2006).
monotherapy five times a week (n=65),
found that an improvement in liver T2* (as a SSaaffe
ettyy ooff ccoom
mbbiinneedd ttrreeaattm
meenntt
surrogate measure of LIC) was greater in the Formal safety data on combined treatment
combination arm (Tanner, 2007). are limited. A meta-analysis of the incidence
of agranulocytosis with combined regimes
EEffffeeccttss ooff sseeqquueennttiiaall uussee oonn hheeaarrtt compared with deferiprone monotherapy
ffuunnccttiioonn suggests that the risk may be increased
In the above-mentioned randomised several-fold, although the number of
controlled study of 65 patients (Tanner, patients that qualify for evaluation is small
2007), with baseline LVEF >56% changes in (Macklin, IND submission to FDA, 2004). The
LVEF improved by approximately 2.5% in the increased incidence appeared to occur
combination arm and 0.5% in the mostly in those regimes where the drugs
desferrioxamine monotherapy arm. Two were administered simultaneously. In a
observational studies have also reported recently reported prospective study, one
changes in heart function under combined case of agranulocytosis and two of
treatment. In 79 patients treated with a neutropenia were seen at one year in the
variable desferrioxamine regimen plus combination arm, including 32 patients
deferiprone at 75 mg/kg seven days a week (Tanner, 2006), while no increase in
for a variable time, there was an arthropathy was observed in the same group
improvement in LVEF measured by of patients.
echocardiography (Origa, 2005). In an
observational study of 42 patients with CCoonncclluussiioonnss aanndd ppoossssiibbllee ttrreeaattm
meenntt
sequential use of treatment over three to rreeggiim
meennss
four years (deferiprone 75 mg/kg/day plus
desferrioxamine two to six days a week), the The above-mentioned studies
LV shortening fraction improved (Kattamis,
2006).
suggest that some combined
regimens can control iron
EEffffeeccttss ooff sseeqquueennttiiaall uussee oonn ccaarrddiiaacc overload in the liver and heart
iirroonn where monotherapy is not
In a randomised controlled study of 65 having the desired effects. In
patients with moderate heart iron loading general, if a patient is not doing
(T2* 8-20 ms), myocardial T2* changes with well with monotherapy,
combined deferiprone 75 mg/kg seven days
a week plus desferrioxamine five days a week
combined treatment offers an
additional approach. However,

54
most of the above studies used
relatively low and intermittent
doses of desferrioxamine. It is
recommended that, in the first
instance, higher-risk patients are
administered at least 50
mg/kg/day of desferrioxamine
for as many hours a day as is
practicable. For patients with
very high levels of heart iron or
cardiac dysfunction, 24-hour
treatment with desferrioxamine
should be considered. If this is
not practicable, some form of
combined treatment may be a
useful option.
Deferasirox (Exjade)
Deferasirox was developed by Novartis as a
once-daily, oral monotherapy for the
treatment of transfusional iron overload. The
drug has been licensed as first-line
monotherapy for thalassaemia major in over
70 countries worldwide, including the US
(2005) and the EU (2006). The average follow
up in large-scale prospective trials at the time
of writing is three years.
Phhaarrm
P maaccoollooggyy
This is an orally absorbed iron chelator, with
two molecules binding each iron atom. The
tablet is dissolved in water (or apple juice)
using a non-metallic stirrer, and consumed as
a drink once daily, preferably before a meal.
Metabolic iron balance studies show iron to
be excreted almost entirely in the faeces,
with less than 0.1% of the drug eliminated in
urine (Nisbet-Brown, 2003). Metabolism
55
occurs predominantly by glucuronidation in
the liver. Due to the long plasma half-life
(nine to 11 hours), once-daily administration
provides 24-hour chelation from labile
plasma iron (Nisbet-Brown, 2003; Galanello,
2003; Dar, 2005). The efficiency of chelation
is 28%, over a wide range of doses and levels
of iron loading.
EEvviiddeennccee ooff eeffffeeccttiivveenneessss ooff
ddeeffeerraassiirrooxx
Deferasirox has undergone preclinical and
clinical evaluation that has included large-
scale prospective randomised studies
involving over 1,000 patients, to assess
safety, efficacy and the dose response
effects of treatment. At this time, evidence
of effectiveness is confined to serum ferritin
and liver iron.
Doossee eeffffeecctt oonn sseerruum
D m ffeerrrriittiinn
A dose-dependent effect on serum ferritin
has been observed in several studies
(Cappellini, 2006; Piga, 2006). A prospective
randomised study comparing the effects of
deferasirox in 296 thalassaemia major
patients with that of desferrioxamine in 290
patients found that 20 mg/kg daily of
deferasirox stabilised serum ferritin close to
2,000 Ìg/L. At 30 mg/kg, serum ferritin was
reduced, with an average fall of 1,249 Ìg/L
over one year (Cappellini, 2006). Longer-term
analysis of ferritin trends shows that the
proportion of patients with ferritin values
<1,000 Ìg/L and less than 2,500Ìg/L is
decreasing progressively with time (Porter,
2006).
DDoossee eeffffeecctt oonn lliivveerr iirroonn aanndd iirroonn
bbaallaannccee
In the same prospective study, iron balance
was achieved at 20 mg/kg/day, with mean
LIC constant over one year (Cappellini, 2006).
Negative iron balance was achieved at 30
mg/kg/day, while mean LIC fell by 8.9 mg/g
dry wt (equivalent to a decrease in body iron
of 94 mg/kg body weight) over one year.
Doses of 10 mg/kg/day are likely to lead to
positive iron balance in most patients. These
are average trends and a closer analysis
shows that the blood transfusion rate
influences the response to treatment
(Cohen, 2005). Thus for patients in the high
or low transfusion category (see Table 7), the
average dose required to achieve iron
balance is accordingly adjusted up or down
from 20mg/kg/day (Cohen, 2005).
A more moderate reduction in LIC occurred
in children under six years old, despite the
administration of an average dose of 21.9
mg/kg in this subgroup. However, these
patients had the highest mean transfusional
iron intake.
E f fe c t s o n h e a r t i r o n a n d h e a r t
E and included abdominal pain, nausea and
fu
f un c t i on
The effects of deferasirox on heart function
Transfusion rate % of patients
so transfused
Low (<0.3 mg/kg/day) 24%
Intermediate (0.3-0.5 mg/kg/day) 59%
High (>0.5 mg/kg/day) 17%
*in mg/g dry wt
Table 7: Relation of transfusion rates with LIC.
56
and estimated heart iron were not evaluated
formally as part of the drug registration
process, and formal prospective studies on
both heart function and heart iron are now
in progress. Retrospective analysis of effects
on myocardial T2* after one year and two
years of treatment suggests that this
measure can be improved in a significant
proportion of patients with pre-existing
abnormal T2* values (Porter, 2005). Patients
with normal LVEF showed no change in this
measure over one year (Porter, 2005).
Unwanted effects
with deferasirox
G a s t ro i n t e s t i n a l e ff e c t s
Gastrointestinal disturbances – typically mild
and transient – occurred in 15% of patients
vomiting, diarrhoea and constipation, lasting
a median of less than eight days. These
LIC change* LIC change*
at 20mg/kg at 30mg/kg
-4 -.9.5
-2 -9.0
+1.8 -4.0
symptoms rarely required dose adjustment or
discontinuation.
SSkkiin
n rraasshheess
These occurred in (11%) of patients and were
typically pruritic, maculopapular and
generalised, but occasionally confined to
palms and soles of the feet. A rash typically
developed within two weeks of starting
treatment. A minority of patients required
permanent discontinuation of therapy, and
mild rashes often resolved without dose
modification.
IIn
nccrreeaassee iinn sseerruum
m ccrreeaattiinniinnee
An increase in serum creatinine ≥30% on at
least two consecutive readings was observed
in 38% of patients receiving deferasirox, most
frequently at doses of 20 mg/kg and 30
mg/kg (Cappellini, 2005). These increases
were sometimes transient and generally
within the normal range, never exceeding
two times the upper limit of normal (ULN),
and were more frequent in the population of
patients having the most dramatic decrease
in LIC and serum ferritin. In the randomised
study, a dose reduction of 33-50% was
planned if at least two consecutive increases
in serum creatinine were >33% above
baseline. As the creatinine spontaneously
normalised in a number of cases, dose
reductions were instituted in only 13%. In
about 25% of those cases, the creatinine
then returned to baseline, while in the rest it
remained stable or fluctuated between
baseline and the maximum increase observed
prior to dose reduction. With follow up of a
median of three years at the time of writing,
no evidence of progressive renal dysfunction
has been reported where the above doses
and modifications are used. Further work on
the mechanism of creatinine increases is
being undertaken.
57
EEffffe
eccttss oonn tthhee lliivveerr
Overall a decrease in ALT* was seen, which
paralleled improvements in LIC (Daugnier,
2005). Two patients out of 296 developed
elevated ALT values greater than twice the
ULN while receiving deferasirox for one year,
which the investigator reported as related to
the administration of the drug.
Otthheerr eeffffeeccttss
O
No agranulocytosis, arthropathy or growth
failure was associated with deferasirox
administration. Comparing 296 patients who
received deferasirox in a one-year
prospective randomised study with 290
patients receiving desferrioxamine, deafness,
neurosensory deafness or hypoacusis were
reported as adverse events in eight patients
on deferasirox and seven in desferrioxamine.
Cataracts or lenticular opacities were
reported as adverse events in two patients
on deferasirox and five on desferrioxamine
(Cappellini, 2006).
CCoonnvveenniieennccee aanndd iim
mppaacctt oonn qquuaalliittyy ooff
lliiffee
Studies comparing satisfaction and
convenience of DFS with DFO in thalassaemia
major show a significant and sustained
preference for DFS (Cappellini et al, 2006).
Total withdrawals in deferasirox-treated
patients were 6% at one year compared with
4% with desferrioxamine (Cappellini, 2006).
This compares with a dropout rate of 15% at
one year with deferiprone (Cohen, 2000).
Based on thalassaemia patient reported
preferences for DFS and DFO, published
compliance data with DFO and the probability
of complications from iron overload in
relation to compliance with DFO, the cost
effectiveness per quality-adjusted life year
(QALY) gained is 4.1 per patient for DFO and
8.1 per patient for deferasirox.
* ALT: Alanine L-Aminotransferase
 The drug also appears to be palatable to
Recommended children at this young age. On the basis of
present knowledge, the criteria for starting
treatment regimens treatment (ferritin level, age, number of
transfusions) do not differ from those of
with deferasirox desferrioxamine.

Reeccoom
R mm
meennddeedd ddoossiinngg OOtthheerr iinnddiiccaattiioonnss aanndd
The drug is taken orally as a suspension in
water, once daily, preferably before a meal. A
ccoonnttrraaiinnddiiccaattiioonnss
Deferasirox is contraindicated in patients with
starting dose of 20 mg/kg is recommended
renal failure or significant renal dysfunction.
for thalassaemia major patients who have
For patients with evidence of significant
received 10-20 transfusion episodes and
heart dysfunction (e.g. LVEF below reference
currently receive standard transfusion at
range) there is very limited clinical experience
rates of 0.3-0.5 mg of iron/kg/day. In those
and treatment cannot be recommended at
patients in whom there is a higher rate of
this time for patients with heart failure or
iron intake from transfusion (>0.5
poor LV function. The combined use of
mg/kg/day) or in patients with pre-existing
deferasirox with other iron chelators has also
high levels of iron loading, where a decrease
not been formally assessed and therefore
in iron loading is clinically desirable, 30
cannot be recommended at this time. The
mg/kg/day is recommended. For patients
drug should not be used in pregnant women.
with a low rate of iron loading (<0.3
mg/kg/day), a dose of 10-15 mg/kg may be
sufficient to control iron loading. Experience of use in patients
with pre-existing renal disease
Aggee ooff ccoom
A mmmeenncceem
meenntt (baseline creatinine outside
Prospectively randomised studies of reference range) is insufficient
deferasirox in children as young as two years at this time to recommend its
of age have been carried out (Cappellini,
2006; Galanello, 2006).
use. As the median follow up in
A fall in LIC was seen across all large-scale studies is three years
age groups analysed, with no at this time, vigilance in
age-related adverse effects: in monitoring for possible long-
particular, no adverse effects on term effects is still advisable.
growth, sexual development or
bones were seen (Piga, 2005).

58
SSu
ummm
maarryy ooff IIrroonn OOvveerrllooaadd aanndd iittss ttrreeaattm
meenntt::
ñ 1.08 mg of iron in 1ml of pure red cells (HCT = 100%);
ñ Rate of iron loading: volume of RBC x 1.08 (annual transfusion requirements x
donor Hct = volume of RBC). On average 200mg iron/donor unit;
ñ Recommended transfusion 100-200 ml/kg/year is equivalent to 116-232 mg
iron/kg/year or 0.32-0.64 mg/kg/day;
ñ Serum ferritin broadly related to body iron. When high, the following should be
considered:
(i) iron overload;
(ii) inflammation;
(iii) hepatitis; and/or
(iv) liver damage.
When serum ferritin is low, the following should be considered:
(i) low body iron;
(ii) vitamin C deficiency.
In thalassaemia intermedia, ferritin underestimates the degree of iron overload.
Ferritin levels related to low risk are below 2,500 mg/l, preferably below 1,000
mg/l;
ñ Ranges of LIC reflecting levels of RISK:-
Very low risk = <1.8 mg/g dry weight
Low to moderate risk = 1.8 - 7 mg/g dry weight;
Moderately high to high risk = 7 - 15 mg/g dry weight;
Very high risk = > 15 mg/g dry weight;
Total body iron stores = 10.6 x LIC (mg/g dry weight);
LIC is measured by:
a) Liver biopsy – indicated if ferritin levels deviate from expected trends, if co-
existent hepatitis and if uncertain response to chelation;
b) SQUID – not universally available;
c) MRI – R2.
ñ Cardiac iron reflected by heart function tests and measured by MRI T2*;
ñ Urinary iron – used to monitor desferrioxamine or deferiprone dose effects.
Variability in daily excretion, and
ñ NTBI and LPI – not yet routinely used.

59
Deessffeerrrriiooxxaam
D miinnee::
ñ Initiate treatment after first 10-20 transfusions or ferritin level above 1,000 Ìg/l;
ñ If before 3 years of age monitoring of growth and bone development is
recommended;
ñ Therapeutic index = mean daily dose (mg/kg) (Mean daily dose = actual dose of each
infusion x doses/7 days) /ferritin (mg/l). Keep index < 0.025 at all times;
ñ Standard treatment: a) Slow subcutaneous infusion over 8-12 hours, b) 10%
desferrioxamine solution (5 ml water for each 500 mg vial), and c) infusion pump
(several types available);
ñ Standard dose: a) children 20-40 mg/kg (not exceeding 40 mg/kg, until growth has
ceased), and b) adults 50-60 mg/kg. Infuse 8-12 hours 6 nights minimum per week;
ñ Alternative route: subcutaneous bolus – two S.C. boluses/day to a total daily dose of 45
mg/kg;
ñ Vitamin C-dose limited to 2-3 mg/kg/day given orally at the time of infusion;
ñ Pregnancy – desferrioxamine can be used in pregnancy. It should be interrupted during
the first trimester and can be used in the second and third trimesters, in selected
cases;
ñ Intensive chelation with desferrioxamine – continuous 24-hourly infusions IV or SC.
Indications:
a) Persistently high serum ferritin;
b) LIC > 15 mg/g dry weight;
c) Significant heart disease, and;
d) Prior to pregnancy or bone marrow transplantation
Dose: 50 mg/kg/day (up to 60 mg/kg/day)
ñ In-dwelling catheters: danger of infection and thrombosis.

60
Deeffeerriip
D prro
onnee::
ñ Standard dose: 75 mg/kg/day in 3 divided dose (up to 100 mg/kg/day, but as yet
not enough information);
ñ Children above 10 years of age;
ñ Vitamin C concomitant treatment not recommended;
ñ Weekly blood counts (more frequently if signs of infection);
ñ Pregnancy – stop treatment. It is recommended that sexually active patients should
use contraception;

CO
C OM
MBBIIN
NAATTIIO
ONN TTH
HEER
RAAP
PYY.. In patients for whom monotherapy with desferrioxamine or
deferiprone is not controlling body levels of iron or myocardial iron, some combined
regimes offer an alternative that can reduce iron levels in both the liver and heart. No
recommendations as to which is the more effective combination can be made at
present.

CAAU
C UTTIIO
ONN:: agranulocytosis may be more frequent in combination therapy, especially in
simultaneous use.

Deeffeerraassiirro
D oxx::
ñ Recommended dose:
Starting dose 20 mg/kg/day. After 10-20 transfusions (iron intake (0.3-0.5
mg/kg/day);
If pre-existing iron overload (or iron intake > 0.5 mg/kg/day), the dose of 30
mg/kg/day is recommended. For patients with low rate of iron loading (<0.3
mg/kg/day), 10-15 mg/kg/day may be sufficient to control iron loading;
ñ Administration: Tablet dissolved in water (or apple juice), using a non-metallic stirrer.
Taken once a day before a meal.
ñ Continuous Monitoring
ñ Use in children > 2 (FDA) and >6 (EMEA) years of age
ñ Contraindicated in renal failure or significant renal dysfunction;
ñ Can not be given during pregnancy

61
62
KEY:

** Keep ≤ 40 mg/kg/day until growth is completed

* Consider desensitisation to desferrioxamine (see text)

^ Consider dose modification of deferasirox (see text)

£ NB ‘successful’ ferritin decreases greater than 1,000 - 2,000 Ìg/L/year are

unrealistic unless values are in excess of 4000 Ìg/L

£ NB ‘successful’ normalisation of cardiac T2* (to >20 ms) may take several years
especially when values are <10 ms

$ If a monotherapy is consistently unsuccessful, consider switching to another

monotherapy or

Consider switching to combination therapy or to 24h desferrioxamine (with or

without deferiprone) if the situation is serious

# There are many variations of combination therapy: some may be more appropriate
than others (see text)

63
Endocrine Complications
In Thalassaemia Major

EEnnddooccrriinnee aabbnnoorrm
maalliittiieess are among the contributing factors to stunted growth in
common complications of thalassaemia. patients with thalassaemia may include
Despite early establishment of appropriate chronic anaemia, transfusional iron overload,
chelation therapy, problems such as delayed hypersplenism and chelation toxicity
sexual maturation and impaired fertility may (DeSanctis, 1991). Other contributing factors
persist. Determining the prevalence of include hypothyroidism, hypogonadism,
endocrine complications is difficult because growth hormone deficiency/insufficiency,
of differences in the age of first exposure to zinc deficiency, chronic liver disease, under-
chelation therapy, and the continuing nutrition and psychosocial stress.
improvement in survival in well-chelated
patients. Diiaaggnnoossiiss aanndd iinnvveessttiiggaattiioonnss
D
The growth rates and endocrine Diagnosis requires careful clinical evaluation
complications of a sample of 3,817 to establish:
thalassaemia patients in 29 countries are
reported in Table 1 (De Sanctis, 2004). ñ ssllo
oww ggrroowwtthh rraatteess:: growth velocity
expressed in cm/year, below 1SD for age
and sex (based on growth velocity charts)
Growth ñ sshhoorrtt ssttaattu urre
e:: height below the 3rd
centile for sex and age (based on national
Growth retardation is common in growth charts) (see Appendix A)
thalassaemia major. Patterns of growth are ñ ssiig
gnnss o off ootthheerr p
piittu
uiittaarryy h
hoorrmmo on
nee
relatively normal until the age of 9-10 years ddeeffiicciieenncciieess (e.g., gonadotrophins)
when growth velocity begins to slow. Key ñ o otth
he err p poossssiib
blle
e ccaauusseess o off rre
ettaarrd
deed
dggrro
owwtth
h..

Nuum
N mbbeerr ooff ppaattiieennttss %%
Short stature males 664 31.1
females 513 30.5
Primary hypothyroidism males 60 2.8
females 64 3.8
Insulin-dependent diabetes mellitus males 75 3.5
females 46 2.7
Impaired glucose tolerance males 109 5.1
females 136 8
Hypoparathyroidism males 40 6.5
females 125 7.4
Hypogonadism males 353 43.3
females 243 37.7
Growth hormone males 53 7.1
deficiency/insufficiency females 148 8.8
Based on a sample of 3,817 thalassaemia patients in 29 countries

Table 1: Growth and endocrine complications in thalassaemia

64
IInnvveessttiiggaattiioonn ooff aa cchhiilldd wwiitthh patients with thalassaemia receiving irregular
tthhaallaassssaaeemmiiaa wwhhoo hhaass ssttuunntteedd ggrroowwtthh transfusion, as well as in those regularly using
iiss ggeenneerraallllyy ssiim
miillaarr tto
o tthhaatt ooff aa cchhiilldd desferrioxamine. In peri-pubertal patients,
wwiitthhoouutt tthhaallaassssaaeem miiaa.. hypogonadism should be carefully
EEvvaallu
uaattiioonn ooff sshhoorrtt ssttaattuurree//rreettaarrddeedd ggrroowwtthh.. investigated before starting growth hormone
treatment which may result in decreased
insulin sensitivity and abnormal glucose
The first step in the tolerance (de Sanctis, 1999).
investigation of short stature or
retarded growth is the regular Oral zinc sulphate supplementation should be
(six-monthly intervals) and given to patients with proven zinc deficiency.
accurate measurement of
standing and sitting height,
pubertal staging (Tanner 1962) Delayed puberty and
and bone age, including
examination of metaphyses. hypogonadism
Interpretation of absolute
height must take into account Delayed puberty and
the height of the parents. hypogonadism are the most
obvious clinical consequences of
Additional endocrine studies that may be iron overload.
helpful include thyroid function tests (FT4,
TSH), assessment of levels of sex hormones, Delayed puberty is defined as the complete
growth hormone (GF) secretion, zinc, lack of pubertal development in girls by the
calcium, alkaline phosphatase, urine analysis, age of 13, and in boys by the age of 14.
and investigation of glucose tolerance. Hypogonadism is defined in boys as the
Possibly useful tests include: Insulin Growth absence of testicular enlargement (less than
Factor-I (IGF 1) and Insulin Growth Factor 4 ml), and in girls as the absence of breast
Binding Protein-3 (IGFBP-3). The secretion of development by the age of 16 (de Sanctis,
GH is normal in the majority of patients with 1995).
thalassaemia. However, an investigation of
transglutaminase antibodies is also essential, Arrested puberty is a relatively common
to exclude celiac disease. complication in moderately or grossly iron
It is important to bear in mind overloaded patients with thalassaemia, and is
that desferrioxamine toxicity is characterised by a lack of pubertal
progression over a year or more. In such
an important cause of delayed cases, the testicular size remains 6-8 ml, and
growth (see Chapter on Iron breast size at B3 (see Table 2). In such cases
load and Iron Chelation) annual growth velocity is either markedly
reduced or completely absent (de Sanctis,
TTrre
eaattm
meenntt 1995).
Anaemia, folate deficiency and hypersplenism
are traditional causes of poor growth in

65
 PPeenniillee ddeevveellooppm
meenntt BBrreeaasstt ddeevveellooppm
meenntt GGrroowwtthh ooff ppuubbiicc hhaaiirr
P1: Prepubertal B1: Prepubertal PH1: Prepubertal

P2: Early puberty B2: Early puberty PH2: Early puberty

(enlargement of scrotum and (breast bud stage) (sparse growth)
testes, 4-5 ml, little or no
enlargement of penis)

P3: Mid-puberty B3: Mid-puberty PH3: Mid-puberty

(enlargement of penis and (breast and areolar (hair extends over
further growth of testes, enlargement) the pubic junction)
8-12 ml, and scrotum)

P4: Advanced puberty B4: Advanced puberty PH4: Advanced puberty

(enlargement of penis in
length and breadth. Increased
pigmentation of scrotal skin
and enlargement of testicles,
15-25 ml)
(areola and nipple project (hair corresponds to adult
separately from the growth but less extensive)
contour of the breast)

P5: Adult B5: Adult PH5: Adult

(Fully developed breast,
the areola no longer projects
separately from the breast
contour)

Table 2: Pubertal assessment according to Tanner

Most women with thalassaemia major present RH), stimulation test for Luteinizing
primary amenorrhoea, with secondary Hormone (LH) and Follicle Stimulating
amenorrhoea developing over time, Hormone (FSH)
particularly in poorly chelated patients. ñ Sex steroids (serum testosterone, serum
Ovarian function in such cases is generally 17-‚ Estradiol)
normal but gonadotrophin response to ñ Pelvic ultrasound to assess ovarian and
Gonadotrophin-Releasing-Hormone (Gn-RH) is uterine size
low compared to patients with normal ñ Transglutaminase antibodies
menstrual cycles. ñ In selected cases, Growth Hormone (GH)
stimulation test
IIn
nvveessttiiggaattiioonnss ñ In selected cases, Insulin Growth Factor-I
(IGF-I), Insulin Growth Factor Binding
ñ Routine biochemical analysis Protein-3 (IGFBP-3), plasma zinc
ñ Bone age (X-ray of wrist and hand)
ñ Thyroid function (TSH and FT4) TTrre
eaattm
meenntt
ñ Hypothalamic-pituitary-gonadal function: The treatment of delayed or
Gonadotrophin-Releasing-Hormone (Gn- arrested puberty and of

66
hypogonadotrophic
hypogonadism depends on
factors such as age, severity of
iron overload, damage to the
hypothalamo-pituitary-gonadal
axis, chronic liver disease, and
the presence of psychological
problems resulting from
hypogonadism. Collaboration
between endocrinologists and
other doctors is critical.
FFoorr ggiirrllss, therapy may begin with the oral
administration of ethinyl estradiol (2.5-5 Ìg
daily) for six months, followed by hormonal
reassessment. If spontaneous puberty does
not occur within six months after the end of
treatment, oral oestrogen is re-introduced in
gradually increasing dosages (ethinyl estradiol
from 5-10 Ìg daily) for another 12 months. If
breakthrough uterine bleeding does not
occur, low oestrogen-progesterone hormone
replacement is the recommended treatment.
FFoorr ddeellaayyeedd ppuubbeerrttyy iinn m
maalleess, low dosages of
intramuscular depot-testosterone esters
(25mg) are given monthly for six months,
followed by hormonal re-assessment. In
patients with hypogonadotrophic
hypogonadism, treatment at a dose of 50
mg per month can be continued until growth
rates wane. The fully virilising dose is 75-100
mg of depot-testosterone esters every 10
days, administered intramuscularly. The same
effects can be achieved with topical
testosterone gel.
For pubertal arrest, the treatment consists of
testosterone esters or topical testosterone
gel, administered as for the treatment of
delayed puberty and hypogonadotropic
hypogonadism.
67
It is important that the treatment of pubertal
disorders is treated on a patient-by-patient
basis, taking account of the complexity of
the issues involved and the many associated
complications.
Hypothyroidism
This may occur in severely anaemic and/or
iron overloaded patients, usually appearing in
the second decade of life. The condition is
uncommon in optimally treated patients (de
Sanctis, 1998; Sabato, 1983).
SSiig
gnnss aanndd ssyym
mppttoom
mss
Pre-clinical hypothyroidism is asymptomatic.
In mild and overt hypothyroidism, symptoms
such as growth retardation, decreased
activity, above normal weight, constipation,
reduced school performance, cardiac failure
and pericardial effusion may be encountered.
The incidence of hypothyroidism is slightly
higher in females. Typically, the thyroid gland
is not palpable, thyroid antibodies are
negative and thyroid ultrasonography shows
an irregular echo pattern with thickening of
the thyroid capsule.
Annual investigation of thyroid function is
recommended, beginning at the age of 12
years. Free T4 and TSH are the key
investigations, and their interpretation, along
with TRH test and TSH response, are shown in
Table 3. Bone age may be helpful in
evaluating hypothyroidism. The majority of
patients have primary thyroid dysfunction.
Secondary hypothyroidism caused by iron-
mediated damage of the pituitary gland
occurs very rarely.
 Hyyppoo--tthhyyrrooiiddiissm
H m SSe
erruum
m FFTT44 SSe
erruum
m TTSSHH TTSSHH RReessppoonnssee TTrre
eaattm
meenntt
ttoo TTRRHH
Subclinical Normal Marginally Increased Observation
increased
(TSH: 4.5-8mIU/l)
Mild Marginally low Elevated Exaggerated L-thyroxin
Overt Low Elevated Exaggerated L-thyroxin

KEY: FT4-free thyroxine; TSH-thyroid stimulating hormone; TRH-thyrotrophin-releasing hormone (adapted

from Evered, 1973)

Table 3: Hypothyroidism and its treatment

TTrre
eaattm
meenntt The pathogenesis resembles type-2 diabetes,
Abnormal thyroid function may be reversible with differences in the age of onset (it may
at an early stage through intensive chelation, start early in the second decade of life) and
and good compliance. slow progression of disturbances in glucose
metabolism and insulin secretion.
Treatment depends upon the severity of
organ failure. Sub-clinical hypothyroidism The type of glycaemia may be classified as
requires regular medical follow-up and diabetic, borderline or normal.
intensive iron chelation therapy.
ñ Diabetic type: Fasting Plasma Glucose
In patients with mild or overt (FPG) ≥7.0 mmol/l (126 mg/dl) and/or
hypothyroidism, L-thyroxine is given. plasma glucose 2 hours after 75 g
glucose load (2hPG) is ≥11.1mmol/l (200
mg/dl). A casual Plasma Glucose (PG)
≥11.1 mmol/l (200 mg/dl) also indicates
Impaired diabetic type. The persistence of “diabetic
type” indicates that a subject has
carbohydrate diabetes.
ñ Normal type: FPG <6.1 mmol/l (110
metabolism mg/dl) and 2hPG <7.8 mmol/l (140
mg/dl).
Impaired glucose tolerance and ñ Borderline type: includes those who are
neither diabetic nor normal types,
diabetes mellitus may be the according to cut-off values for venous PG
consequence of ‚-cell measurements.
destruction secondary to iron
overload, chronic liver disease, Diabetes in thalassaemia is rarely complicated
viral infection and/or genetic by ketoacidosis.
factors.

68
IIn
nvveessttiiggaattiioonnss
Oral Glucose Tolerance Test (OGTT) should be
performed annually from the age of puberty.
For children, a dose of 1.75 g/kg (to a
maximum of 75 g) is used for OGTT.
TTrre
eaattm
meenntt
ñ Impaired glucose tolerance may be
improved by a strict diabetic diet, weight
reduction, where applicable, and possibly
intensive iron chelation therapy
ñ In symptomatic patients, insulin
treatment is normally required but
metabolic control may be difficult to
achieve
ñ Where hyperinsulinism is insufficiently
managed by diet alone, acarbose may be
a useful first-line therapy for glycaemic
control
ñ The role of oral hypoglycaemic agents
remains to be fully determined
M
Mo onniittoorriinngg ddiiaabbeetteess aanndd iittss
ccoommpplliiccaattiioonnss
ñ Blood glucose (daily or on alternate days)
ñ Ketones – check if blood sugar is above
250 mg/dl
ñ Fructosamine estimation is more helpful
than glycosylated haemoglobin levels
ñ Urinary glucose is influenced by increased
renal glucose threshold
ñ Renal function (serum creatinine)
ñ Serum lipids (cholesterol: HDL, LDL,
triglycerides)
ñ Urinary protein
ñ Evaluation of retinopathy
Hypoparathyroidism
Hypocalcaemia, due to hypoparathyroidism,
is a recognised late complication of iron
overload and/or anaemia and usually begins
69
after the age of 16 (de Sanctis, 1995). The
majority of patients show a mild form of the
disease accompanied by paraesthesia. More
severe cases may demonstrate tetany,
seizures or cardiac failure.
Investigations should begin from the age of
16 and should include serum calcium, serum
phosphate and phosphate balance. In cases
with low serum calcium and high phosphate
levels, parathyroid hormone should also be
evaluated. Parathormone may be normal or
low, with low readings for 1,25
dihydroxycholecalciferol (vitamin D).
Bone radiology shows osteoporosis and
malformations.
TTrre
eaattm
meenntt
ñ Oral administration of vitamin D or one of
its analogues. Some patients require high
doses of vitamin D to normalise their
serum calcium levels. This should be
carefully monitored, as hypercalcaemia is
a common complication of this
treatment.
ñ Calcitriol, 0.25-1.0 Ìg, twice daily, is
usually sufficient to normalise plasma
calcium and phosphate levels. Weekly
blood tests are required at the start of
treatment, followed by quarterly plasma
and daily urinary calcium and phosphate
measurements.
ñ In patients with persistently high serum
phosphate levels, a phosphate binder
(other than aluminium) may be
considered.
ñ Tetany and cardiac failure due to severe
hypocalcaemia require intravenous
administration of calcium, under careful
cardiac monitoring, followed by oral
vitamin D.
Management of Fertility and
Pregnancy in ß-thalassemia
Advances in the primary care of ‚-
thalassaemia major (HbTh) by optimal blood
transfusion and chelation therapy have
improved patient survival into adulthood. At
the same time, patients’ quality of life has
also increased significantly, and the
expectation of having a family—an important
dimension of quality of life—is consequently
an important aspiration for many.
Although spontaneous fertility can occur in
well-chelated and -transfused patients with
spontaneous puberty, the majority are
infertile due to hypogonadotrophic
hypogonadism (HH) consequent to
transfusional haemosiderosis (Chatterjee and
Katz, 2000) and need AAssisted R
Reproductive
TTechniques (AAR
RTT).
Planned pregnancy is essential
both in spontaneous and ART
conceptions, as HbTh
pregnancies are high risk for the
mother and the baby. However,
these risks can be minimised
through pre-pregnancy
counselling with the
haematologist, the reproductive
medicine specialist, the
cardiologist and the
obstetrician, in conjunction with
the specialist nurse.
The management of patients of thalassaemia
intermedia (TI) is similar to that of
thalassaemia major (TM), with minor
modifications. Older patients with
thalassaemia major usually have
hypogonadotrophic hypogonadism and are
unlikely to conceive spontaneously, whereas
patients with thalassaemia intermedia are
potentially fertile with intact pituitary-
70
gonadal axis (Chatterjee and Katz, 2000;
Skordis, Christou et al, 1998). Also, the
management during pregnancy are different
in that TI patients have an increased
thrombotic risk and need transfusion during
pregnancy (Nassar, Usta et al, 2006), whereas
TM’s, in addition to complications specific to
iron overload, also face the risk of thrombo-
embolism, particularly those with
splenectomy and autoimmune antibodies.
Management of
fertility
Although 80-90% of patients have HH,
gonadal function is usually intact in the
majority of patients, indicating that fertility is
usually salvageable, i.e. ovulation in females
and spermatogenesis in males can be
induced by exogenous gonadotrophin
therapy, ‘bypassing’ the H-P axis. However,
other endocrine disorders, namely diabetes
and hypothyroidism, may also influence the
outcome of fertility treatment and need to
be corrected by standard care. Successful
spontaneous pregnancies, as well those
resulting from the induction of
gametogenesis, have been documented in
HbTh females and males (Aessopos et al,
1999).
Management of infertility requires a
thorough work-up, including pre-pregnancy
counselling of the couple (see below).
Fertility assessment of patients with
thalassaemia should also include evaluation
of the partner according to standard criteria
(see http://www.rcog.org.uk). The fertility
options are dependent on two factors (a)
partners’ carrier status and (b) site of
damage to the H-P-G axis.
If both partners are homozygous for ‚-
thalassaemia, use of donor gametes,
preferably donor sperm is the ideal option, as
sperm can be more easily available from
sperm banks, whereas the use of donor eggs
is technically more complicated with an
unpredictable success rate (Deech, 1998
review). If the partner is heterozygous, then
PPre-implantation GGenetic D PGGD
Diagnosis (P D) is
another option, where diagnosis can be
made prior to conception. This method may
be more acceptable to certain communities
with religious beliefs against termination of
affected pregnancy. Lastly, in patients with
severe organ damage or where both partners
have HbTh, another option may be adoption,
where there is good family support.
Methods for
induction of
ovulation
Induction of ovulation with pulsatile GnRH
infusion is only possible at the early stage of
FIGURE1
71
H-P damage, when gonadotrophins are
pulsatile. But majority of patients with HH are
apulsatile with functional gonads, and are
therefore likely to benefit from HMG/HCG
therapy with 80% success rate. Patients with
endometrial damage respond better to IVF
programmes.
Induction of ovulation should only be
undertaken by a specialist reproductive team,
according to Human Fertilisation and
Embryology Authority (HFEA) guidelines
(Deech, 1998 review). Patients should be
counselled regarding risk of hyper-
stimulation syndrome, multiple pregnancy,
ectopic pregnancy and miscarriage. The risk
of hyper-stimulation and multiple births can
be minimised by vigilant monitoring of the
induced cycle, followed up through, vaginal
ultrasound scans. For such procedures, it is
important to obtain the consent both and
imperative of the patients and involved
clinicians and carefully documented notes
should be kept throughout. The regime to be
followed will be dependent on the team’s
local protocol (See Figure 1 for an
established protocol).
Key points in induction of ovulation:
ñ Careful monitoring of the cycle by serial
vaginal ultrasound scans
ñ DFO should be continued until HCG is
injected/biochemical pregnancy is
confirmed
ñ Luteal support with progesterone may be
required
ñ After a maximum of six cycles, reassess
and refer for IVF
Induction of
spermatogenesis
The induction of spermatogenesis in male
patients with thalassaemia is more difficult
that the induction of ovulation in their
female counterparts, with a success rate of
10-15% in moderate to severely iron loaded
patients. The induction process must be
undertaken according to HFEA guidelines,
with an emphasis on consent and counselling
(Deech, 1998 review) (See Figure 2 for an
established protocol).
However, the recent advent of
micromanipulation techniques such as intra-
cytoplasmic sperm injection (ICSI) has
improved conception rates, even in oligo-
asthenospermic patients. Therefore, sperm
should be cryopreserved in all subjects unless
azoospermic, to better preserved fertility and
so the chance of conception. However, our
recent literature on sperm DNA damage in
HbTH (Perera, Pizzey et al, 2002) males raises
anxiety about mutagenic risks in these
individuals, especially after ICSI, where natural
protective barrier against gamete selection
during fertilisation is lost.

FIGURE 2

IIN
NDDU
UCCTTIIO
ONNO
OFF SSP
PEER
RMMAATTO
OGGEEN
NEESSIISS

ñ Baseline testosterone and semen analysis

ñ HCG 2000 units twice-weekly for 6 months
ñ Monitor testosterone level
ñ Repeat semen analysis-no sperm
ñ Continue HCG with combined HMG 75 units three times weekly
for additional 6 months
ñ If semen analysis is satisfactory SSA
AV
VEE
ñ If azoospermia persists, stop treatment

72
 before encouraging women with
Pre-pregnancy thalassaemia major to embark on pregnancy:
cardiac impairment, liver dysfunction and the
counselling vertical transmission of viruses.

Before embarking on fertility treatment, it is 1. The most important is cardiac function

important that patients and their partners
attend pre-pregnancy counselling, which has
a three-fold purpose (a) evaluation of
eligibility, (b) physicians to review
medications involved and (c) physician/s,
patient and partner to discuss the risks
associated with induced fertility and
pregnancy.
Evaluation of
eligibility ((FFiigguurree 33))
Each patient should be assessed regarding
suitability to embark on pregnancy with
optimum outcome both for the mother and
the fetus. There are at least 3 important
factors that must be seriously considered
because cardiac complications remain the
leading cause of death in both transfused
and untransfused patients. The cardiac
load is increased during pregnancy by at
least 25-30% due to increased heart rate
and stroke volume. This, along with iron
load, has a real potential for premature
death from cardiac failure. Therefore it is
prudent that all patients with TM should
have cardiac assessment by ECHO (Left
ventricular ejection fraction >65%;
fractional shortening >30%), by ECG, both
at rest and with exercise, and by 24 hr
tapes to check for rhythm disorders. If LV
dysfunction can be demonstrated in
patients under stressful conditions or if
significant arrhythmias have occurred,
then women should be strongly advised
against planning pregnancies (Hui et al,

Figure 3
EEV
VAALLU
UAATTIIO
ONNO
OFF EELLIIG
GIIB
BIILLIITTYY FFO
ORRP
PRREEG
GNNA
ANNC
CYY

ñ Heart: ECG, Echo, MRI

ñ Liver: LFT, ultrasound, biopsy
ñ Endocrine: diabetes, thyroid, parathyroid and
ñ Risk of thrombo-embolism: thrombophilia screen
ñ Viral infections: HBV, HCV, HIV, rubella
ñ Bone health: Vitamin D, calcium, DEXA, x-ray
ñ Iron overload: ferritin, liver and heart Fe
ñ Ascertain hemoglobinopathy status of partner
ñ Optimise lifestyle issues (smoking, etc).

73
 2002). Most of the non-invasive cardiac
investigations are relatively insensitive for
detecting early cardiac loading. Modified
MRI has recently been developed using
gradient T2* measurements to quantify
iron levels, and can accurately relate
these to LV dimensions assessed using
the same technique (Anderson et al,
2001). If the facility exists, cardiac MRI
should be performed and the aim should
be to have T2* closer to 20 ms.
2. Liver function should be evaluated by
biochemical test while iron overload
status by liver biopsy and MRI. Liver
biopsy can also provide information on
fibrosis and cirrhosis.
3. All patients should be screen for HIV,
Hepatitis B, Hepatitis C and rubella. The
opportunity should not be missed to
ensure rubella immunity prior to
pregnancy. If the patient is HIV positive
and wishes to have a family, she should
be advised of the usual recommendations
for care which include appropriate
antiviral agents, delivery by CS and the
avoidance of breast feeding to reduce
the risk of vertical transmission to <5%
(RCOG clinical Green Top Guidelines,
2004). As regards Hepatitis C-positive
cases, these women should be given a
course of antiviral agents to attain
Hepatitis C RNA negative status.
4. Before embarking on pregnancy, it is also
important to establish bone heath by X-
ray of spine and DEXA scan of hip and
spines (BMD score) and correction of
osteoporosis/osteopenia by institution of
appropriate therapy (see Chapter 6:
74
Diagnosis and Management of
Osteoporosis in ‚-thalassaemia). Patients
should also be screened for diabetes,
thyroid function, and acquired red cell
antibody. Both partners should be
screened for haemoglobinopathy.
Review of
medications ( F i g ure 4 )
This is a good opportunity to review
medications and to give advice to patients
regarding diet, smoking and alcohol, and to
commence supplements of folic acid, calcium
and vitamin D. Patients on oral chelators
(deferasirox or deferiprone) are
recommended to switch to desferrioxamine
prior to induction of
ovulation/spermatogenesis (Singer and
Vichinsky, 1999). Hormone replacement
therapy should also be stopped at least 4-6
weeks prior to induction of gametogenesis.
Bisphosphonate is contraindicated during
pregnancy and breast-feeding, as both are
states of considerable negative calcium
balance. It is therefore prudent to ensure
adequate calcium and vitamin D intake
before and throughout pregnancy. Other
medications that should be discontinued at
least six months prior to fertility treatment
include interferon, ribovarin and hydroxy
urea. Hypothyroid patients receiving thyroid
replacement therapy should receive
increased doses, to ensure they are
euthyroid. Hyperthyroidism is rare in patients
with thalassaemia. However, if a patient is
receiving an anti-thyroid drug such as
carbimazole, this should be replaced by
propyl thiouracil.
 Figure 4

REEV
R VIIEEW
WOOFF M
MEED
DIIC
CAATTIIO
ONNSS P
PRRIIO
ORR TTO
OPPR
REEG
GNNAAN
NCCYY

ñ Stop HRT
ñ Stop interferon, ribovarin, hydroxy urea
ñ Stop bisphosphonates six months prior to fertility treatment
ñ Switch from warfarin to heparin
ñ Switch from oral hypoglycaemic to insulin
ñ Switch from oral iron chelation to DFO
ñ Review thyroid medication
ñ Give calcium and vitamin D supplements
ñ Start folic acid supplement to prevent neural tube defect

overloaded and that have adequate cardiac

Risks associated with
pregnancy ((FFiigguurree 55))
All patients should be made aware that
pregnancy per se does not alter the natural
history of thalassaemia. If pregnancy is
managed in a multidisciplinary setting, the
foetal outcome is usually favourable with a
slight increase in incidence of growth
restriction (Aessopos, Karabatsos et al, 1999;
Ansari, Kivan and Tabaroki, 2006; Tuck,
Jensen et al, 1998). It has been shown that
the risks of pregnancy-specific complications
such as ante-partum haemorrhage and pre-
eclampsia in thalassaemia are similar to the
background population. It has also been
shown that DFO is not required during
pregnancy in patients that are not iron
function prior to pregnancy. Serum ferritin is
likely to alter by 10%, despite increase in
frequency of blood transfusion (Aessopos,
Karabatsos et al, 1999; Tuck, Jensen et al,
1998; Daskalakis, Papageorgiou et al, 1998;
Butwick, Findley and Wonke, 2005). The aim
during pregnancy is to maintain pre-
transfusion haemoglobin concentration
above 10g/dL (Aessopos et al, 1999).
Management of
pregnancy ((FFiigguurree 66))
Once pregnancy is confirmed, the patient
should be managed in a multidisciplinary
team consisting of obstetrician, midwife,
physician, haematologist and anaesthetist.

75
 Figure 5

R i s ks a s s o c i a t e d w i t h p r e g n a n c y

ñ Pregnancy does not alter the natural history of the disease

ñ Requires intense/vigilant monitoring
ñ Cardiac complications
ñ Risk of pregnancy-specific complications same as background population
ñ Risk of miscarriage same as background population
ñ Risk of foetal malformation: no increase
ñ Risk of foetal growth restriction: two-fold increase
ñ Preterm labour risk: two-fold increase
ñ Risk of transmission to the fetus/baby of Hepatitis B/C, HIV
ñ Risk of iso-immunisation
ñ Risk of pre-maturity and growth restriction is increased in multiple births

The patient should be made aware that
although pregnancy is high risk, the outcome
is usually favourable (Aessopos, Karabatsos et
al, 1999).
The main risk to the mother is
cardiac complications, which
can be minimised by ensuring
optimal cardiac function before
embarking on pregnancy.
The key points include evaluation of cardiac
function by ECHO, and of liver and thyroid
functions, in each trimester. All patients
should be screened for gestational diabetes
at 16 weeks and, if normal, this should be
repeated again at 28 weeks. Serial ultrasound
scans from 24-26 weeks onwards must be
undertaken to monitor foetal growth. In
selected cases, particularly those with
thalassaemia intermedia, thromboprophylaxis
by low molecular weight heparin is required
from mid-trimester (Nassar, Usta et al, 2006;
Eldor and Rachmilewitz, 2002). Although
there is a predisposition to venous
thrombosis in post-splenectomy patients, no
reports of thrombotic episodes have been
reported in the literature (Tuck, Jensen et al,
1998; Daskalakis, Papageorgiou et al, 1998).
Folate demand in pregnancy is normally
increased and this may be relevant in
patients with thalassaemia due to bone
overactivity. Regular folic acid
supplementation is recommended in mothers
with thalassaemia major to prevent

76
superimposed megaloblastic anaemia,
although this has only been demonstrated
individuals with ß-thalassaemia minor
(carriers) (Leung, Lao and Chang, 1989). If
cardiac function deteriorates during
pregnancy, DFO may be used, with caution,
as evidence regarding teratogenicity of DFO
is equivocal (Singer and Vichinsky, 1999). As
regards the newer oral chelating agents, data
on fetotoxicity are lacking. However, the
manufacturer’s product information for DFO
includes risk of skeletal anomalies in animal
pregnancies. Although there are currently no
reports regarding human foetal anomaly
from DFO, patients should be informed about
this prior to its use during pregnancy.
As regards the management of labour, if
pregnancy is non-complicated, one could
await the spontaneous onset of labour. But,
similar to reported data, it is the authors’
experience that 80% of women with
thalassaemia will require caesarean section
(CS) because of higher frequency of
cephalopelvic disproportion, largely due to
short stature and skeletal deformity in this
cohort, combined with normal foetal growth.
It is desirable to use epidural anaesthesia for
CS wherever feasible, to avoid the risk of
difficult intubation associated with general
anaesthesias due to severe maxillo-facial
deformity in TM patients (Orr, 1967).
Although most skeletal deformities are largely
prevented by regular transfusion, spinal
abnormalities associated with TM are relevant
to regional blockade. Osteoporosis and
scoliosis are common in TM, despite
transfusion therapy (Borgna-Pignatti, 2006).
77
Patients with osteoporosis usually have
vertebral bodies with reduced height and the
segmental position of the conus may be
lower than predicted (Borgna-Pignatti, 2006).
It is therefore important to correct
osteoporosis prenatally by hormone
replacement (and premidronate therapy),
where required, to increase bone density so
that spinal anaesthesia at CS becomes
feasible.
After delivery, DFO can be recommenced but
not oral chelating agents. Breastfeeding
should be encouraged in all cases except in
those who are HIV and/or hepatitis C RNA-
positive and/or HBsAg positive because of
the risk of transmission via breast milk.
All patients should be counselled regarding
contraception. Intrauterine devices should be
avoided because of risk of infection. Taking
oestrogen-containing birth control pill is also
not advisable because of the risk of
thrombo-embolism (Orr, 1967). In most
cases, progesterone-only pill or barrier
methods are usually appropriate. Male
patients with hypogonadotrophic
hypogonadism are not fertile spontaneously
and therefore contraception is not required.
Calcium and vitamin D supplements should
be continued during breast-feeding, however
bisphosphonate therapy for osteoporosis
should only be resumed after cessation of
breastfeeding.
 Figure 6

K e y p o i n t s f or p r e g n a n c y c a r e

ñ Check cardiac, liver and thyroid function once each trimester

ñ Screen for gestational diabetes
ñ Increase frequency of blood transfusion to maintain pre-transfusion Hb
above 10 g/dL
ñ Serial ultrasound scans to monitor fetal growth
ñ Higher incidence of caesarean section
ñ Encourage breastfeeding unless HIV positive and/or ∏CV RNA and/or
HBsAg positive
ñ Resume DFO after delivery
ñ Discuss contraception, where appropriate
ñ POP, barrier method
ñ Avoid intrauterine device and oestrogen-containing preparations
ñ Resume bisphosphonate after breastfeeding has ceased

78
Diagnosis and
Management of
Osteoporosis in ‚-thalasaemia
Osstte
O eoop
poorro
ossiiss is a skeletal disease
characterised by low bone mass and micro
architectural deterioration with a resulting
increase in bone fragility and hence
susceptibility to fracture (Sambrook et al,
2006). With increased life expectancy,
osteopenia-osteoporosis syndrome (OOS) is a
major cause of bone pain of hip and spine
and fragility fractures especially of the
lumbar spine which may be found in 70-80%
adult patients with ‚-thalassaemia world-
wide, accounting for significant bone
morbidity (Chatterjee et al, 2001).
Aetiology and
pathogenesis
Several studies have shown reduced bone
mass in osteoporotic patients with
thalassaemia (Chatterjee et al, 2000; Borgna-
Pignatti 2006; Chan et al, 2002; Morabito et
al, 2004; Voskaridou et al, 2003) but the
underlying pathogenesis is still speculative.
The causes of OOS in thalassaemia syndromes
are multifactorial (Chatterjee et al, 2000),
and include marrow expansion secondary to
ineffective erythropoiesis (Borgna-Pignatti,
2006), anaemia , transfusional
haemosiderosis (Borgna-Pignatti 2006) ,
delayed puberty (Chatterjee et al, 2000), use
of deferioxamine (Voskaridou et al, 2003) or
oral chelation agents for iron overload (Chan
et al, 2002), multiple endocrinopathies such
as hypogonadothrophic hypogonadism or
primary hypogonadism (Chatterjee et al,
2000), low IGF1 (Lasco et al, 2002), low
vitamin D levels due to aberrant vitamin D-
PTH axis (Borgna-Pignatti, 2006). Genetic
factors, for instance, polymorphism of the
VDR gene and COL 1 gene seem to play an
important role in the development of low
bone mass (Borgna-Pignatti, 2006; Morabito
79
et al, 2004; Voskaridou et al, 2003; Lasco et
al, 2001). The diminished osteoblast function
with reduced osteocalcin (Morabito et al,
2004) is accompanied by a comparable or
even greater increase in osteoclast activity
through RANK/RANKL/osteoprotegerin
pathway as the final, dominant mediator
(Voskaridou et al, 2003).
Diagnosis and
investigations
((FFiig
guurree 11 aan
ndd FFiig
guurree 22 ))
The commonest presentation is bone pain
and backache with or without past history of
fractures. Patients may also be asymptomatic
in 20% cases.
((A
A)) D
DEEXXA
A SSccaan
n
The diagnosis is best confirmed by bone
mineral density (DEXA) according to WHO
criteria (Figure 1). Although bone mineral
density remains the best available non-
invasive assessment of bone strength in
routine clinical practice, many other skeletal
characteristics also contribute to bone
strength (Mahachoklertwattana 2006). These
include bone macro architecture (shape and
geometry), bone micro architecture (both
trabecular and cortical), matrix and mineral
composition, as well as the degree of
mineralisation, micro damage accumulation,
and the rate of bone turnover, which can
affect the structural and material properties
of bone which are complicated and difficult
to assess in routine clinical practice
(Sambrook et al, 2006).
 Figure1

Woorrlldd HHeeaalltthh OOrrggaanniissaattiioonn ((W

W WHHOO)) ccrriitteerriiaa ffoorr ddiiaaggnnoossiiss ooff OOOOSS
Osstteeooppoorroossiiss
O
BMD > 2.5 SD below the young normal mean (T score) or
Standard deviations in relation to patient’s age (Z score)

Osstteeooppeenniiaa
O
BMD >1.5-2.5 SD below the young normal mean (T score)

Figure 2

LLiisstt o
off iinnvveessttiiggaattiioonnss
ñ Bone profile-serum Ca, PO4, 25(0H) vitamin D, PTH 24h urinary calcium.
ñ Endocrine profile FSH, LH, E2/T, TFT
ñ Liver function test
ñ Spinal X-ray
ñ DEXA-Spine-hip, radius, ulna-annually
ñ Markers of iron overload

((B
B)) BBiioocchheem
miiccaall patients who may have micro fractures.
All patients must have endocrine and bone
profile including 25 (OH) vitamin D3, PTH, ((D
D))M
MRRII
calcium, phosphate, liver function tests, MRI of spine, if available, must be undertaken
(alkaline phosphate, ALT, bilirubin, albumin) to determine extramedullary haematopoiesis,
FSH, LH, testosterone and oestradiol assays specially in TI patients and also to check for
(Chatterjee et al, 2001; Chatterjee et al, degenerative changes, skeletal dysplasia and
2000). disc prolapse.

((C
C)) RRaaddiioollooggyy ((EE)) AAsssseessssmmeenntt ooff iirroonn llooaadd aanndd
AP and lateral X-ray of the spine is important cchheellaattiioonn tthheerraappyy (see Chapter 3: Iron
to rule out fractures even in asymptomatic Overload).

80

MANAGEMENT
Principles of management of OOS are the
same as other patients with osteoporosis due
to other conditions (Sambrook et al, 2006).
The aim is to improve BMD score and
prevent/reduce future risk or fracture
with/without offering pain relief in
thalassaemia patients. General guidelines
include assessment of other drugs, lifestyle
issues, exercise and diet.
((A
A)) TThheerraappeeuuttiicc OOppttiioonnss ((FFiigguurree 33))
Controversy exists regarding the best
therapeutic option for osteopenia-
osteoporosis. It is likely that the factors
contributing to OOS in thalassemia intermedia
(TI), while overlapped with those of
thalassaemia major (TM) have a different
emphasis with intramedullary expansion
being more important and hypogonadism
less important than in TM. The choice of
therapy depends on the age of the patient,
the type of thalassaemia including
transfusion dependence, symptoms and
severity of clinical presentation, the past
history of type and number of fractures,
previous therapy, presence of risk factors of
nephrocalcinosis, associated hypogonadism,
hyperparathyroidism. An ideal therapy should
be safe and effective, able to correct the
specific defect of bone remodelling unit,
strengthen the bone and offer symptomatic
relief.
((1
1)) SSeexx sstteerrooiidd rreeppllaacceem
meenntt tthheerraappyy
In symptomatic or asymptomatic TM
patients with proven OOS (DEXA scan) and
hypogonadism, it is logical to correct
hypogonadism first by sex hormone
replacement therapy for at least two
years (Chatterjee et al, 2001; Chatterjee
et al, 2000; Lasco et al, 2001; Carmina et
al, 2004).
81
((2
2)) CCaallcciim
miim
meettiiccss
Vitamin D deficiency must be corrected
(oral dose of 1000-1500 IU/day) and
calcium supplementation (500 mg-1G
orally/day) (Sambrook et al, 2006).
((3
3)) AAnnttii--rreessoorrppttiioonn aaggeennttss
Bisphosphonates represent the biggest
advance in the treatment of osteoporosis
in the past decade in non-thalassaemic
patients (Sambrook et al, 2006), with
results of clinical trials showing reductions
in the risk of vertebral fractures (40–50%)
and non-vertebral fractures (20–40%),
including hip fractures. Bisphosphonates,
the potent inhibitors of osteoclast
function, can be used as second line
therapy in TM patients (non-responders
or poor responders) and those without
hypogonadism (TI) with encouraging
results.
RRoouuttee ooff aaddm miin niissttrraattiio
onn aan
nddd
doosse
e:: They
can be given as pamidronate 1-2 mg/kg
body weight once a month as IV infusion
for 3-5 years (Chatterjee et al 2001),
orally as alendronate 70 mg orally per
week (Borgna-Pignatti, 2006) or
zolandronic acid two–three times per year
(Mahachoklertwattana 2006).
Daily alendronate and risedronate have
reduced the risk of single and multiple
spine fractures, asymptomatic
(morphometric) and symptomatic spine
fractures in women with bone mineral
density T scores of less than -2.5 and one
or more prevalent spine fractures
(Borgna-Pignatti 2006). Despite their
impressive anti-fracture efficacy, several
issues are now arising with respect to
bisphosphonates including the risk of jaw
osteosclerosis in long-term users (Borgna-
Pignatti 2006).
((4
4)) CCoom
mbbiinnaattiioonn tthheerraappyy
Combination of pamidronate to HRT
regime in TM has been used with
successful results (Chattergee et al,
2001).
((B
B)) M
Moonniittoorriinngg ooff TTrreeaattm
meenntt
Treatment should be monitored with
biochemical parameters (bone and sex
steroid profile) and annual DEXA scan of
spine and femoral neck to determine the T
scores. A rise of 1-2% per year is expected in
the femoral neck with or without change in
femoral scores (Mahaklertwattana et al,
2003). After 3 years of pamidronate, usually
the BMD effect plateaus. Also long-term
treatment for >5 years is not recommended
as it may induce osteosclerosis, specially of
the jaw (Borgna-Pignatti, 2006) and may
even aggravate the existing problem.
Biochemical correction of hypogonadism
must be confirmed from optimal peak and
trough sex steroid levels. Caution must be
exercised in prescribing vitamin D
replacement therapy patients with risk of
nephrocalcinosis and bisphosphonate is also
given in caution (Borgna-Pignatti 2006).
Patients on thyroxine and corticosteroid
replacement therapy must be monitored
carefully as excess replacement can
aggravate osteoporosis.

Figure 3

Reeccoom
R mmmeennddaattiioonnss
ñ Diet and exercise
ñ Vitamin D and calcium supplementation
ñ Sex hormones replacement in HH-HRT
ñ Anti-resorption agents-Bisphosphonate
ñ Combination therapy-Bisphosphonate+HRT

82
 The Management
of Cardiac Complications in
Thalassaemia Major
The quality and duration of life of
transfusion-dependent patients with
thalassaemia has been transformed over the
last few years, with their life expectancy
increasing well into the third decade and
beyond, with a good quality of life (Olivieri
1995; Zurlo 1989).
Nevertheless, cardiac symptoms and
premature death from cardiac causes are still
major problems.
Iron related heart complications
are the leading cause of death
and one of the main causes of
morbidity.
In the absence of effective iron chelation
therapy, many patients sustain iron-induced
myocardial damage resulting in cardiac
failure, cardiac arrhythmia, progressive
congestive cardiac failure or sudden death
(Brittenham,1994).
Even after significant effects on
heart muscle, however,
including symptoms of heart
failure, aggressive iron chelation
can restore myocardial function
to normality.
The unique capacity of the heart to recover
from the effects of iron overload only
emphasises the importance of early
detection and, ideally, prevention; once overt
heart failure is manifest, acute survival may
be as low as 50%.
The regular assessment of
cardiac status helps physicians
to recognise the early stages of
heart disease and allows for
83
prompt intervention.
Ideally, a quantitative assessment of the
degree of myocardial iron overload is
required in order to identify those patients at
risk of developing heart complications as well
as, importantly, those where the risk may be
minimal. Establishing the best treatment
protocols requires co-operation between the
treating physician and cardiologists
experienced in dealing with
cardiomyopathies.
Clinical
manifestations
Patients with considerable iron
overload of the heart may
remain free of symptoms. Once
myocardial dysfunction
develops, discernible symptoms
are related to the degree of
ventricular impairment. Subtle
early signs may be confused
with the effects of the
underlying condition.
For example, breathlessness during exercise
may be attributed to anaemia. In more
advanced stages of heart failure, clinical
presentations are equivalent to those seen
with any severe heart muscle disease and
may include dyspnoea, peripheral oedema,
hepatic congestion and severe exercise
limitation. Signs and symptoms of right heart
failure may predominate, but bi-ventricular
involvement is the norm. The development
of the signs of classical heart failure implies
advanced disease with a poor prognosis, until
the acute situation is resolved.
As mentioned above, an important
distinguishing feature of heart failure due to
iron overload is the capacity of heart
function to make a complete recovery with
appropriate chelation therapy—a fact that
may not be widely appreciated by physicians
and cardiologists unaccustomed to dealing
with patients with thalassaemia. It must be
emphasised that the patient may require
support of failing circulation for a period of
several weeks in order to achieve a full
recovery.
Symptoms of palpitations are common in
patients with thalassaemia, and are a
frequent cause for anxiety—both for patients
and their physicians. In brief, the prognostic
implications of arrhythmia are related to the
degree of myocardial iron-overload and any
associated myocardial dysfunction. Thus in
the case of a non-iron overloaded patient,
the development of an arrhythmia such as
atrial fibrillation (AF) deserves simple
investigation and possible pharmacological
treatment, but does not necessarily imply an
adverse outcome. The same arrhythmia in a
heavily iron overloaded heart, particularly if
cardiac dysfunction is present, may be the
harbinger of severe decompensation and
requires immediate response and probable
hospitalisation.
PPaallppiittaattiioonnss must therefore be investigated
and treated in the context of the patient as a
whole. Ectopic activity, usually supra-
ventricular but occasionally ventricular, can
produce symptoms requiring prophylactic
drug treatment (often with beta-blockers),
especially as these transient events can
trigger more sustained arrhythmias,
particularly AF. Arrhythmias that produce
symptoms of haemodynamic compromise
(dizziness, syncope or pre-syncope) pose a
significant clinical risk and are associated with
84
significant myocardial iron-overload.
Treatment is directed towards the relief of
iron overload, with a secondary strategy of
symptomatic treatment of the documented
arrhythmia.
Chest pain is uncommon in thalassaemia, but
may accompany intercurrent illnesses
including pericarditis or myocarditis. The
frequency of these complications appears to
differ between countries, being rare in the
UK but more prevalent elsewhere.
Patients frequently present with epigastric
pain due to liver congestion, diminution in
exercise capacity and also dyspnoea and
cough.
Clliinniiccaall eexxaam
C miinnaattiioonn
A thorough medical history and physical
examination are required for a basic
cardiological assessment, which should also
include: 12-lead electrocardiogram and a
detailed echocardiogram, undertaken
according to published guidelines. Where
available, cardiac magnetic resonance
imaging (CMR), used to quantitatively
estimate cardiac iron overload, has become
an invaluable tool in the estimation of clinical
risk for the development of heart
complications in thalassaemia. Additional
tests may also be valuable for the detailed
assessment of individual clinical problems,
such as the investigation of cardiac
arrhythmia (Holter or 24-hour ECG) or
functional assessment by exercise tests.
EElle
eccttrrooccaarrddiiooggrraam
m
The electrocardiogram is frequently
abnormal, but changes are typically non-
specific. These changes commonly include
depolarisation changes in the T-waves and ST
segments of the anterior chest leads, and
sometimes a preponderance of right
ventricular voltages. Occasionally P-waves are
also affected, suggesting bi-atrial
enlargement. Conduction disturbance in the
forms of bundle branch block may be seen
but higher degrees of conduction
disturbance are rare. When new ECG
abnormalities appear during follow-up,
further investigation is required in order to
detect the cause.
Am
A mbbuullaattoorryy m
moonniittoorriinngg ooff EECCGG
The standard method for detecting and
investigating cardiac arrhythmia is via Holter
ECG recording for 24 or more hours. There
are now many types of recorders suited to
the detection of intermittent cardiac
arrhythmia.
EExxe
errcciissee EECCGG
Exercise testing, by treadmill or cycle
ergometer, may be of value in identifying
patients at risk for cardiac arrhythmias or for
assessing functional capacity. Adequacy of
treatment of cardiac disease can also be
gauged by exercise test performance.
An exercise test with gas-exchange
evaluation allows verification of: VO2 peak
(maximal O2 utilisation at the peak of the
stress) and VO2 AT (anaerobic threshold),
which are parameters closely related to the
functional status and prognosis of patients
with left-ventricular dysfunction.
EEcch
hooccaarrddiiooggrraapphhyy
Echocardiography is widely available,
relatively inexpensive and easy to perform. A
large number of parameters can be obtained
from the cardiac ultrasound investigation but
even the simplest measurements of chamber
size can provide immediate and valuable data
on cardiac status and clinical progress, as
long as they are obtained by a skilled
practitioner following a standardised
85
protocol. A minimum data set should include:
right and left heart dimensions, biventricular
function (left ventricular fractional
shortening and ejection fraction), estimated
intracardiac pressures (pulmonary artery
pressure, systolic and mean) and Doppler
analysis of intra-cardiac flows. Longitudinal
follow-up assessments should be carried out
at approximately the same time in the
patient’s transfusion cycle, to minimise
variability of clinical parameters.
Examination by echocardiography of the
ventricular response to exercise may also be
useful, highlighting individuals with sub-
clinical disease in whom the ejection fraction
fails to rise, or even falls, in response to
exertion or simulated exercise using i.v.
dobutamine.
R a d i oi s o t op e s t ud i e s :
Radioisotope studies: The use of MUGA
(Multiple Uptake Gated Acquisition) to
determine the overall left-ventricular ejection
fraction is an outmoded technique (both in
requiring the use of radioactive isotopes and
its high cost). Greater accuracy can be
achieved by monitoring resting ejection
fraction and the response to a reproducible
stress, in order to establish whether the
ejection fraction can rise from its basal level.
CCaarrddiiaacc M
Maaggnneettiicc RReessoonnaannccee IIm
maaggiinngg
((CCM
MRR))
The CMR scan provides a
combination of morphological,
functional information on the
heart as well as—uniquely—
quantitative estimates of tissue
iron overload.
As a result, CMR is rapidly becoming the tool
of choice in the clinical assessment of
patients with thalassaemia and is hampered
only by the limitation in access to
appropriate scanners in some parts of the
world. Scan times have been progressively
reduced with modern protocols and very few
patients are unable to tolerate the procedure
due to claustrophobia.
Caarrddiioollooggiiccaall m
C maannaaggeem
meenntt pprroottooccoollss
The frequency of cardiological assessments
described above depends on the age of the
patient and a clinical assessment of the likely
risk of significant myocardial iron overload, or
awareness of high total body iron burden.
ñ Well-chelated patients: first assessment at
puberty, with repeat examinations yearly.
The timing of a first CMR is not
determined but should probably wait
until the time of greatest actuarial risk,
i.e. late teens to early 20s.
ñ Asymptomatic patients with any evidence
of cardiac impairment: every three to six
months. An initial CMR will give evidence
of specific myocardial iron burden, which
may then be followed by repeat
examinations at six to 12 months to
ensure treatment strategies are
associated with a fall in heart iron
content (rise in CMR T2* parameter
towards 20 msec).
ñ Patients with symptoms of cardiac
impairment: weekly to every one to four
months, depending on clinical condition.
An immediate CMR will help guide
management while subsequent scans
provide an indication of response to
treatment.
Overall Management
Strategy
The therapeutic strategy to diminish the risk
of heart complications in patients with
86
thalassaemia involves a number of general
measures, along with particular cardiological
interventions. Such measures might include:
ñ Maintenance of pre-transfusional
haemoglobin level close to 9-10.5 g/dl in
patients without heart disease, and 10-
11 g/dl in patients with heart disease;
ñ Regular iron-chelation therapy and, for
patients with high iron loads or cardiac
disease, constant infusion regimens (s.c.
or i.v.); consideration of combined
chelation regimes using parenteral and
oral chelators simultaneously.
ñ Surveillance and adequate management
of other causes of heart failure such as
hypothyroidism, hypoparathyroidism,
renal dysfunction, coincidental valve or
structural heart disease, vitamin C
deficiency. Avoidance of unhealthy life
styles, including smoking, lack of physical
exercise and excess alcohol consumption.
Monitoring cardiac function can be a useful
guide to a patient’s overall prospects.
Impaired myocardial function may require
specific cardiac treatment, but it also calls
attention to the immediate need for much
stricter adherence to chelation protocol or
the initiation of a more intensive chelation
programme, in order to prevent an
inexorable progression to severe cardiac
failure.
SSp
peecciiffiicc CCaarrddiioollooggiiccaall CCaarree
The essence of treatment of
cardiac disease should be
aggressive chelation therapy to
rapidly counteract iron toxicity
and progressively remove
excessive iron deposits (Davis
and Porter 2000).
(see Chapter 3: Iron Overload for details on
designing an appropriate chelation
programme under these conditions).
Over recent years there has been a trend
towards treating patients with thalassaemia
exhibiting mild ventricular dysfunction with
agents known to improve myocardial
function in other forms of cardiomyopathy.
Treatment of myocardial dysfunction is best
undertaken using angiotensin converting
enzyme inhibitors (ACE inhibitors). In
controlled trials, these agents have been
shown to reduce mortality in patients
without thalassaemia established
cardiomyopathy and to reduce the rate of
appearance of heart failure in those with
asymptomatic left-ventricular dysfunction.
These results are very promising, and while
their extension to heart failure in
thalassaemia remains conjectural, it is widely
applied in clinical practice. The usual
precautions for initiating treatment in
patients who are well hydrated and starting
at low doses are recommended. The dose
should be increased to the maximum
tolerated, limited by hypotension in patients
with thalassaemia. Certain patients are unable
to tolerate ACE inhibitors due to the
development of chronic cough. These
individuals should be treated with
angiotensin II receptor antagonists, such as
losartan. Even though support for this drug
in cardiac failure is not strong at present, the
haemodynamic profile approximates that of
ACE inhibitors.
Diiggooxxiinn should not be used in the early
D dangerous situation of massive diuresis,
stages of cardiomyopathy but may have a
role as an inotropic agent in patients with
cardiac dilatation accompanied by low blood
pressure. Digoxin has a very specific role in
the maintenance of reasonable ventricular
87
rates in patients with established atrial
fibrillation.
Diiuurreettiiccss are the mainstay in producing
D
symptomatic improvement in those
individuals who develop pulmonary
congestion or signs of right-sided heart
failure. Loop diuretics such as Frusemide and
Bumetanide will produce a reduction in
circulating volume, which may considerably
decrease pre-load. These diuretics should
therefore be used with caution in patients
with thalassaemia. The tendency for patients
with thalassaemia to have restrictive
physiology, with diastolic heart failure, means
that the reduction in pre-load due to a loop
diuretic can produce a sudden fall in cardiac
output. These effects may precipitate pre-
renal failure. To restate, loop diuretics should
be used cautiously and mainly in the late
stages of disease.
Recent evidence supports the use of
spironolactone as adjunctive treatment in
non-thalassaemic patients with cardiac
failure. This and related agents reduce
potassium depletion induced by loop
diuretics and counteract hyperaldosteronism.
Potassium sparing agents can be used with
ACE inhibitors, but require careful monitoring
of electrolytes.
When dealing with severe congestive cardiac
failure in hospital, it is advantageous to use
constant intravenous infusions of loop
diuretics. This aids careful titration of the
doses of diuretic on an hour-to-hour basis,
according to urine output, thus avoiding the
volume depletion, fall in cardiac output and
worsening of renal function that can follow
large i.v. bolus doses of loop diuretics.
Inotropic support may be indicated in severe
cases.
Managing such patients can be aided by
utilising biochemical markers of heart failure
(BNP or pro-N-terminal BNP). Values are high
in decompensated heart failure and fall in
response to treatment. Data support delaying
hospital discharge in decompensated heart
failure until BNP levels have reverted to
normal.
A n t i -a r rh y t h m i c a g e n t s :
Anti-arrhythmic agents: In many
instances, the use of drugs to treat relatively
benign but symptomatic arrhythmias may
produce greater morbidity and mortality than
in untreated individuals. The decision to treat
arrhythmias in patients with thalassaemia
must therefore be carefully considered,
bearing in mind that iron toxicity is the
primary cause of this complication. Intensive
chelation treatment has been demonstrated
to reduce arrhythmias. In the majority of
instances, the arrhythmias are
supraventricular, although ventricular
tachycardia may occur in seriously ill
individuals. The development of arrhythmia
may be associated with a deteriorating
ventricular function, and can be improved by
addressing the latter problem. Overall,
arrhythmias require very careful assessment.
For most supraventricular arrhythmias,
reassurance of the patient is generally
appropriate, whereas patients with
ventricular arrhythmias require urgent
attention to address associated high
myocardial iron load, via
intensified chelation.
Beettaa--bblloocckkiinngg aaggeennttss can also be used to
B dwelling central venous lines require formal
control many arrhythmias, and are indicated
in patients with stabilised heart failure as
they improve the medium- to long-term
prognosis. Dosages should be low at first
with careful slow upward titration over days
and weeks. In heart failure, Carvidelol and
Bisoprolol have a special role, while Sotalol
88
may have advantages for the prophylactic
treatment of AF.
A m i o d a ro ne
Amiodarone has a very wide spectrum of
effectiveness against supraventricular and
ventricular arrhythmias and produces a
survival benefit in non-thalassaemic
individuals with life-threatening ventricular
dysrhythmias. However, Amiodarone does
have an enormous potential for side effects,
one of which—disturbances of thyroid
function—is of particular relevance in
patients with thalassaemia.
The role of other drugs, such as calcium-
antagonists and class I antiarrhythmic agents,
has yet to be established. Generally, these
agents should be avoided, since they all have
a tendency to produce negative inotropic
effect. Their use has not been widespread,
since arrhythmias tend to be associated with
more severe levels of myocardial impairment.
Without more formal study, the use of such
drugs cannot yet be recommended for the
treatment of patients with thalassaemia.
Cardioversion should be considered in
patients who fail to respond to iron chelation
therapy and pharmacological intervention. In
the situation of acute heart failure,
cardioversion from AF to normal rhythm
should be considered early on, as re-
establishing synchronised cardiac conduction
improves cardiac failure.
A n t i - c o a g ul a t i on :
Anti-coagulation: All patients with in
anti-coagulation with warfarin or other
suitable Coumadin derivatives, to prevent the
potentially life-threatening complication of
intra-atrial thrombus formation with
embolisation and the development of
pulmonary hypertension. Patients in AF also
should be considered for anti-coagulation, if
only as a temporary measure prior to
cardioversion.
Heart transplant: A few patients have
undergone heart transplant for severe,
irreversible cardiac damage, and this
procedure has also been combined with liver
transplant (Olivieri, 1994). The outcome of
transplant in patients with thalassaemia
needs to be carefully studied to determine
the effectiveness of this approach. The
presence of iron-induced damage to other
organs may adversely affect the outcome of
heart transplant. If surgery is successful,
intensive chelation therapy is still required to
remove iron from other organs and to
prevent iron accumulation in the
transplanted heart.
Summary
A) For asymptomatic patients with a normal
heart and no myocardial iron content by
CMR (or, where no CMR is available,
patients with proven good chelation
records and an absence of iron-related
complications):
ñ encourage continuation of current,
effective chelation
ñ encourage maintenance of a healthy
lifestyle
B) For patients with increased cardiac iron
content (measured by CMR) but normal
cardiac function (or, where no CMR is
available, those with iron related
complications and/or a poor chelation
history):
ñ intensification of iron chelation: s.c. or
i.v. desferrioxamine (24 hours x 7
days/week); consider combination
treatment with oral deferiprone and s/c
desferrioxamine
ñ as for group A
89
C) For patients with cardiac impairment,
with or without symptoms:
ñ intensification of iron chelation: i.v.
desferrioxamine (24 hours x 7
days/week); consider combination
treatment with oral deferiprone and s/c
desferrioxamine
ñ slow blood transfusion with diuretics
ñ specific cardiac medications:
ñ ACE inhibitors, or ARII blockers where
ACE not tolerated
ñ beta-blockers: carefully introduce
once acute heart failure stabilised;
bisoprolol or carvidelol remain first
choice
ñ diuretics, for the symptomatic relief
of fluid overload; use sparingly whilst
monitoring renal function;
spironolactone should be introduced if
possible
ñ digitalis, if in atrial fibrillation,
Warfarin: if central line in situ, or if in AF
Conclusion
The prospects for patients with thalassaemia
have improved with a greater understanding
of the disease and with better, individualised
regimes of management. Close co-operation
between the medical disciplines is called for.
At the same time, the fundamental
treatment aim remains to provide regular,
effective iron chelation, in forms that
encourage patients to comply with
treatment—treatment that must be allied to
more precise definition of tissue-specific iron
loads, so that patient and physician alike have
a better idea of individualised risk.

The prevalence,
pathophysiology,
diagnosis and
management of
pulmonary
hypertension in
‚-thalassemia
Cardiac involvement represents the primary
cause of mortality in both thalassemia major
(TM) and thalassemia intermedia (TI). In this
context, pulmonary hypertension (PHT) is
part of the cardiopulmonary complications of
the disease.
Pulmonary hypertension was initially
documented in a small group of 7 TI patients
with right heart failure. In a subsequent
study of a large 110-patient series, age-
related PHT was found in nearly 60% of cases
followed by right heart failure in 5% of
patients. It should be noted that all those
patients had preserved left ventricular
systolic function and normal pulmonary
capillary wedge pressure. Thus, following
those observations PHT is currently
considered to be the primary cause of heart
failure in TI patients.
In what concerns the development of PHT in
TM, a recent study (Aessopos Kefarmakis,
2007) compared cardiac disease between
two large aged-matched groups of TM
(n=131) and TI (n=74) patients, both treated
uniformly in the currently accepted manner,
namely regular transfusion and chelation
therapy in TM and absence of any particular
90
treatment in TI. According to this study,
moderate to severe PHT was observed only in
TI patients with a prevalence of 23%. Systolic
left ventricular dysfunction, in contrast, was
present only in TM cases with a prevalence of
8%. Heart failure was observed in 3% of TI
patients and 4% of TM ones.
In terms of pathophysiology, it seems that
PHT in ‚-thalassemia results from a rather
complex combination of mechanisms, which
lead to the increase of both cardiac output
and pulmonary vascular resistance. Chronic
tissue hypoxia and chronic hemolysis are
believed to hold the central pathogenetic
role, while individual mechanisms involved
include the prolonged anemic state, the
increased percentage of hemoglobin F, the
hepatic abnormalities, the presence of a
hypercoagulabilable state, the thalassemia-
related elastic tissue defects, and the
coexistent endothelial dysfunction.
The diagnosis of PHT in patients with
thalassaemia may be performed simply and
non invasively using transthoracic Doppler
echocardiography. It has been shown that a
peak systolic tricuspid pressure gradient in
the presence of tricuspid regurgitation
higher than 30 mmHg is indicative of the
presence of pulmonary hypertension. A
follow-up strategy with clinical examination
of the cardiovascular system,
electrocardiography, chest X-ray and
echocardiography, performed on an annual
basis, or in shorter intervals if clinically
indicated, should be applied in every patient
with thalassaemia. A close collaboration
between attending physicians, hematologists
and cardiologists is required in this context.
Although both forms of the disease share a
common molecular background, the diverse
severity of the genetic defect and of the
resulting clinical phenotype impose a
different therapeutic approach. The currently
applied regular lifelong therapy in TM
patients eliminates chronic hypoxia and thus
prevents the development of PHT. On the
other hand, the absence of systematic
treatment in TI leads to a cascade of
reactions that compensate for chronic
anemia but at the same time allow the
development of PHT. The accumulated
experience indicates that a large number of
TI patients, if not the majority of them,
should be considered for regular transfusion
and chelation therapy. Two crucial points
that remain to be clarified are the patient
selection criteria and the timing of treatment
onset. Until research data becomes available,
the judgement should be based on individual
clinical and laboratory assessment of
patients. The applied treatment, once
started, should definetely aim at prevention
and not palliation of anaemia-induced
complications.

91
The Liver
in Thalassaemia
Under normal circumstances, about one-third
of storage iron (ferritin and haemosiderin) in
the body is found in the liver. Approximately
98% of hepatic iron is found in hepatocytes,
which make up 80% of total liver mass; the
remaining 1.5-2% of total liver iron is found
in reticuloendothelial cells, endothelial cells,
bile ductular cells and fibroblasts. Iron that
enters the cell in excess of that required
accumulates in the major storage forms of
iron, ferritin, and haemosiderin. Progressive
accumulation of storage iron is associated
with cellular toxicity, although the specific
pathophysiologic mechanisms for
hepatocytes injury and liver fibrosis are not
entirely understood. These include lipid
peroxidation of organelle membranes,
increased lysosomal fragility and decreased
mitochondrial oxidative metabolism. Iron also
has a direct effect on collagen synthesis
and/or degradation, and alterations in
microsomal enzymes.
The liver plays a central role in iron
homeostasis. In addition to iron released
from transfused red cells, an enhanced rate
of gastrointestinal iron absorption has been
suggested. This excess iron is initially
confined to the Kupffer cells but when
transfusion requirements produce massive
iron overload, spillover to hepatic
parenchyma cells quickly occurs, with the risk
of late development of fibrosis and cirrhosis.
In patients with ‚-thalassaemia, in absence of
co-factors, the threshold hepatic iron
concentration for the development of
fibrosis is about 16 mg/g dry weight liver
(Angelucci, 2002). Clinical studies suggest a
relationship between hepatic iron
concentration and the development of iron-
induced hepatotoxicity.
Hepatic iron concentration (HIC) is the gold
standard for the measurement of body iron
92
overload (HIC in mg/g dry weight x 10.6 =
whole body iron store in mg/kg) (Angelucci,
2000). Non-invasive techniques used to
assess hepatic iron include computed
tomography, biomagnetic liver
susceptometry (SQUID) and magnetic
resonance imaging (MRI). Of these, relaxation
rates R2 (1/T2) and R2* (1/T2*) measured by
MRI appear to be the most promising and
accurate (Wood, 2005).
Hepatic iron stores are closely
correlated with cumulative
transfusional iron load and have
been used as a marker for the
effectiveness of chelation
therapy and prognosis. An
increase in hepatic iron is
associated with an increased risk
of impaired glucose tolerance,
diabetes mellitus, cardiac
disease and death.
Hepatitis C Virus
(HCV)
This RNA virus was first characterised in 1989,
having previously been termed non-A non-B
hepatitis. The majority of HCV isolates studied
so far can be divided into six major groups,
designated genotypes 1-6, with subdivisions
in each (subtype a, b, c, etc.). Antibodies
that develop after infection are not
protective but rather are indicative of
current or past infection. Active infection is
diagnosed by the presence of circulating HCV
RNA in blood (Sharara, 1996)
Preventative measures to
minimise the risk of post-
transfusional hepatitis C include
careful selection of voluntary
donors and appropriate blood
donor screening.
Natural history and
complications of
infection
A c u t e i n fe c t i o n :
Acute infection: generally benign, with
>80% asymptomatic. Anicteric Fulminant
Hepatitis is very rare.
Chhrroonniicc iinnffeeccttiioonn:: develops in 70-80% of
C develops in 1-5% of infected individuals after
cases, leading to chronic liver disease.
However, the clinical outcome is highly
variable, for reasons that are not completely
understood. Determinants of disease severity
or chronicity as well as response to therapy
include age at acquisition, as well as host-
specific (e.g. immunity) and virus-specific
(e.g. genotype) factors and, most important,
co-morbidities.
C i r rh os i s :
Cirrhosis: develops in a variable percentage
of HCV-infected patients, ranging from < 5%
in young, healthy people, to approximately
25-35% of cases of patients with relevant co-
morbidities. Age and co-morbidities appear
to be the most important factors affecting
the risk of developing cirrhosis. Cirrhosis
usually takes as long as two to three decades
to develop from the time of acquisition. Five-
year survival in patients with compensated
cirrhosis is 91%, with a 79% rate of 10-year
survival. When cirrhosis is decompensated
however, 5-year survival falls to just 50%.
93
R e v e r s ib ili t y :
Reversibility: The reversibility of advanced
fibrosis and even early cirrhosis (Child A –
compensated or well-compensated*) has
been documented in thalassaemia once
causes of liver injury (iron overload and HCV
infection are removed) (Muretto, 2002).
E n d -s t a g e l i v e r d i s e a s e :
End-stage liver disease: should lead to
consideration of liver transplantation.
Hepatitis C is currently the commonest
reason for liver transplantation worldwide.
Recurrent hepatitis C infection occurs in >
90% of cases after transplant but is usually
mild. Long-term survival after liver
transplantation for hepatitis C is similar to
that for other diagnoses, averaging 65% after
5 years (Gane, 1996).
Heeppaattoocceelllluullaarr ccaarrcciinnoom
H maa ((HHCCCC))::
20 years, particularly after the development
of cirrhosis, increasing by 1-4% each year
thereafter (Colombo, 1991). Prevention and
early detection of HCC are more effective
than attempted cure. Cirrhosis patients
should undergo a regular six-monthly
screening programme, including liver
ultrasound examination and alpha-feto-
protein check, for the early detection of
hepatocellular carcinoma.
E xt r a - h e p a t i c
Extra-hepatic manifestations of HCV
infection include porphyria cutanea tarda,
essential mixed cryoglobulinemia,
glomerulonephritis, autoimmune thyroidits
and vasculitis (Sharara, 1996).
* Liver cirrhosis is divided to 3 stages following the
Child-Pugh score, Score 5-6 (Score A) is
characterised by: No ascites, Bilirubin < 2mg/dl,
Albumin>3.5g/dl. INR <1.7, no encephalopathy.
Therefore, Child-Pugh stage A can be defined as
“well compensated disease”.

Special features of
hepatitis C in
thalassaemia major
The severity of chronic hepatitis C in patients
with thalassaemia may be greater because of
concomitant iron overload, other concurrent
viral infections (HBV, HIV) and possible
infection with mixed hepatitis C genotypes. It
has been demonstrated that iron and HCV
infection are independent but mutually
reinforcing risk factors for the development
of liver fibrosis and cirrhosis, with a reciprocal
multiplicative effect (Angelucci, 2002). It
appears therefore that patients with
thalassaemia, particularly those with poor
control of iron overload, face an increased
risk of developing cirrhosis.
Diagnosis and
monitoring
Annttiibbooddyy tteessttiinngg
A
This is most valuable for screening blood and
blood products and as initial testing in
patients with chronic unexplained elevation
in serum transaminases or those suspected
of having chronic liver disease. Confirmatory
testing is done using HCV RNA detection by
polymerase chain reaction (PCR), the current
standard for the confirmation of viremia.
Ascertaining the genotype and quantity of
HCV RNA in serum is useful only in
determining the type and duration of
treatment (see below).
LLiivve
err bbiiooppssyy iinn tthhaallaassssaaeem
miiaa m
maajjoorr
Liver biopsy prior to treatment is helpful in
determining the extent of liver damage and
94
to guide decisions on therapy and anticipate
complications (Angelucci, 1995).
Treatment
This is a rapidly changing field and the
treatment of hepatitis in patients with
thalassaemia should therefore be undertaken
in close collaboration with a specialist in liver
disease.
Similar to non-thalassaemia patients,
treatment of HCV in patients with
thalassaemia is aimed at eradication of the
virus, improvement in liver histology,
reduction of the risk of liver cirrhosis and
hepatocellular carcinoma.
SSe
elleeccttiioonn ooff ppaattiieennttss ffoorr tthheerraappyy
Patients diagnosed with acute HCV infection
and persistently positive serum HCV RNA
after 12 weeks of exposure or diagnosis
should receive treatment (Sharara, 2006).
Initiation of treatment in chronic hepatitis C
has traditionally been based on one or more
of the following:
ñ confirmed presence of HCV-RNA
ñ moderate to high serum ALT levels
ñ abnormal liver histology
Encouraging results for the treatment of HCV
in thalassaemia, combined with the above-
mentioned risks of greater severity of chronic
hepatitis C in such patients, means that the
presence of serum HCV-RNA alone is
sufficient to consider treatment in patients
with thalassaemia, where the patient has no
other contraindications to treatment or other
significant co-morbidities.
Reessppoonnssee ttoo ttrreeaattm
R meenntt
Depending on HCV genotype and viral load,
40-80% of patients with chronic hepatitis C
will respond to the current standard
treatment of pegylated interferon and
ribavirin. Response is defined on the basis of
a negative highly sensitive qualitative HCV
RNA PCR assay, carried out 24 weeks after
completion of therapy.
Patient responses are classified as follows:
E a r l y v i r a l r e s p on s e ( E V R ) :
ñ Early viral response (EVR): defined as
an undetectable HCV RNA or a > 2-log
reduction in viral load after 12 weeks of
treatment
R e s p o n s e a t e nd o f t r e a t m e n t
ñ R e s p o n s e a t e nd o f t r e a t m e n t
( ETR ) :
(ETR): defined as absence of HCV-RNA at
the end of treatment
Sustained viral response (SVR):
ñ Sustained viral response (SVR):
absence of HCV-RNA > 6 months after
concluding treatment. This is in practice
equivalent to viral eradication of HCV
N o n -r e s p o n d e r s :
ñ Non-responders: lack of significant
decline (defined as > 2-log reduction
from baseline) in HCV RNA after 12 weeks
of therapy
R e l a p s e rs :
ñ Relapsers: re-emergence of HCV-RNA
after a satisfactory end of treatment
response
Moonniittoorriinngg rreessppoonnssee
M example of an algorithm used for Hepatitis C
Depending on HCV viral genotype, the
current recommendation is to measure the
biochemical (serum ALT) and virological (HCV-
RNA) response after 4 to 12 weeks of
therapy, and to continue therapy for an
additional 12 to 24 weeks in patients with
undetectable HCV-RNA. Because serum ALT
may be raised for other reasons in patients
with thalassaemia (iron overload,
concomitant infections), monitoring response
is based on viral HCV RNA.
Prreeddiiccttiioonn ooff ppoooorr rreessppoonnssee
P in the first two weeks after starting
Negative predictors in all patients with
hepatitis C are:
95
ñ High baseline HCV-RNA level and the
absence of its early decay (4-12 weeks)
upon initiation of treatment
ñ HCV genotypes 1 or 4
ñ Presence of bridging fibrosis or cirrhosis
ñ Co-existence of other viruses (HBV, HIV)
Controversial in this specific setting is the
role of iron overload.
Since no baseline factor is specifically
predictive of treatment success or failure,
withholding therapy on the basis of factors
suggesting a poor response is unwarranted.
Because of the possible role of iron overload
in reducing the likelihood of successful
treatment of hepatitis C and for general,
well-known clinical reasons, effective
chelation therapy should be strongly
considered before initiation of antiviral
therapy in patients with bad control of
transfusional iron.
Treatment regimens
The gold standard is combination therapy
with pegylated interferon and ribavirin. An
managament is presented in Figure 1.
T y p e o f i n t e r f e r on :
Type of interferon: Pegylated interferon
·-2a or ·-2‚ given subcutaneously once
weekly
Duurraattiioonn:: 24 to 48 weeks, depending on
D
genotype
S i d e e f fe c t s :
Side effects: Typical side effects in most
patients include flu-like symptoms, insomnia,
and cognitive and mood changes, especially
interferon. Dose-dependent neutropenia and
thrombocytopenia commonly occur during
Figure 1

96
interferon therapy. Particular attention
should be paid to this complication in
patients with thalassaemia and
hypersplenism. Since both deferiprone and
interferon may cause neutropenia, there are
theoretical risks associated with their
combined use, and this combination should
be initiated with caution and under careful
monitoring. Hypothyroidism is an important
complication of interferon treatment.
Some patients have experienced
exacerbation of local reactions at the site of
desferrioxamine infusion during interferon
treatment. Heart failure has been seen in a
few patients with thalassaemia receiving
interferon, and special care should be given
if prescribing interferon for patients with
pre-existing heart disease.
M on i t o ri ng f o r s i d e e f f e c t s :
Monitoring for side effects: Close
monitoring for hypothyroidism is mandatory
in patients receiving interferon, and testing
for thyroid function and the presence of
anti-thyroid antibodies should precede
initiation of therapy. Regular monitoring of
blood counts is also necessary, to identify
neutropenia or thrombocytopenia. Cessation
of therapy should be considered if the
absolute neutrophil count falls below 1,000.
Ribavirin
Ribavirin is a nucleoside (guanosine)
analogue, well absorbed orally, and typically
given in doses of 800-1200mg/d. Alone, it
has limited antiviral activity in hepatitis C but
in combination therapy with interferon has
been shown to significantly increase
sustained response rates compared to
interferon alone.
Si de e f f e cts :
Side effects: Haemolysis occurs in most
patients without thalassaemia, with a
decrease in haemoglobin of 10-20% from
baseline levels.
97
In thalassaemia major this may be associated
with a more marked haemolysis and a 30%
increase in transfusion requirement, which
requires careful adjustment of the
transfusion interval and intensification of iron
chelation therapy (Li, 2002; Inati, 2005).
It is important to note that dose-reduction of
ribavirin is associated with an inferior
sustained viral response and it is hence
recommended that transfusion-chelation
requirements be adjusted to compensate for
ribavirin-associated haemolysis rather than
altering the recommended ribavirin dose
(Inati, 2005).
TTrreeaattmmeenntt dduurraattiioonn aanndd vviirraall llooaadd
m
mo onniittoorriinngg: Depends primarily on the HCV
genotype. For genotypes 1 or 4, treatment is
administered for 48 weeks provided there is
a positive early viral response (EVR) at 12
weeks. In the absence of EVR, treatment is
usually discontinued and further treatment
options considered.
This approach has been validated in patients
with thalassaemia where an SVR of 64% is
seen in patients infected with genotype 1
and 4 and who have exhibited an
undetectable HCV RNA at 12 weeks of
treatment (Inati, 2005). For genotypes 2 or
3, treatment is limited to 24 weeks. Given the
high rate of SVR for genotypes 2 and 3,
approaching 80%, a 12-week determination
of viral load is not usually necessary.
TTrreeaattmmeenntt ooppttiioonnss ffoorr nnoonn--
rreessppoonnddeerrss
These have not been firmly established and
are currently considered experimental. An
expedited second treatment option may
need to be considered in patients with
advanced fibrosis on liver biopsy.
Maan
M naaggeem meenntt ooff ssppeecciiaall ppaattiieenntt HBsAg, and other public health
ppooppuullaattiioonnss measures, have led to a
Consultation with a physician experienced in
the management of liver disease is especially
significant reduction in
important in the clinical management of the hepatitis B infections in most
following patient populations: countries of Europe and North
ñ Children America, as well as other parts
ñ Patients with cirrhosis of the world. Hepatitis B
ñ Immunosuppressed patients nevertheless remains a
ñ Pregnant patients
ñ Patients with acute hepatitis C formidable medical problem,
mainly in developing
Prreevveennttiioonn
P countries.
There is currently no vaccine or
immunoglobulin to prevent hepatitis C. The Current HBsAg positivity in thalassaemia
following recommendations are made to major ranges from <1% to >20% and
reduce the risk of non-parenteral Hepatitis B infection remains a significant
transmission: cause of chronic liver disease and
hepatocellular carcinoma in patients with
Sexual transmission
Sexual transmission risk is generally low. thalassaemia in many regions of the
However, insufficient data exist to developing world.
recommend changes in current
recommendations: that patients encourage Clliinniiccaall ssiiggnniiffiiccaannccee ooff HHBBVV m
C maarrkkeerrss
their sexual partners to be tested for Despite the availability of good screening
hepatitis C, and that safe sexual practices tests for hepatitis B, the interpretation of
should be encouraged. results may be difficult or misleading.

G e ne r a l m e a s ur e s
General measures, such as avoiding ñ A
Accu
uttee iinnffeeccttiioonn.. HBsAg is a reliable marker
sharing toothbrushes, razors, etc. are (can be present for 4-5 months). HBeAg
advised, to avoid transmission to family is also transiently present (1-3 months).
members. However, the risk of transmission Anti-HBc IgM is the most reliable test for
is low, and special measures such as to the diagnosis of acute HBV infection.
segregate towels and eating utensils are
probably unnecessary. ñ C
Chhrroonniicc iinnffeeccttiioonn (overt carrier) is marked
by the presence of HBsAg and anti-HBc in
the blood (usually accompanied by HBeAg
or anti-HBe). In accordance with
Hepatitis B Virus international definitions, overt carriers
can be classified as:
(HBV)
ñ aaccttiivve
e ccaarrrriieerrss, identified by the
IIn
ncciiddeennccee presence of HBeAg or anti-HBe
Vaccination strategies, antibodies and a viral load ≥5 log10
screening of blood donors for copies/ml (although others cite a figure

98
 of ≥4 log10 copies/ml), corresponding
to about 17,200 IU/ml, according to
most recent standardisations. The great
majority of active carrier cases are
associated with the presence of hepatic
disease.
ñ iin
naaccttiivvee ccaarrrriieerrss, characterised by the
persistent normality of transaminase in
an anti-HBe-positive subject, associated
with levels of viremia below the
threshold (<5 Log10) and, eventually,
with IgM anti-HBc <0.2 IMx Index. In the
majority of such subjects, the
histological finding, when available, does
not reveal significant liver disease
(necroinflammatory activity <4 HAI),
while in a small minority of cases it is
possible to observe effects of a chronic
(sometimes even cirrhotic) disease
which have became silent spontaneously
or thanks to the effect of the antiviral
treatment.
ñ p re v i o u s i n fe c t i o n :
previous infection: the presence of
anti-Hbc antibodies ± anti-Hbs indicates
previous infection. In particular
circumstances, such as deep
immunosuppression (i.e. hemopoietic
stem cell transplantation), the possibility
of HBV reactivation after a previous
infection has been demonstrated. This
category of patients can therefore also
be defined as potential occult carriers
(Marzano, 2007).
ñ v ac c in at io n :
vaccination: the presence of HBsAg
antibodies (if anti-HBc is not present)
indicates vaccination.
Patients with thalassaemia should be
screened for all serological markers of
hepatitis B and classified according to
Table 1, which provides a list of possible
99
interpretations of screening results.
Natural history
A c u t e he p a t i t i s :
Acute hepatitis: This is the most common
presentation, with an incubation period of 4-
20 weeks. Severity is variable, with an icteric
period often preceded by a prodromal illness
with arthralgia and urticaria. Progression to
fulminant hepatic failure is rare (≤1%). Acute
hepatitis B is usually managed by supportive
measures alone.
Prrooggrreessssiioonn ttoo cchhrroonniicc hheeppaattiittiiss BB
P
occurs in 5-10% of otherwise healthy adults
and in 90% of neonates. In acute icteric
hepatitis B in adults, transition to chronicity
appears to be rare, probably occurring in less
than 2% of cases. For patients with chronic
hepatitis B infection, co-infection with
hepatitis C may increase the severity and rate
of progression of liver disease.
C i rr ho s i s
Cirrhosis occurs at a rate of 1-2.2% per
year. Iron loading in thalassaemia may
increase the risk, as may concomitant HCV
infection.
H e p a t oc e l l ul a r c a r c i n o m a
Hepatocellular carcinoma is a well-
recognised complication of chronic hepatitis
B infection.
 TTe
esstt Reessuullttss
R IIn
ntteerrpprreettaattiioonn Reeccoom
R mmmeennddaattiioonn
HBsAg - Susceptible to infection/never Consider vaccination
anti-HBc - exposed to virus
anti-HBs

HBsAg + Acute or chronic infection Further evaluation

anti-HBc + or -

HBsAg - Resolution of previous infection

anti-HBc +/-
anti-HBs +
anti-HBeAg -

HBsAg - Past infection*- potential

anti-HBc +/- occult carrier.
anti-HBs -
anti-HBeAg -

HBsAg + Carrier with chronic infection Further evaluation,

anti-HBc + (if HBsAg+ 6 months or more) including HBV-DNA
anti-HBs - Highly infectious levels
HBeAg +

HBsAg - Carrier with chronic infection Further evaluation,

anti-HBc - (if HBsAg+ 6 months or more) including HBV-DNA
anti-HBs + levels
HbeAg -
Anti-HBe -

HBsAg - Immunisation without infection

anti-HBc -
anti-HBs +
HBeAg -
Anti-HBeAg -

* Other interpretations include:

1. Recovering from acute HBV infection, with loss of HBsAg but anti-HBs has yet to appear
(“window period”).
2. Immune to HBV but anti-HBs never appeared or has fallen below the level of detection.
3. Chronic HBV infection with undetectable serum levels of HBsAg.
4. False positive anti-HBc, with susceptibility to HBV infection.
* Interpretations 2 and 4 are the most common explanations of this serologic pattern.

Table 1: Possible interpretations of Hepatitis B screening results

100
Prevention: HBV 2007 Treatment
Vaccination: All newly Overview
(Hepatitis Annual Update 2007
diagnosed patients with ‚- website:http://clinicaloptions.com/Hepatitis/AnnualUpdates)

thalassaemia should be The primary goal of therapy for Chronic

vaccinated against hepatitis B. Hepatitis B (CHB) is long-term suppression of
Three injections (at 0, 1 and 6 serum HBV-DNA which in turn will likely
reduce progression to cirrhosis, liver failure
months) are required to and hepatocellular carcinoma.
produce an antibody response
in 95% of normal individuals. The key endpoints in determining the
The vaccine is ineffective in efficacy of therapy include suppression of
those already exposed to serum HBV DNA to low and preferably
hepatitis B. undetectable levels, normalisation of ALT
levels, histologic improvements, HBeAg
In individuals acutely exposed to known seroconversion in HBeAg-positive patients,
contaminated blood, hyperimmune globulin and the relatively rare event of HBsAg
can limit the risk of acute infection. seroconversion.

Prreevveennttiioonn ooff vveerrttiiccaall ttrraannssm

P miissssiioonn::
Transmission of hepatitis B from mother to
infant occurs during the perinatal period. The
risk of infection is 26-40% if the mother is
HBeAg positive. Mothers with acute hepatitis
B during pregnancy transmit the virus in up
to 70% of pregnancies if infection occurs in
the third trimester, and up to 90% if it occurs
within 8 days of delivery.
Measures to prevent vertical transmission
include administration of hepatitis B vaccine
and hepatitis B immuno-globulin (HBIG) to
neonates within 12 hours of delivery by a
carrier. This results in >90% reduction of the
risk of transmission.
Unlike hepatitis C, hepatitis B is highly
infectious through the sexual route and close
personal contact. Detailed advice and
immunisation need to be given to the
patient’s immediate family and sexual
partner(s).
The information provided below is derived
from US treatment algorithms, AASLD*,
EASL**, and APASL*** Guidelines, according
to which, the currently preferred first-line
monotherapy treatment options include the
use of Adefovir, Entecavir and Pegylated
Interferon, which has almost completely
replaced standard interferon alfa-2b.
Lamivudine and Telbivudine are not preferred
first-line drugs in most populations, because
of high resistance rates.
Recent trends include treatment of patients
with any elevation of HBV-DNA with
compensated or decompensated cirrhosis.
Combination therapy with nucleos(t)ide
analogues is also now widely used in cirrhotic
patients as well as in patients with HBV and
HIV co-infection or in patients who have
undergone BMT after HBV infection.
*AAAASSLL:: American Association for the study of Liver Disease
** EEA
ASSLL:: European Association for the study of Liver Disease
*** AAPPA ASSLL:: Asian Pacific Association for the study of Liver
Disease

101
SSuum mm maarryy:: IIm
mpplliiccaattiioonnss ffoorr CClliinniiccaall ñ The rates of genotypic resistance with
PPrraaccttiiccee long-term therapy are high with
The key recommendations based on updated lamivudine (70% at 4-5 years), somewhat
treatment guidelines for treatment of less with telbivudine (21.6% in HBe-Ag-
chronic Hepatitis B are as follows: positive and 8.6% in HBeAg-negative
ñ Patients with HBeAg-positive chronic patients at year 2), intermediate with
Hepatitis B should receive treatment adefovir (30% at 5 years of therapy in
when serum HBV DNA levels are ≥ 20,000 HBe-Ag-negative patients), and low with
IU/mL and ALT levels are elevated, entecavir in nucleoside-naïve patients
particularly 2-fold (<1% at year 4), but higher in lamivudine-
resistant patients (~42% at year 4). Oral
ñ Patients with HBeAg-negative chronic drugs with a high genetic barrier to
Hepatitis B should receive treatment resistance and/or high potency are
when serum HBV DNA levels are ≥2,000 generally preferred to reduce the
IU/mL and ALT levels are elevated likelihood of resistance. Interferon and
peginterferon therapy have not been
ñ Genotype testing should be used more associated with the development of
broadly. Knowledge of genotype may be resistance
useful in predicting natural history. For
example, genotype C HBV is associated ñ Potential future therapies for chronic
with more advanced disease and a higher Hepatitis B include pegylated interferon
rate of HCC than genotype B in Asians. and other nucleos(t)ide analogues,
For patients considering pegylated particularly tenofovir that is in late-stage
interferon therapy, genotype is useful in studies and shows promise of high
predicting response to therapy: HBV potency and low rates of resistance. The
genotype A responds much better than role of combination therapy is evolving,
genotype D (common genotypes in primarily to reduce the rate of resistance
whites), and genotype B responds with long-term therapy
somewhat better than genotype C
(common genotypes in Asia)

ñ All patients with chronic hepatitis B and

cirrhosis with HBV DNA levels ≥ 2,000
IU/mL should be treated. In addition, it
may be appropriate to treat all patients
with cirrhosis and viraemia regardless of
HBV DNA levels, particularly if ALT levels
are elevated. Preliminary evidence also
supports the use of combination
nucleos(t)ide agents in these patients,
and therapy should probably used be
long-term, even after HBeAg
seroconversion in HBeAg-positive patients

102
EExxaam
mpplleess ooff ttrreeaattm
meenntt aallggoorriitthhm
mss ffoorr ssppeecciiffiicc ggrroouuppss wwiitthh HHBBVV iinnffeeccttiioonn iinncclluuddee::
UUSS TTrreeaattm
meenntt AAllggoorriitthhm m RReeccoom mm meennddaattiioonnss ffoorr TTrreeaattm
meenntt ooff HHBBeeAAgg--PPoossiittiivvee
oorr HHBBeeAAgg--NNeeggaattiivvee CCiirrrrhhoottiicc PPaattiieennttss
ñ HBV DNA < 2,000 IU/mL and compensated cirrhosis
- May choose to treat or observe
- Adefovir or entecavir preferred; pegylated interferon alfa-2a may be option in early
well-compensated cirrhosis

ñ HBV DNA ≥ 2,000 IU/mL and compensated cirrhosis

- Treat; adefovir or entecavir are first-line options
- Long-term treatment required, and combination therapy may be preferred
(adefovir or tenofovir plus lamividine, telbivudine or entecavir)

ñ HBV DNA < 200 IU/mL or ≥ 200 IU/mL and decompensated cirrhosis
- Combination therapy preferred (adefovir or tenofovir plus lamivudine,
telbivudine or entecavir)
- Long-term treatment required
- Wait-list for liver transplantation

Reference: Hepatitis Annual Update 2007 website:http://clinicaloptions.com/Hepatitis/AnnualUpdates

22000077 AAAASSLLDD GGuuiiddeelliinneess oonn M

Maannaaggeem
meenntt ooff CChhrroonniicc HHeeppaattiittiiss BB PPaattiieennttss wwiitthh
CCoom
mppeennssaatteedd CCiirrrrhhoossiiss
ñ Who to treat
- Patients who are HBeAg positive or negative
- Patients with HBV DNA > 2,000 IU/mL; no ALT specified
- Consider treating if ALT elevated for patients with HBV DNA < 2,000 IU/mL
- Observe for patients who are HBV DNA negative

ñ Drugs of Choice
- Adefovir or entecavir preferred

Reference: Hepatitis Annual Update 2007 website:http://clinicaloptions.com/Hepatitis/AnnualUpdates

103
22000077 AAAASSLLDD GGuuiiddeelliinneess oonn M
Maannaaggeem
meenntt ooff CChhrroonniicc HHeeppaattiittiiss BB PPaattiieennttss wwiitthh
DDeeccoom
mppeennssaatteedd CCiirrrrhhoossiiss
ñ Who to treat
- HBeAg positive or negative at any HBV DNA level

ñ Drugs of choice
- Combination of lamivudine or telbivudine plus adefovir or entecavir
monotherapy is preferred (interferons contraindicated)

ñ Duration of therapy
- Long-term

ñ Other recommendations
- Refer for transpalntation
Reference: Hepatitis Annual Update 2007 website:http://clinicaloptions.com/Hepatitis/AnnualUpdates

Pootteennttiiaall M
P Maannaaggeem
meenntt ooff HHeeppaattiittiiss BB AAnnttiivviirraall DDrruugg RReessiissttaannccee
Reessiissttaannccee TTyyppee
R SSttrraatte
eggyy
Lamivudine Continue lamivudine and add adefovir (preferred over switch to
adefovir) or tenofovir
Switch to emtricitabine/ tenofovir*

Adefovir Continue adefovir and add lamivudine or telbivudine (preferred

over switch to lamivudine or telbivudine)
Switch to or add entecavir (if no prior lamivudine resistance)
Switch to emtricitabine/tenofovir*

Entecavir Switch to or add adefovir or tenofovir*

Telbivudine Continue telbivudine and add adefovir or tenofovir*

Switch to emtricitabine/tenofovir*

* Not approved by the FDA for the treatment of Hepatitis B

Reference: Hepatitis Annual Update 2007 website:http://clinicaloptions.com/Hepatitis/AnnualUpdates

104
 Ad
A dvvaan
nttaag
geess aan
nddD
Diissaad
dvvaan
nttaag
geess o
off C
Cuurrrreen
ntt TTh
heerraap
piieess ffo
orr C
Chhrro
onniicc H
Heep
paattiittiiss B
B
Ag
A geen
ntt Ad
A dvvaan
nttaag
geess Diissaad
D dvvaan
nttaag
geess
Interferon alfa-2b ñ HBsAg loss rates ñ Parenteral administration
ñ Short treatment duration ñ Frequent adverse effects
ñ No drug resistance
Lamivudine ñ Oral administration ñDrug resistance common
ñ Excellent tolerance (~20%/yr and up to 70% with
ñ Use in ESLD* 4-5 yrs of therapy)
ñ Use in adefovir failures
Adefovir ñ Oral administration ñ 24-to 48-week HBV response less
ñ Excellent tolerance potent than entecavir and telbivudine
ñ Use in ESLD* ñ Drug resistance delayed and less
ñ Use in lamivudine failures common than with lamivudine, but
more common than with entecavir
with extended therapy (0% at Yr 1, 3%
at Yr 2, 11% at Yr 3, 19% at Yr 4, and
30% at Yr 5 of therapy in HBeAg-
negative patients)
Entecavir ñ Oral administration ñ Drug resistance: rare in nucleoside-
ñ Excellent tolerance naïve parents (estimated at < 1% at
ñ High potency in lowering Yr 4), but common in patients with
HBV DNA levels lamivudine resistance (estimated at
ñ Use in adefovir failures 6% at Yr 1, 14% at Yr 2, 33% at Yr 3,
and 42% at Yr 4)
Pegylated ñ HBsAg loss ñ Parenteral administration
Interferon ñ Fixed duration of treatment ñ Frequent adverse effects but
ñ No drug resistance less than recombinat standard
interferon
Telbivudine ñ Oral administration ñ Drug resistance: intermediate rates
ñ Excellent tolerance of drug resistance in treatment-naïve
ñ High potency in lowering patients (5.0% at Yr 1, and 21.6% at
HBV DNA levels Yr 2 in HBeAg-positive patients, and
8.6% at Yr 2 in HBeAg-negative
patients)

* ESLD, end-stage liver disease

Reference: Hepatitis Annual Update 2007-Emmet B. Keeffe, website:http://clinicaloptions.com/Hepatitis/AnnualUpdates

The authors of this book have made an effort treatment of CHC/B, should be decided in
to provide readers with essential information consultation with and monitored by a
on CHC and CHB treatment. However, specialist hepatologist.

105
Infections
in Thalassaemia Major

Infections are the second commonest cause
of death in thalassaemia major. Clinicians
involved in the care of thalassaemia will be
fully aware of this risk and the importance of
any intervention that may limit it (Rahav,
Volach et al, 2006). However, all medical and
nursing staff, including those with the
briefest interaction with patients with
thalassaemia, should have the same
awareness, as should patients themselves. A
basic outline of the effects of infection in
thalassaemia and their practical implications
are provided in Table 1 (see also Table 2 for
more blood-borne infections).

Blood
borne Relevance for severity Orientation for practical management
trans-
mission

Anaemia Splenectomy Iron Iron Vaccine Sensitive to broad Suspend Note

overload chelation available spectrum chelation
antibiotics if suspected

Parvovirus B19 ++ +++ - - - No - No Pregnancy

HIV +++ +- +? + - No - No
HBV +++ - - +? - Yes - No
HCV +++ - - ++ - No - No
CMV ++ + - ? - No - No Stem cell
transplant
Streptococcus - +? +++ - - Yes Yes Yes
pneumoniae
Meningococcus - - +++ - - Yes Yes Yes
Hemophilus - - +++ - - Yes Yes Yes
Influenzae
Klebsiella - + - + - No Yes Yes
Pseudomonas - + ++ + - No Yes Yes
Vibrio vulnificus - + - + - No Yes Yes
Escherichia coli - + - + - No Yes Yes
Salmonella - + + + - No Yes Yes
Yersinia + - - +++ +++ No No Yes deferrioxamine
enterocolitica
Mucor species - - - ++ ++ No No Yes Deferrioxamine-
Immunosup-
pression
Pythium - ++ +++ ++ - Yes No Yes? Farming
insidiosum

Table 1: A summary of the effects of infection in thalassaemia and their practical implications.

106
A patient with thalassaemia major must not
be considered as immuno-compromised per
se, particularly if the disease is well
compensated by treatment. On the other
hand, many alterations to the body’s immune
system have been described in thalassaemia,
including reduction in neutrophil numbers,
changes in number and function of natural
killer cells, increase in number and function
of CD8 suppress cells, occurrence of
macrophages, chemotaxis and phagocytosis
and interferon gamma production.
Even in the absence of any evidence-based
data on a direct relationship between these
alterations and the development of severe
infections in thalassaemia, it is recognised by
treating physicians through clinical
observations and practice that several factors
linked to the disease, its complications and
treatment may facilitate or aggravate the
severity of infections.
Where infection is suspected, the main
causes to be considered include:
ñ Splenectomy;
ñ Transmission of pathogens by blood
transfusion;
ñ Iron overload and
ñ Iron chelation.
Splenectomy
The major long-term risk after
splenectomy is overwhelming
sepsis. In older studies, the risk of post-
splenectomy sepsis in thalassaemia major is
increased more than 30-fold in comparison
with the normal population (Singer, 1973).
Modern preventative measures (see below)
have reduced this risk but the overall impact
of these measures is unclear.
107
The pathogens most commonly associated
with post-splenectomy sepsis are
encapsulated organisms, particularly:
ñ Streptococcus pneumoniae (accounting
for more than 75% of documented
bacterial infections in asplenic patients);
ñ Haemophilus influenzae, and;
ñ Neisseria meningitides.
IInnffeeccttiioonnss wwiitthh ggrraam
m--nneeggaattiivvee, rod-shaped
bacteria, notably Escherichia coli, Klebsiella
species (e.g., pneumoniae) and Pseudomonas
aeroginosa, occur with increased frequency
in asplenic patients and are often associated
with high mortality. Other gram-negative
organisms have also been implicated in post-
splenectomy sepsis.
PPrroottoozzooaann iinnffeeccttiioonnss due to Babesia have
been implicated in a fulminant haemolytic
febrile state in splenectomised patients, and
Maallaarriiaa iiss rre
M eppe
eaatte
ed dllyy rre
eppo
orrtte
edd aass m
moorree sseevveerree
in asplenic people with an increased risk of
death (Boone and Watters, 1995)
(for blood-borne infections see Table 2).
Iron overload
The role of iron load in
susceptibility to infection has
not yet been fully established in
clinical trials. It is clear, however,
that a variety of micro-
organisms are more pathogenic
in the presence of iron
overload.
The best-described association between
bacterial infection, iron and iron chelators
involves Yersinia enterocolitica (see below).
Many other organisms, such as Klebsiella
species, Escherichia coli, Streptococcus
pneumonia, Pseudomonas aeroginosa,
Legionella pneumophila and Listeria
monocytogenes, have been shown to have
increased virulence in the presence of excess
iron. On the other hand, phagocytic
efficiency, tested in vitro, is impaired in
patients with thalassaemia with iron overload
compared with individuals without
thalassaemia.
Several observations in vivo indicate that
infections are more frequent or severe in
patients with iron overload either related to
genetic haemochromatosis or to
transfusions, as in thalassaemia. The role of
iron overload in aggrevating Mucormycosis in
bone marrow transplanted patients has been
demonstrated.
IIrro
onn cchheellaattoorrss
A potential risk of natural siderophores, as in
deferoxamine, is that they may be used by
micro-organisms as a source of iron, and so
become more virulent. This has been
demonstrated in vitro and in vivo for Yersinia
enterocolitica, which has a receptor on the
outer membrane that efficiently binds
ferrioxamine.
A clear relationship between Mucormycosis
and desferrioxamine has been reported in
dialysis patients but only sporadically in
thalassaemia. Similar observations have been
reported for Rhizopus infections.
Specific infections
Viral Infections
Huum
H maann PPaarrvvoovviirruuss BB--1199 ((HHPPVV BB1199))
Parvovirus B-19 is a common pathogen that
may cause a wide range of clinical
108
manifestations: erythema infectiosum or
fifth disease in children, mild to severe
aplastic crises and myocarditis. During
pregnancy severe foetal anaemia and
myocarditis may lead to lethal non-immune
hydrops fetalis.
In patients with an already shortened red cell
lifespan (15-20 days) combined with anaemia
due to haematological disorders such as
spherocytosis, sickle-cell anaemia,
autoimmune haemolytic anaemia and
thalassaemia, B-19 infection may cause an
acute, life-threatening red cell aplasia,
commonly referred to as “transient aplastic
crisis”. The cessation of erythropoiesis lasts
for 5-7 days and haematologically
complicates chronic haemolytic anaemia. The
condition is characterised by:
ñ A variable fall in haemoglobin;
ñ Disappearance of reticulocytes from
peripheral blood (< 0.2%);
ñ A virtual absence of red blood cell
precursors in the bone marrow at the
beginning of the crisis and
ñ B-19 DNA viraemia.
Following recovery from an acute B-19
infection, patients are typically immune to
further infections by the agent. Where
patients are immunosuppressed (e.g.
transplanted, HIV-infected) and fail to mount
an effective antibody response to the virus,
the infection may be persistent and may
mimic or trigger autoimmune inflammatory
disorders.
B-19 may be transmitted via the respiratory
system or blood derivates. The incidence of
B-19-infected individuals with persistently
detectable levels of B-19 DNA, despite the
presence of specific IgG, is estimated at 1%
of blood donors. The resulting risk of
infection is estimated at between 1/625 and
1/50,000, depending on a number of factors
(including detection methods, seasonal
outbreaks, B-19 DNA load of the donor and
co-presence of B-19 IgG antibodies) (Lefrere,
Maniez-Montreuil et al, 2006). There is
currently no general rule on action to be
taken to prevent blood-borne transmission of
B-19 in high-risk populations, including
thalassaemia major patients.
Management of acute B-19 crises includes
close monitoring and adequate blood
transfusion adjustment. Immunoglobulin
administration may be beneficial in chronic
illness.
Human
Immunodeficiency
Virus (HIV)
RRiisskk ooff ttrraannssffuussiioonn--aassssoocciiaatteedd
iinnffeeccttiioonn
Although sensitive and specific laboratory
serologic tests became available soon after
the discovery and description of HIV, a
number of patients with thalassaemia who
received transfusions previous to HIV
screening have been infected. Many more
are still being infected in countries where
effective protective measures for blood
safety, including blood donor selection and
testing, have yet to be applied.
The prevalence of HIV infection
in thalassaemia varies greatly
worldwide, from <1% to >20%. In Italy,
for example, the prevalence is currently 1.7%
while in Cyprus it is 0.17%. The rate of HIV
infection as with other infections among
transfused patients depends on the timing of
introduction and quality of public health
109
policies addressing the problem, as well as on
the local prevalence of blood transmissible
pathogens.
With the use of standard
procedures for prevention, it is
possible to keep the risk of HIV
transmission very low; with the
use of the most sensitive
screening measures, it is
possible to lower this risk still
further.
Naattuurraall hhiissttoorryy
N
In the absence of treatment, the median
time from HIV seroconversion to the onset of
AIDS in transfused patients is about 7-11
years. Factors affecting progression are
symptomatic primary infection, age at
infection and viral load (HIV1-RNA
concentration in plasma).
Maannaaggeem
M meenntt ooff HHIIVV iinn tthhaallaassssaaeem
miiaa
A detailed account of the treatment and
monitoring of HIV patients is beyond the
scope of this book. Patients with
thalassaemia identified with HIV infection
should be managed in collaboration with an
infectious diseases’ unit with expertise in HIV.
Advances in drug treatment have
revolutionised the care of patients from
strategies aimed at preparing patients to die
to treatments that may fully control the
disease. However, accessing the best—and
most expensive—treatment will depend on
local conditions.
SSp
peecciiaall ccoonnssiiddeerraattiioonnss iinn tthhaallaassssaaeem
miiaa
Although antiretroviral therapy should be
administered to patients with thalassaemia
major based on the same general guidelines
used for other infected non-thalassaemic
individuals, side effects such as endocrine
dysfunction and diabetes could be more
significant.
Viirruusseess
V
enveloped HIV-1, HIV-2, HTLV-I, HTLV-II
CMV, HHV-6, HHV-8, EBV
HBV, HCV, HGV
non-enveloped HAV; parvo B19, TTV

Baacctteerriiaa
B
Gram-positive Staphylococcus epidermidis
Staphulococcus aureus
Coagulase negative stachylococci
Streptococcus viridans
Enterococcal species
Bacillus cereus
Gram-negative Yersinia enterocolitica
Pseudomonas fluorescens
Salmonella enteritidis
Citrobacter freundii
Serratia marcescens
Enterobacter cloacae
Coliform bacteria
Flavobacterium species

Prroottoozzooaa
P
Plasmodium vivax Trypanosoma cruci
Plasmodium falciparum Babesia microti
Plasmodium malarias Toxoplasma gondii
Plasmodium ovale Leishmania donovani

Otthheerrss
O
Treponema pallidum
Prions

Abbreviations in Table 2:
HIV: human immunodeficiency virus, HTLV: human T-cell leykaemia/lymphoma virus; CMV: cytomegalovirus,
HHV: human herpes virus; EBV: Epstein-Barr virus; HBV: hepatitis B virus; HCV: hepatitis A virus; parvo B 19:
parvovirus B19;TTV: transfusion-transmitted virus. Ref. A. Modell, ZLB Central Laboratory Swiss Red Cross,
Bern, Switzerland 2000.

Table 2: Transfusion transmitted pathogens

110
There is general agreement that a patient’s
iron status influences the outcome of HIV-1
infection. In HIV-infected patients with
thalassaemia major, the rate of progression
of HIV was significantly faster in patients with
low level of chelation with deferoxamine and
higher serum ferritin concentrations. Further
to the capacity to remove iron, iron
chelators, mainly deferiprone, show
interesting antiviral properties in vitro, but
there is so far no evidence of a direct
antiviral effect. Optimal control of iron
overload with iron chelation is therefore
recommended in HIV-positive patients with
thalassaemia and the choice of chelator
should take into consideration the above
data as well as the individual’s needs.
Because of an increased risk of neutropenia,
deferiprone should be used with caution in
such cases.
While there is no direct evidence that
splenectomy facilitates the progression of
HIV infection, a decision to perform
splenectomy in an HIV-positive patient with
thalassaemia should be made with extreme
caution. Of particular concern is the removal
of an important fraction of T cells and the
potential for overwhelming infection in
immuno-compromised patients.
Human
Cytomegalovirus
(HCMV)
Transfusion-associated CMV has a wide
clinical spectrum. In the immuno-competent
patient-host, it is usually sub-clinical or may
appear as an infectious mononucleosis-like
syndrome. In the immuno-compromised
host, however, such as bone marrow or
111
organ transplant recipients, CMV infection
constitutes a major, if not one of the most
important causes of morbidity and mortality.
Unlike the case with other infectious agents,
the presence of serum CMV IgG antibodies
does not preclude infectiousness. It is
estimated that approximately 2-12% of anti-
CMV positive healthy donors are infectious,
i.e. can transmit the virus.
The increasing use of bone marrow
transplantation as a treatment for
thalassaemia demands special attention to
the serological status of CMV. Prevention of
transmission through blood products is
effectively achieved by the use of anti-CMV
negative donation, but this policy may be
applied only in special conditions, such as
stem cell transplantation, because exclusion
of CMV positive donors (50-75% of the adult
population are anti-HCMV positive) will affect
significantly the national pool of blood
supply. As CMV is WBC-associated virus, the
widespread use of leucocyte filtration, in
recent years recommended for all patients
with thalassaemia, no matter what their
condition, constitutes an effective
preventative measure.
Bacterial infections
Yersinia enterocolitica
Mechanisms of infection
The Yersinia organism is most commonly
transmitted by the ingestion of
contaminated food, meat, milk or water,
although it is commensal in healthy
individuals. On rare occasions it becomes
virulent, crossing the intestinal membrane
and provoking life-threatening infections. The
best known factor predisposing the organism
to virulence is the availability of a large
amount of iron, as is the case in severe iron
overloaded patients or in those undergoing
iron chelation with desferrioxamine (Vento,
Cainelli and Cesario, 2006), as described
above.
Transfusion-associated transmission of
Yersinia enterocolitica may occur from
apparently healthy donors, albeit rarely, as
the organism can survive and multiply under
normal storage conditions (4oC). The
mortality rate among recipients of
contaminated blood is >50%.
Clliinniiccaall m
C maanniiffeessttaattiioonnss
The clinical manifestations of Yersinia
infection depend on the age and health of
the host. While variable, these manifestations
are severe in over 80% of cases involving
patients with thalassaemia. Fever is the most
common presenting feature, often
associated with abdominal pain and diarrhoea
or vomiting. Extra gastrointestinal
manifestations, such as acute respiratory
distress syndrome, arthralgia and skin rashes,
are also sometimes seen.
The most typical clinical picture is an ‘acute
abdomen’ that mimics and may even be
indistinguishable from acute
appendicitis/peritonitis, caused by
mesenteric lymphadenitis. It is important to
have this critical point in mind, as the two
conditions require a very different
antimicrobial approach.
The most dangerous condition is septicaemia,
which, in the absence of specific antibiotics,
may be fatal in more than 50% of cases.
Complications may include abdominal,
hepatic or splenic abscess, intussusception,
nephritis, ileo-psoas abscess and meningitis.
112
Post-infection sequelae include erythema
nodosum and reactive arthritis, mostly in
adults.
LLaab
boorraattoorryy ddiiaaggnnoossiiss
Specific culture conditions (at 22oC for 48
hours) are necessary to identify Yersinia
species and in this context, the treating
physician should inform the laboratory of
his/her suspicions in order to enable it to
proceed to the correct culture conditions for
blood and stool samples.
Serologic tests for Yersinia are problematic
because of the likelihood of cross-reactivity.
However, a four-fold rise in IgG titres in serial
samples obtained 15 days apart may be
suggestive of recent infection. Overall, the
pickup rate for stool, blood culture and
seroconversion is low. In some cases
diagnosis may only be made after obtaining
samples of affected tissue (e.g. gut, lymph
node).
TTrre
eaattm
meenntt
The basic but most important point is that
anyone involved in the care of a patient with
thalassaemia with the above-described
symptoms must be aware of the risk of
Yersinia infection and its management.
Simple information leaflets issued by the
treating centre and carried by the patient or
parents of children may be of help, especially
when travelling.
In the absence of a quick reliable laboratory
diagnosis, treatment must begin on the basis
of clinical suspicion. In such cases, the
following measures should be taken:
ñ Stop iron chelation therapy
immediately
ñ Obtain suitable laboratory
samples
ñ Commence antibiotic
treatment immediately
Yersinia species are typically intracellular and
therefore antibiotics with good intracellular
penetration are recommended. In mild
suspected cases, oral ciprofloxacin is the
recommended first line treatment. In
severely unwell patients, immediate
parenteral therapy is mandatory with the
same drug. I.v. trimethoprim-
sulfomethoxazole or cephalosporins may be
added or used as an alternative.
It is generally advisable to continue
antibiotics for at least two weeks after
proven infection. Iron chelation should not
be restarted until the patient has been
asymptomatic for over a week. Some
patients relapse after restarting
desferrioxamine. Whenever possible, an
alternative chelator should be prescribed. In
contrast to deferoxamine, the synthetic
chelators, deferiprone and deferasirox do not
seem to trigger Yersinia enterocolitica
virulence.
Other bacterial
infections
Other micro-organisms that may cause
severe infections and should be seriously
considered in the management of unwell
patients with thalassaemia include Klebsiella
species, Pseudomonas species, Vibrio
vulnificus, Escherichia coli, Salmonella species
and Mucor species. Recent papers also report
113
infection by Campylobacter and
Chryseobacterium meningosepticum. Despite
the in vitro data for micro-organisms such as
Listeria monocytogenes and Salmonella,
there is no in vivo evidence that the
prevalence and severity of related infections
in thalassaemia is higher than in the non-
thalassaemic population.
Klebsiella species
Klebsiella infections in thalassaemia major
and even more in HbE/b-thal are associated
with high mortality and morbidity rates are
occasionally reported in the literature. In a
large retrospective study including 160
patients, the prevalence was reported to be
7.5%, with a clinical spectrum including
sinusitis, intracranial infection, meningitis,
septicaemia and pyogenic abscesses of the
liver, lung and kidney. Mortality rate was 16%,
and permanent neurological sequelae 25%.
Predisposing factors seemed to be iron
overload and liver function derangement
(Chung et al, 2003).
Pseudomonas aeruginosa in
thalassaemia constitutes the most common
pathogen-related infection to the central
venous catheter. It may cause severe
infections such as meningitis (Wang, Lin et al,
2003). Splenectomy seems to be the main
predisposing factor.
Melioidosis of the musculoskeletal system
caused by Pseudomonas pseudomallei has
been sporadically reported in thalassaemia.
Vibrio vulnificus is sporadically reported as
the cause of severe infections, including
septicaemia, wound infections and meningitis
in patients with thalassaemia in South-East
Asia. Iron overload is likely to be the most
important predisposing factor.
Escherichia coli is not reported as a
significant pathogen in thalassaemia major,
being clinically significant in patients with
HbE/‚-thalassaemia, as for Klebsiella.
Salmonella species
Many in vitro data suggest that patients with
thalassaemia, particularly those that are
splenectomised, have a decreased opsonic
activity and phagocytic efficiency against
Salmonella species. Overall, however, in vivo
the prevalence of Salmonella infections does
not seem higher than in normal subjects.
Haemophilus influenzae
Thalassaemics appear to have a lower natural
immunity to this microorganism, however
vaccine-induced immunity seems to be
effective.
Fungi
Mucor species
Mucormycosis or Zygomycoses are
opportunistic fungal infections caused by
ubiquitous organisms of the Zygomycetes
class. The relationship with conditions of iron
overload and deferoxamine use is well
known.
In thalassaemia, severe infections have been
observed only in immunocompromised
subjects after stem cell transplantation.
Pythiosum insidiosum
Pythiosis is caused by the oomycete
Pythium insidiosum. Human pythiosis has
been reported in Thailand among
farmers and their relatives although
zoonosis is prevalent in many other
parts of the world. The most
severe forms (cutaneous, vascular
and disseminated pythiosis)
114
have been observed in patients with
thalassaemia (Krajaejun et al, 2006).
The disease has high rates of morbidity and
mortality and early diagnosis and prompt
initiation of effective treatment are
extremely important. The organism does not
respond to antifungal agents. A vaccine has
been recently developed which has
demonstrated at this preliminary stage
effectiveness in patients with thalassaemia.
(Krajaejun et al, 2006)
Common infections
not related to
thalassaemia
Dengue
Haemorragic fever due to d de
enng
guue
e vi r a l
iin
nffe
eccttiio
onn is endemic in Southeast Asian
countries where thalassaemias are also
common. In an uncontrolled study from
Thailand, dengue was reported to be
frequent and more severe than expected in
patients with thalassaemia, underscoring the
need for providing special awareness of
proper diagnosis and management,
particularly in these regions of the world.
Helicobacter pylori
In one study of patients with thalassaemia
with recurrent abdominal pain, the
prevalence of H. pylori infection was not
statistically different from matched non-
thalassaemic healthy subjects.
Malaria and
thalassaemia
There is evidence that in most cases, being a
healthy carrier of a haemoglobinopathy
provides protection against the clinical
severity of malaria.
However, the same is not true for the
homozygous state. Patients with ‚-
thalassaemia major or
intermedia are not protected
from severe malaria and may
indeed be more prone to severe
forms of the disease, depending
on their clinical condition
(anaemia, splenomegaly, iron
overload and other
complications). Patients must
therefore be provided with
specific advice for the
prevention of malaria before
and during periods of travel in
endemic areas.
115
∆ransfusion-related
Malaria and Chaga’s
disease
Post-transfusion malaria and Chaga’s disease
have been known for more than 50 years.
Plasmodium species and Trypanosoma cruzii
may remain viable for at least two weeks in
refrigerated blood components as well as in
frozen plasma, and in this context, there are
great concerns that increased tourism to and
from endemic countries might increase the
frequency of transfusion-transmission of
these pathogens. Both infections remain an
important topic for blood transfusion
services, and national standards including
donor selection have been drawn up based
on WHO, Council of Europe, EU and North
American Authorities’ recommendations, in
order to prevent or minimise the
transmission of these diseases.
Splenectomy in
‚-thalassaemia
Many patients with thalassaemia major
require splenectomy. However, optimal
clinical management from the time of
diagnosis may delay or even prevent
hypersplenism, thereby increasing the
efficiency of transfusion therapy and
reducing the need for splenectomy.
Throughout the care of the patient with
thalassaemia, the size of the spleen should
be carefully monitored on physical
examination and, as needed, by
ultrasonography.
Splenectomy should be considered when:
ñ Annual blood requirements exceed 1.5
times those of splenectomised patients,
provided that they are on the same
transfusion scheme and have no other
reasons for increased consumption. Such
reasons include new alloantibodies,
infection, and changes in the haematocrit
of the transfused units. For patients
maintaining a pre-transfusion Hb level of
about 10 g/dl, this increase in transfusion
requirements represents consumption of
more than 200-220 ml of red cells
(assuming haematocrit of transfused cells
is 75%)/kg/year (Modell, 1977; Cohen,
1980). The rate of iron overload should
also be taken into consideration. For
patients who maintain effective chelation
therapy despite increased blood
requirements, splenectomy may be
unnecessary. For patients with increasing
iron stores despite good chelation
therapy, reduction in the rate of
transfusional iron loading by splenectomy
may be an important component of the
overall management of iron overload.
ñ Splenic enlargement is accompanied by
symptoms such as left upper quadrant
pain or early satiety. Massive
116
splenomegaly causes concern about
possible splenic rupture.
ñ Leucopenia or thrombocytopenia due to
hypersplenism causes clinical problems
(e.g. recurrent bacterial infection or
bleeding).
Splenomegaly due to periods of under-
transfusion with blood of inappropriately low
haemoglobin may be reversible. Before
considering splenectomy in this situation, the
patient should be placed on an adequate
transfusion programme for several months
and then re-evaluated.
It is generally advisable to delay
splenectomy until patients are
at least five years old because
of the increased risk of
overwhelming sepsis below this
age (see below).
Surgery
The two surgical techniques most commonly
employed for total splenectomy are the open
and laparoscopic approaches. The
laparoscopic approach requires a longer
operative time and may not be practical for
patients with very large spleens, but the
recovery period is shorter and there is
virtually no surgical scar. Many surgeons now
have extensive experience with this
approach.
In some centres, p
paarrttiiaall ssp
plle
enneeccttoom
myy is used
to preserve some of the immune function of
the spleen while reducing the degree of
hypersplenism (De Montalembert, 1990). The
long-term success of this approach is still
undergoing evaluation. In particular, the
likelihood of splenic re-growth and the
volume of splenic tissue required to preserve
immune function are two questions
outstanding. Any surgery on the spleen
should include a careful search for accessory
spleens.
Reduction of splenic tissue by e
emmb
boolliissaattiio
onn is
a less invasive approach to hypersplenism
than complete or partial surgical
splenectomy (Pringle, 1982). However, this
approach has not gained wide acceptance
and may be complicated by fever, significant
pain and the possible need for a subsequent
total splenectomy. Embolisation does not
permit a search for accessory spleens.
An evaluation for gallstones should be
performed prior to surgery, especially if the
patient has experienced symptoms
suggestive of biliary tract disease. In some
cases, positive findings will lead to
cholecystectomy at the same time as
splenectomy. Removal of the appendix at the
time of splenectomy may prevent later
problems in distinguishing infection with
Yersinia enterocolitica from appendicitis.
Splenectomy also provides a good
opportunity for a liver biopsy to assess the
liver histology and iron concentration.
Appropriate immunisations
should be administered at least
2 weeks before splenectomy
(see below).
Coom
mpplliiccaattiioonnss ooff sspplleenneeccttoom
myy
C Malaria is reportedly more severe in asplenic
Peri-operative complications include
bleeding, atalectasis and subphrenic abscess.
Postoperative thrombocytosis is common,
with platelet counts often reaching
1,000,000-2,000,000/mm3. Because patients
with thalassaemia may have an increased
117
thrombotic tendency, special consideration
should be given to the use of low-dose
aspirin (80 mg/kg/d) for patients with high
platelet counts, or the use of anticoagulation
for patients with a history of previous
thrombosis or other risk factors.
The major long-term risk after splenectomy is
overwhelming sepsis. In older studies, the risk
of postsplenectomy sepsis in thalassaemia
major is increased more than 30-fold in
comparison with the normal population
(Singer, 1973). Modern preventative
measures (see below) have reduced this risk
but the overall impact of these measures is
unclear. The pathogens most commonly
associated with postsplenectomy sepsis are
encapsulated organisms (Pedersen, 1983),
particularly:
ñ Streptococcus pneumoniae (accounting
for more than 75% of documented
bacterial infections in asplenic patients)
ñ Haemophilus influenzae
ñ Neisseria meningitidis
Infections with gram negative, rod-shaped
bacteria, notably Escherichia coli, Klebsiella
and Pseudomonas aeroginosa, occur with
increased frequency in asplenic patients and
are often associated with high mortality.
Other gram-negative organisms have also
been implicated in postsplenectomy sepsis.
Protozoan infections due to Babesia have
been implicated in a fulminant haemolytic
febrile state in splenectomised patients.
people (Boone, 1995) and carries an
increased risk of death.
Characteristics of overwhelming post-
splenectomy sepsis include the sudden onset
of fever and chills, vomiting and headache.
The illness rapidly progresses to hypotensive
shock, and is commonly accompanied by
disseminated intravascular coagulation.
Postsplenectomy sepsis has many of the
features of adrenal haemorrhage
(Waterhouse-Friederichsen syndrome). The
mortality rate for such infections is
approximately 50%, despite intensive
supportive measures. Therefore, early
intervention on the basis of clinical suspicion,
even in the absence of many of the above
findings, is critical.
The risk of overwhelming postsplenectomy
infection varies with:
ñ Age—risk is very high in children <2 years
of age. However, fulminant bacteraemia
has been reported in adults as much as
25-40 years after splenectomy.
ñ Time since splenectomy—the greatest risk
appears to be in the period 1-4 years
after surgery
ñ Immune status of patient
Preventative
measures
The three types of protective measures a
physician can utilise to prevent post-
splenectomy sepsis include:
1. Immunoprophylaxis
2. Chemoprophylaxis
3. Patient education
Immunoprophylaxis
Vaccination against Streptococcus
pneumoniae is a critical step in preventing
overwhelming infection after splenectomy
118
(Landgren, Bjorkholm et al, 2004). The
currently available pneumococcal vaccine is a
23-valent polysaccharide vaccine that can be
given subcutaneously or intramuscularly. A
conjugate vaccine will be available shortly.
The protection rate with the 23-valent
vaccine is 70-85%. Pneumococcal vaccine
should be given at least 2 weeks in advance
of a splenectomy and then in 3-5 years. The
immune response to this polysaccharide
vaccine is poor in children less than two years
of age. Children vaccinated under the age of
two should be re-vaccinated at age two.
Patients who underwent splenectomy
without being given pneumococcal vaccine
may still benefit from vaccination post-
splenectony.
If not administered as part of routine
childhood immunisations, Haemophilus
influenzae vaccine should be given to
patients before they undergo splenectomy
and should also be given to splenectomised
patients (Spoulou, Tsoumas et al, 2006).
Meningococcal polysaccharide vaccine should
also be administered to patients who are
undergoing splenectomy and to non-
immunised, previously splenectomised
patients.
These vaccines can be given at the same
time in different syringes at different sites.
Yearly administration of influenza virus
vaccine is recommended to prevent this
febrile illness that might otherwise require
intensive evaluation and management of a
febrile episode in the splenectomised host
with thalassaemia (see below).

Chemoprophylaxis
Chemoprophylaxis with oral penicillin, 125
mg b.i.d. for children under two years, and
250 mg b.i.d. for children two years and over
is recommended to reduce the risk of post-
splenectomy sepsis. Alternative antibiotics for
patients unable to take penicillin include
amoxicillin, trimethoprim-sulfomethoxazole
and erythromycin. All splenectomised
children under five years of age should be
treated with prophylactic antibiotics. The
value of chemoprophylaxis after this age is
unproven. Some clinicians continuously treat
all splenectomised patients with prophylactic
antibiotics, irrespective of age, while others
treat patients whose spleens are removed
after the age of five years only for the first
two years after splenectomy. The use of
prophylactic antibiotics will need to be
regularly re-evaluated as improved vaccines
become available and as new data regarding
antibiotic-resistant bacteria are developed.
The importance of compliance with
prophylactic antibiotics should be stressed
repeatedly to patients and parents. However,
the limitations of antibiotic prophylaxis must
also be emphasised. Patients and parents
should recognise that chemoprophylaxis does
not prevent all cases of post-splenectomy
sepsis: the risk of death from febrile illnesses
remains, and rapid evaluation of febrile
episode is essential (see below).
Education
Patient and parent education can be highly
effective in preventing overwhelming post-
splenectomy infection. Physicians should
emphasise to the patient and parents the
importance of recognising and reporting
119
febrile illnesses and seeking immediate
medical attention. For all febrile episodes,
the physician should strongly consider:
Evaluating the patient, including a
complete physical examination
Obtaining blood and other cultures as
indicated.
Beginning treatment with an
antimicrobial regimen effective against
Streptococcus pneumoniae and Neisseria
meningitidis.
If bacteraemia is suspected, the patient
should be treated with parenteral antibiotics
and observed in a medical facility until the
cultures are evaluated.
Patients also need to be made aware of the
potential for travel-related infections such as
babesiosis and malaria, as well as the risk
inherent in travel to an area where medical
care is not readily accessible. In the latter
case, an appropriate antibiotic should be
made available for the patient to carry with
him/her.
Patients should be reminded always to alert
consulting physicians about their
splenectomised status.
Other complications which have been
recognized in splenectomised patients
include:
ñ Thrombophilia
ñ Pulmonary hypertension
T hr om b o p h i l i a
Thrombophilia- this is a complication
which occurs more frequently in thalassaemia
intermedia (see relevant chapter), but a
higher risk is seen in splenectomised patients.
The phenomenon of increased coagulability is
related to the fact that damaged red cells
normally removed by the spleen, persist in
the circulation and trigger mechanisms of
Thrombin generation (see Figure 2 Chapter
11: Thalassaemia Intermedia and HbE). In
postsplenectomy patients markers of
thrombin generation such as thrombin AT III
(TAT) complexes, prothrombin fragments
(F1,2) fibrinopeptide A (FPA) and D-dimer
should be assessed annually, and anti-
coagulant prophylaxis prescribed where
indicated.

P ul m on a r y h y p e r t e n s i on
Pulmonary hypertension – this
complication is more frequent in
thalassaemia intermedia, but it is also
increasingly identified in thalassaemia major,
especially in splenectomised patients.

120
Thalassaemia Intermedia
and HbE
Definition
The clinical phenotypes of thalassaemia
intermedia (TI) lie between those of
thalassaemia minor (heterozygous state) and
major (homozygous state), although there is
substantial clinical overlap between the three
conditions. TI was first described in 1955 by
Rietti-Greppi-Micheli, who referred to
patients as being ‘too haematologically
severe to be called minor, but too mild to be
called major’.
Thalassaemia intermedia encompasses a wide
clinical spectrum. Mildly affected patients are
completely asymptomatic until adult life,
experiencing only mild anaemia and
maintaining haemoglobin levels between 7-
10g/dL. These patients require only
occasional blood transfusions, if any. Patients
with more severe thalassaemia intermedia
generally present between the ages of 2 and
6 years, and although they are able to survive
without regular transfusion therapy, growth
and development can be retarded. The
clinical spectrum of thalassaemia intermedia
indicates the need for an individualised
treatment approach. Despite the availability
of a number of treatment options, the lack
of clear guidelines can present a significant
clinical challenge (Taher, Ismaeel and
Cappellini, 2006; Camaschella and Cappellini,
1995).
Mechanism of TI
The pathophysiology of thalassaemias is
based on an imbalance of globin-chain
synthesis. In the case of ‚-thalassaemia
intermedia, the imbalance is greater than
that seen in ‚-thalassaemia trait and less than
that of ‚-thalassaemia major.
121
Most TI patients are homozygotes or
compound heterozygotes for ‚-thalassaemia,
meaning that both ‚-globin loci are affected.
The mild clinical characteristics of TI
compared with thalassaemia major are
primarily the result of the following three
mechanisms:
ñ inheritance of a mild ‚+ mutation;
ñ presence of a polymorphism for the
enzyme Xmn-I in the GÁ- promoter
region, associated with increased HbF;
and
ñ co-inheritance of ·-thalassaemia on the
‚-globin locus.
The phenotype of TI may also result from the
increased production of ·-globin chains,
occurring either by the triplication of ·
genotype associated with ‚-heterozygosity,
or by the interaction of ‚- and ‰‚-
thalassaemia (Taher, Ismaeel and Cappellini,
2006).
Analysis of the genotypes of patients with
thalassaemia intermedia is important for an
early diagnosis of the milder disease, thus
avoiding unnecessary blood transfusions.
Predicting phenotype from genotype in TI is
still difficult, due to the interaction of
genetic and environmental factors. Primary
genetic modifiers are the numerous genetic
alleles at the ‚-chain locus, which can cause
either complete or marked reduction in ‚-
chain synthesis. Secondary genetic modifiers
are those that have a direct effect on
modifying the amount of excess ·-chains
(inheritance of abnormal ·- or Á-chain
genes). Tertiary modifiers are polymorphisms
occurring at loci involved in bone, iron and
bilirubin metabolism that can affect clinical
expression. Relevant environmental factors
include social conditions, nutrition and the
availability of medical care (Taher, Ismaeel preventing or delaying hypersplenism and
and Cappellini, 2006). reducing the risk of red cell antigen
sensitisation. Unfortunately, however, the
accurate identification of these two
Differential diagnosis phenotypes at the onset is remarkably
difficult. Nevertheless, a careful analysis of
Differentiation at presentation between clinical, haematological, genetic and
thalassaemia major and thalassaemia molecular data may allow a reasonable
intermedia is essential for designing conclusion for treatment (Taher, Ismaeel and
appropriate treatment for an individual Cappellini, 2006; Wainscoat, Thein and
patient. The accurate prediction of a mild Weatherall, 1987; Weatherall, 2001). (see
phenotype may avoid needless transfusions Table 1 for an outline of the major
and their complications, while the timely differences between thalassaemia intermedia
diagnosis of thalassaemia major will allow an and major).
early start to a transfusion programme, thus

Heellppffuull cclluueess iinn ddiiffffeerreennttiiaattiinngg bbeettwweeeenn tthhaallaassssaaeem

H miiaa m
maajjoorr aanndd
tthhaallaassssaaeemmiiaa iin
ntteerrm
meeddiiaa
Thalassaemia major Thalassaemia intermedia
more likely more likely
CClliinniiccaall
Presentation (years) <2 >2
Hb levels (g/dl) 6-7 8-10
Liver/ spleen enlargement Severe Moderate to severe

HHaaeem
maatto
ollooggiiccaall
HbF (%) >50 10-50 (may be up to 100%)
HbA2(%) <4 >4

GGeenneettiicc
Parents Both carriers of high One or both atypical carriers:
HbA2 ‚-thalassaemia - High HbF ‚-thalassaemia
- Borderline HbA2

Mo
M olle
eccu
ullaarr
Type of mutation Severe Mild/silent
Coinheritance of No Yes
·-thalassaemia.
Hereditary persistence of No Yes
fetal haemoglobin
‰‚ thalassaemia No Yes
GÁ XMN1 Polymorphism No Yes

Table 1

122

Pathophysiology of
Thalassaemia
Intermedia (TI)
Three main factors are responsible for the
clinical sequelae of thalassaemia intermedia:
ineffective erythropoiesis, chronic anaemia
and iron overload. The severity of clinical
sequelae depends primarily on the underlying
molecular defects. a-chains are highly
unstable and precipitate into erythroid
precursors in the bone marrow, causing
membrane damage and cell death (i.e.
ineffective erythropoiesis). Hypertrophy of
erythroid marrow in medullary and
extramedullary sites, a consequence of
severe ineffective erythropoiesis, results in
characteristic deformities of the skull and
face and may also cause cortical thinning and
pathological fractures of long bones. The
Figure 1: Pathophysiological sequelae of untreated thalassaemia and corresponding clinical
manifestations
123
degree of ineffective erythropoiesis is the
primary determinant of the development of
anaemia, while peripheral haemolysis of
mature red blood cells and an overall
reduction in haemoglobin synthesis are
secondary determinants.
Complications and
management of TI
In addition to the defining symptoms of
thalassaemia intermedia, which are seen to a
lesser or greater extent in other forms of
thalassaemia, patients with thalassaemia
intermedia experience a number of specific
complications that are rare in thalassaemia
major. Figure 1 highlights the multitude of
complications in untreated thalassaemia
(Taher, Ismaeel and Cappellini, 2006;
Cappellini, Cerino et al, 2001).
Splenomegaly and
Splenectomy
Splenectomy is now uncommon and is mainly
performed late in life. The main indications
for splenectomy in thalassaemia intermedia
are a significant enlargement of the spleen
and a decrease in mean haemoglobin levels
in the absence of other transient factors
such as infection (Taher, Ismaeel and
Cappellini, 2006; Cappellini, Cerino et al,
2001; Borgna-Pignatti, Rigon, Merlo et al,
2003; Galanello, Piras, Barella et al, 2001). As
for the type of surgery, the laparoscopic
approach is safe and feasible and preferred
over open surgery, as a minimally invasive
alternative that may become the treatment
of choice in ‚-thalassaemia patients who
require concurrent operations. During
splenectomy, surgeons should assess the
gallbladder for any stones and perform
cholecystectomy whenever gallstones are
found (Leandros et al, 2006).
Gall stones and
cholecystectomy
Gallstones are much more common in
thalassaemia intermedia than in thalassaemia
major as a result of ineffective erythropoiesis
and peripheral haemolysis. Similar to
laparoscopic splenectomy, laparoscopic
cholecystectomy has more favourable and
feasible outcome than open cholecystectomy
(Taher, Ismaeel and Cappellini, 2006;
Cappellini, Cerino et al, 2001; Borgna-
Pignatti, Rigon, Merlo et al, 2003; Galanello,
Piras, Barella et al, 2001; Leandros et al,
2006).
124
Extramedullary
haematopoiesis
Extramedullary haematopoiesis is a
compensatory mechanism where bone
marrow activity increases in an attempt to
overcome the chronic anaemia of
thalassaemia intermedia, leading to the
formation of erythropoietic tissue masses
that primarily affect the spleen, liver, lymph
nodes, chest and spine. These masses can be
detected by magnetic resonance imaging
(MRI). They may cause neurological problems
such as spinal cord compression and
paraplegia, and intra-thoracic masses.
In case of spinal cord compression, clinical
awareness is crucial for early diagnosis and
prevention of irreversible neurological
complications. MRI is the radiological method
of choice for diagnosing extramedullary
haematopoietic masses and for delineating
the extent of spinal cord involvement.
Management includes transfusion therapy, as
well as radiotherapy and hydroxyurea (Taher,
Ismaeel and Cappellini, 2006; Chehal, Aoun,
Koussa et al, 2003; Castelli, Graziadei, Karimi
and Cappellini, 2004; Saxon, Rees, Olivieri,
1998). Hypertransfusion is a promising
treatment method, targeting at higher Hb
levels, involving many blood transfusions
over a period of weeks to compensate for
the demands of erythropoiesis.
Kidney stones
As a result of ineffective erythropoiesis and
peripheral haemolysis TI patients are
susceptible to kidney stones, which can lead
to hydronephrosis and kidney failure. The
cause is associated with hypertrophic stones
that block the renal tubules and even the
calyces. The kidneys are frequently enlarged
in thalassaemia, due to the presence of
extramedullary haematopoiesis.
Leg ulcers
Leg ulcers are more common in older rather
than younger patients with thalassaemia
intermedia. It is unclear why ulcers develop.
However, once an ulcer has started to
develop it is very painful and difficult to cure,
although regular blood transfusions may
provide some relief in persistent cases. Zinc
Figure 2: Thrombotic mechanism in thalassaemia intermedia
125
supplementation can help accelerate the
healing of ulcers. Hydroxyurea also has some
benefit, either alone or in combination with
erythropoietin or platelet-derived growth
factor. In addition, the use of an oxygen
chamber can provide moderate relief since
tissue hypoxia may be an underlying cause of
the ulceration (Taher, Ismaeel and Cappellini,
2006; Gimmon, Wexler and Rachmilewitz,
1982).
Thrombophilia
Patients with thalassaemia intermedia have
been shown to have an increased
predisposition to thrombosis compared with
thalassaemia major patients. Such events
mainly occurred in the venous system and
comprised deep vein thrombosis (40%),
portal vein thrombosis (19%), stroke (9%),
pulmonary embolism (12%) and others (20%).
Moreover, splenectomised patients have
been shown to have a higher risk of
thrombosis than non-splenectomised
patients (Cappellini, Robbiolo, Bottasso et al,
2000). (See Figure 2 for more on the
thrombotic mechanism in thalassaemia
intermedia.)
Management of thrombophilia has two arms:
prevention and treatment. Prevention
consists of proper anticoagulation prior to
any surgical or other high-risk procedure.
Treatment entails the adequate use of
anticoagulation according to the
recommendations for hypercoagulable
states. Awareness is important since
thromboembolism plays an important role in
pulmonary hypertension and right heart
failure (Taher, Ismaeel and Cappellini, 2006;
Taher, Ismaeel, Mehio, Bignamini et al, 2006;
Eldor, Rachmilewitz, 2002; Cappellini,
Robbiolo, Bottasso et al, 2000; Taher, Abou-
Mourad, Abchee et al, 2002).
Pulmonary
hypertension and
congestive heart
failure
Pulmonary hypertension (PHT) is prevalent in
patients with thalassaemia intermedia. In a
study of 110 thalassaemia intermedia
patients (60.9% untransfused or minimally
transfused), 59.1% were shown to have PHT,
126
which is thought to be the primary cause of
congestive heart failure in this patient
population (Aessopos, Farmakis, Karagiorga et
al, 2001). The mechanism underlying
pulmonary hypertension in thalassaemia
intermedia is unclear.
As anaemia and iron overload are uncommon
in well-transfused and chelated thalassaemia
major patients, the two conditions are likely
to be at the root of the pathophysiology of
pulmonary hypertension. Regular transfusion
and iron chelation therapy is therefore
indicated in thalassaemia intermedia patients
who are well-stratified according to the early
detection of pulmonary hypertension indices.
Sildenafil has also been successfully used to
treat pulmonary hypertension, although data
from large patient numbers are lacking in
thalassaemia intermedia (Taher, Ismaeel and
Cappellini, 2006; Aessopos, Farmakis,
Karagiorga et al, 2001; Aessopos, Farmakis,
Deftereos et al, 2005).
Hepatitis
Hepatitis due to viral (B and C) infection is
less frequent in thalassaemia intermedia than
in patients with thalassaemia major, since
blood transfusions are much less common in
thalassaemia intermedia. Abnormal liver
enzymes (increased alanine and aspartate
aminotransferase) are frequently observed in
patients with thalassaemia intermedia,
primarily due to hepatocyte damage resulting
from iron overload. Normalisation of liver
enzyme levels is often observed during
appropriate chelation therapy (Taher, Ismaeel
and Cappellini, 2006; Cappellini, Cerino,
Marelli and Fiorelli, 2001).

Endocrine function
Hypogonadism, hypothyroidism and diabetes
mellitus are quite rare in thalassaemia
intermedia. Although patients with
thalassaemia intermedia generally experience
puberty late, they have normal sexual
development and are usually fertile.
Hypothyroidism is sometimes observed late in
life (Taher, Ismaeel and Cappellini, 2006;
Cappellini, Cerino, Marelli and Fiorelli, 2001).
Pregnancy in TI
Women with thalassaemia intermedia may
have spontaneous successful pregnancies,
although complications during pregnancy
may occur. The chronic anaemia of
thalassaemia intermedia can cause an
increase in spontaneous abortions, pre-term
labour and intrauterine growth retardation,
while endocrine complications due to
haemosiderosis are common.
Folic acid deficiency is common in
thalassaemia intermedia and occurs due to
poor absorption, low dietary intake or, most
significantly, an increased demand for folic
acid from active bone marrow. During
pregnancy, women with thalassaemia
intermedia should be given oral folic acid
supplementation (around 1 mg/day), and
should be carefully monitored in order to
assess the need for transfusion therapy and
to avoid haemodynamic compromises (Taher,
Ismaeel and Cappellini, 2006; Nassar,
Rechdan, Usta and Taher, 2006).
Iron overload
Just as in thalassaemia major, TI patients are
susceptible to complications of iron overload.
127
However, the mechanism involved in TI is
increased absorption from the gut rather
than blood transfusions. The resulting iron
overload can lead to a number of serious
complications, including cardiac failure and
endocrine abnormalities such as diabetes
mellitus and hypogonadism (Taher, Ismaeel
and Cappellini, 2006; Weatherall, 2001).
Initiation of iron chelation depends on the
amount of excess iron, rate of iron
accumulation, and duration of exposure to
excess iron. Increased levels of liver iron
concentration (LIC) have been observed with
small increases in serum ferritin (Fiorelli,
Fargion, Piperno et al, 1990). Thus, direct
assessment of LIC by biopsy or MRI is
recommended. Chelation therapy should be
initiated if LIC ≥ 7 mg/g dry weight of liver
(Taher, Ismaeel and Cappellini, 2006).
Osteoporosis
( a l s o s e e c h a p t e r o n o s t e op o ro s i s )
There is a high incidence of osteoporosis of
the spine and hip in both sexes in
thalassaemia intermedia. The severity
increases with age and even young patients
exhibit a spinal bone mineral density far
below that of age-matched controls.
Management consists of bisphosphonates
and calcium supplementation with follow up
bone-mass densitometries (Origa, Fiumana et
al, 2005).
Pseudoxanthoma
elasticum (PXE)
PXE is a rare hereditary connective tissue
disorder, characterised by generalised
degeneration of the elastic fibres with a
broad phenotypic expression. The clinical
picture consists mainly of cutaneous, ocular
and vascular manifestations; skin
histopathology involves swollen, irregularly
clumped and multiply-fragmented elastic
fibres in the middle and deep reticular
dermis, with secondary calcium deposition.
This condition has been described as
occurring in Ùhalassaemia.
Management of
thalassaemia
intermedia
There are a number of options currently
available for managing patients with
thalassaemia intermedia, including
splenectomy, transfusion therapy,
modulation of fetal haemoglobin production
and bone marrow transplantation (Taher,
Ismaeel and Cappellini, 2006; Cappellini,
Cerino, Marelli and Fiorelli, 2001).
Splenectomy
Splenectomy is no longer a major mode of
management. However, the main indications
for splenectomy include growth retardation
or poor health, leucopenia,
thrombocytopenia, increased transfusion
demand and symptomatic splenomegaly.
Splenectomy before the age of 5 carries a
high risk of infection and is therefore not
generally recommended.
128
Transfusion therapy
and iron chelation
Although transfusion therapy is not currently
a routine treatment approach for patients
with thalassaemia intermedia, it can afford
significant benefits. The decision to initiate
therapy should be based on the presence
and severity of signs and symptoms of
anaemia, including failure of growth and
development. As the rate of iron loading is
variable in thalassaemia intermedia, an
assessment of liver iron concentration is
advisable before initiating transfusion
therapy. Patients with thalassaemia
intermedia may benefit from an individually
tailored transfusion regimen, compared with
the regular transfusion regimens
implemented in thalassaemia major, to help
prevent transfusion-dependency.
Alloimmunisation is a relatively common
observation in thalassaemia intermedia,
although the risk is decreased if transfusion
therapy is initiated before the age of 12
months (Pippard, Callender, Warner and
Weatherall, 1979; Mourad, Hoffbrand, Sheikh-
Taha et al, 2003; Cappellini, 2005).
Transfusions are indicated where the
following are observed:
ñ failure to thrive in childhood in the
presence of significant anaemia;
ñ emergence of bone deformities;
ñ increasing anaemia not attributable to
rectifiable factors;
ñ evidence of a clinically relevant tendency
to thrombosis;
ñ presence of leg ulcers;
ñ development of pulmonary hypertension;
ñ delayed or poor pubertal growth spurt
and
ñ progressive splenic enlargement.

Modulation of fetal
haemoglobin
production
Increasing the synthesis of fetal haemoglobin
can help to alleviate anaemia and thereby
improve the clinical status of patients with
thalassaemia intermedia. Agents including
cytosine arabinoside and hydroxyurea may
alter the pattern of erythropoiesis and
increase the expression of Á-chain genes.
Erythropoietin has been shown to be
effective, with a possible additive effect in
combination with hydroxyurea. Butyrates are
a further experimental category, still
unlicensed and with difficult intake. Good
responses have been reported; however,
most patients complain of the difficulty of
intake orally and intravenously. Further
clinical evaluation is required to clarify the
value of this approach (Taher, Ismaeel and
Cappellini, 2006; Karimi, H. Darzi, M. Yavarian,
2005; Dettelbach and Aviado, 1985; Dixit,
Chatterjee, Mishra et al, 2005; Perrine,
Ginder, Faller et al, 1993; Cappellini,
Graziadei, Ciceri et al, 2000; Olivieri, Rees,
Ginder et al, 1997). (For more details, see
Chapter 13: Alternative approaches to the
treatment of thalassaemia.)
Bone marrow
transplantation
Bone marrow transplantation is an
established treatment for ‚-thalassaemia.
Although marrow transplantation can lead to
cure, the degree of its success depends
primarily on the health and age of the
patient. The decision as to which patients are
129
eligible for transplantation is complex and is
related to both quality of life and expected
survival time of the transplanted patient. This
is particularly relevant in patients with
thalassaemia intermedia, especially in those
who are only mildly affected. In stable
asymptomatic TI patients who do not require
transfusions, bone marrow transplantation is
not needed.
Recommendations
for the management
of thalassaemia
intermedia
Two major issues regarding the management
of thalassaemia intermedia are 1) the
approach and management of complications
in adult thalassaemia intermedia patients and
2) preventing such complications in younger
patients. A stratification of the management
of TI between adults and young patients has
therefore been established.
The scheme for adult thalassaemia
intermedia patients is as follows:
ñ each patient to be reviewed separately
and stratified by risk;
ñ hydroxyurea introduced as a suitable
initial approach;
ñ transfusion and iron chelation therapy
with deferoxamine subcutaneous infusion
and concomitant steroids for protection
from alloimmunisation are essential;
ñ aspirin for stroke prevention, post-
splenectomy and life-long anticoagulation
in patients with a history of thrombotic
events is a must;
ñ liver MRI assessment of iron
concentration (or liver biopsy if MRI is
 unavailable) is important to determine
liver iron status for future chelation.
There are no clear guidelines for the
management of thalassaemia intermedia in
the young. Thus, the authors recommend
the following:
ñ a guarded approach to the need for
splenectomy and delay in initiating
transfusion unless considered necessary
based on the above mentioned
indications;
ñ early initiation of transfusion and iron
chelation therapy if there is evidence of
growth abnormalities, poor performance
at school or a psychological impact
secondary to facial deformities;
ñ regular follow-up with echocardiodoppler
for cardiac complications and initiation of
therapy at earlier disease onset to
prevent progression;
ñ regular follow up of liver iron
concentration with MRI or liver biopsy;
ñ discourage smoking, prolonged
immobilisation and the use of oral
contraceptives or an intrauterine device.
See Table 2 for indications for transfusion
and splenectomy.
Indications for transfusion
Growth failure or poor performance at school
Transient stressful conditions
(e.g.pregnancy, infection)
Symptomatic anaemia
CHF+PHT
Leg ulcers
(Taher, Ismaeel and Cappellini, 2006)
Table 2: Indications for transfusion and splenectomy in thalassaemia intermedia
130
Definition of ‚-
thalassaemia/HbE
Haemoglobin E has the clinical phenotype of
a mild form of ‚-thalassaemia, and is most
frequent in southeast Asia, particularly
eastern Thailand and Laos. The combination
of HbE with ‚-thalassaemia spans
thalassaemia phenotypes, from a condition
indistinguishable from thalassaemia major to
a mild form of thalassaemia intermedia (TIF,
2002; Premawardhena et al, 2005).
Clinically, ‚-thalassaemia/HbE may be
classified into three categories, each of
which has its own unique clinical
management requirements:
Mild ‚-
thalassaemia/HbE
Mild ‚-thalassaemia/HbE patients do not
require treatment and rarely develop clinical
problems. Haemoglobin levels may be as high
as 9-12 g/dl. Care should be taken not to
Indications for splenectomy
Growth retardation or poor health
Leukopenia
Thrombocytopenia
Increased transfusion demand
Symptomatic splenomegaly
confuse this group of patients with
individuals having iron deficiency or with
carriers of ‚-thalassaemia, by careful
investigation of the red cell morphology,
including iron status and haemoglobin
electrophoresis (TIF, 2002; Premawardhena
et al, 2005).
Moderately severe
‚-thalassaemia/HbE
This group encompasses the majority of ‚-
thalassaemia/HbE patients. Most patients
have steady haemoglobin levels of 6-7 g/dl.
Clinically, these patients manifest symptoms
similar to thalassaemia intermedia and
normally do not require blood transfusions
unless they develop infections precipitating
further anaemia. Other complications such as
iron overload may occur in these patients.
Where this is the case, iron chelation therapy
should be initiated. Patients in this group
often have a somewhat shortened lifespan,
but with careful monitoring and treatment
can have an open-ended prognosis (TIF,
2002; Premawardhena et al, 2005).
131
Severe
‚-thalassaemia/HbE
Patients present with the clinical symptoms
of thalassaemia major, including defective
physical development, bone deformities
including facial changes, anaemia, jaundice
and hepatosplenomegaly. Haemoglobin levels
can be as low as 4-5 g/dl. The clinical
management of this group of patients needs
to be addressed as in thalassaemia major
(TIF, 2002; Premawardhena et al, 2005).
Complications and
management of
‚-thalassaemia/HbE
Complications in ‚-thalassaemia/HbE patients
depend on the category they belong to, as
indicated above. The worst of the
complications occur in the severe group, in
which the clinical picture is similar to that ‚-
thalassaemia major. This includes the
multitude of problems brought about by iron
overload due to dependence on transfusions
(see sections on complications in ‚-
thalassaemia major for further explanation).
Stem Cell
Transplantation
Outcome and patient
selection
Bone marrow transplantation from HLA-
identical siblings has been increasingly
adopted for the cure of
haemoglobinopathies. Since 1981, a large
clinical experience has been gained with
more than 1,500 bone marrow transplants
performed in centres around the world. Over
that time, a number of factors – the use of
cyclosporin, more effective treatment of
cytomegalovirus infection, improved aseptic
techniques and the evolution of systemic
antibiotic therapy – have led to a remarkable
improvement in the outcome of bone
marrow transplantation procedures (Lucarelli,
1997).
Three patient classes have been
identified on the basis of the
following risk factors, which
have been found to have a
significant influence on post-
transplant outcome:
ñ inadequate iron chelation
therapy,
ñ presence of liver fibrosis and
ñ hepatomegaly (Giardini, 1995)
Patients in Class I have none of the above
characteristics, patients in Class II have one or
two, and patients in Class III exhibit all three
characteristics.
Among Class I children with thalassaemia
major transplanted early in the course of the
disease, the probabilities of survival and
disease-free survival are 93% and 91%
respectively, with a 2% risk of rejection and
an 8% risk of transplant-related mortality (see
132
Figure 1). Class II patients have an 87%
probability of survival and an 83% chance of
disease-free survival, with a 3% risk of
rejection and a 15% risk of non-rejection
mortality (see Figure 2), while Class III
patients have a 79% probability of survival
and a 58% chance of disease-free survival,
with a 28% risk of rejection and a 19% risk of
non-rejection mortality (see Figure 3).
(Centres performing transplants in patients
with broadly similar characteristics have
shown comparable outcomes [Lucarelli
1997].) In the case of Class III patients, the
introduction of conditioning regimens
containing less than 200 mg/kg of
cyclophosphamide resulted in a significant
decrease in transplant-related mortality, but
with a concomitant increased risk of graft
rejection. Among adults (aged >16), the
probability of surviving a bone marrow
transplant procedure is 66% with a 62%
probability of cure, a 35% chance of
transplant-related mortality and a 5% chance
of returning to the pre-transplant
thalassaemic condition (see Figure 4).
Based on these outcomes, bone
marrow transplantation in
thalassaemia should be
considered for patients at an
early age or before
complications due to iron
overload have developed.
However, a final decision must
be based on an assessment of
the relative advantages and
disadvantages of bone marrow
transplantation and
conventional therapy, requiring
the physician, patient and family
to weigh the outcome and risks
of each.

HLA-matched sibling
donors
The general applicability of bone marrow
transplantation is limited by the availability of
a related HLA-matched donor. There is a one-
in-four chance that any given sibling will be
HLA identical, with the likelihood of a
thalassaemic patient having an HLA identical
sibling donor varying according to family size.
Matched unrelated
donor transplantation
Because most patients with thalassaemia do
not have a compatible sibling donor, there is
interest in using unrelated but otherwise
matched donors. Unfortunately, the
complication rates of transplants using
matched unrelated donors are generally
much higher than with sibling matched
transplants. It is hoped that with continuing
improvements in matching techniques,
complication rates will be reduced to
acceptable levels. There has been some
application of transplantation using matched
unrelated donors in thalassaemia, suggesting
that if unrelated donors are from a closely
related genetic background the outcome
may be improved (Dini, 1999; Miano, 1998).
Experience so far is limited, however.
Cord blood
transplantation
The use of stem cells obtained from umbilical
cord blood collected at the time of delivery
has recently received considerable interest.
133
There are several possible advantages to this
approach. First, stem cells can be obtained
easily at birth, and often in sufficient
quantity for a successful donation – thus
avoiding the bone marrow harvest of a donor
at a later age. Second, it has been suggested
that graft versus host disease (GVHD) may be
less severe when stem cells are obtained at
this early point in life. Third, the routine
collection of cord blood stem cells from all
births would provide a wider pool of donors
for BMT therapy.
However, the evidence of decreased GVHD
using cord blood is not persuasive. And in
many cases, the quantity of stem cells
obtained is insufficient for engraftment in an
adult recipient. Thus, while cord blood
transplantation has been successfully used to
treat some patients with thalassaemia
(Miniero, 1998), its overall value in treating
the condition has yet to be firmly
established.
Mixed chimerism
Persistence of residual host haematopoietic
cells, normally termed mixed chimerism,
frequently occurs after bone marrow
transplantation in ‚-thalassaemia (Andreani,
1996). Reduction of the dose of busulfan or
cyclophosphamide in the conditioning
regimens produced higher rates of mixed
chimerism – a risk factor for graft failure.
None of the patients showing full donor
engraftment rejected the transplant, while
29% of patients with mixed chimerism
rejected the graft within two years of
marrow infusion. Nevertheless, a condition of
long-term (> 2 years) persistent mixed
chimerism has been observed after
successful BMT in thalassaemia. This
observation may have a significant impact on
the design of future bone marrow transplant
strategies.

Post-transplant
follow-up
Post-transplant clinical follow-up
of BMT is particularly important.
Within the first year, careful
monitoring of haematological
and engraftment parameters,
infectious complications and
graft versus host disease is
essential.
Long-term follow-up is of particular interest
with respect to monitoring the evolution of
multi-system problems (iron overload,
pubertal development, growth, endocrine
deficiencies) related to the primary disease. A
number of reports indicate that iron
overload, chronic hepatitis, cardiac function
and endocrine deficiencies can be more
easily managed after transplant, sometimes
permitting the healing of damaged organs. It
is particularly important to remove excess
iron after transplant. This can usually be
achieved by repeated venesection (6 ml/kg
blood withdrawn at 14-day intervals)
(Angelucci 1997).

134
 Figure 1: Kaplan and Meier probabilities of
survival, event-free survival,
rejection and non-rejection
mortality in 119 Class I thalassaemic
patients aged less than 17 years.
Figure 3: Kaplan and Meier probabilities of
survival, event-free survival, rejection
and non-rejection mortality in 126
Class III thalassaemic patients aged
less than 17 years.
135
Figure 2: Kaplan and Meier probabilities of
survival, event-free survival,
rejection and non-rejection
mortality in 291 Class II
thalassaemic patients aged less
than 17 years
Figure 4: Kaplan and Meier probabilities of
survival, event-free survival,
rejection and non-rejection
mortality in 115 adult thalassaemic
patients (aged more than 16
years).
Alternative Approaches to the
Treatment of Thalassaemia
There is currently no definitive treatment for
any of the serious haemoglobin disorders,
other than bone marrow transplantation—an
option available only to a small minority of
patients that have a suitable donor and are in
good clinical condition. Another, promising,
approach involves the use of therapeutics to
definitively correct the globin chain
imbalance in ‚-thalassaemia, by re-activating
the foetal globin genes.
Modulation of fetal
haemoglobin
Foetal haemoglobin is the predominant non-
· globin produced in humans until around six
months of age, when it is typically
suppressed and the production of ‚-globin is
increased. This pattern is the norm even
when the genes are mutated, as in ‚-
thalassaemia.
Patients with ‚-thalassaemia who continue to
produce high levels of foetal globin, such as
those with Hereditary Persistence of Foetal
Haemoglobin, have less globin imbalance and
less severe anaemia.
The therapeutic stimulation of
foetal globin could therefore
benefit many patients, even
rendering some transfusion
independent.
Several candidate therapies now offer the
potential to correct or modulate the
underlying pathology.
Cyyttoottooxxiicc aaggeennttss
C haemoglobin levels significantly in some
Following observations that foetal
haemoglobin synthesis is reactivated during
136
recovery from bone marrow suppression
after the use of cytotoxic drugs, attention
has focused on the possible role of cytotoxic
agents as therapies in the treatment of
serious haemoglobin disorders. Several
cytotoxic agents that alter the pattern of
erythropoiesis, favouring the expression of
foetal (Á)-globin genes and so increasing the
number of red cells containing HbF (F-cells),
have been explored over the past 20-25
years (Pace and Zei, 2006; Fathallah and
Atweh, 2006; Gambari and Fibach, 2007).
TThhee ddeem meetthhyyllaattiinngg aaggeennttss 55--aazzaaccyyttiiddiinnee aanndd
ddeecciittaabbiinnee have been administered to a few
‚-thalassaemia patients with good responses,
raising total haemoglobin levels by a mean of
2.5 g/dl above baseline and clearly
prolonging the lives of end-stage patients
(Lowrey, 1993; Dunbar, 1989; Ley, 1982). The
mutagenic potential and instability of
formulations of 5-azacytidine have limited its
investigation, but higher oral doses of
decitabine have been effective in baboons
(Lavelle, 2006), and studies are planned in
selected patients.
HHyyddrrooxxyyuurreeaa has been studied in HbE/ ‚-
thalassaemia patients, with lower responses
but reduced haemolysis (Fuchareon, 1996;
Zeng, 1995). Hydroxyurea has been less
beneficial in thalassaemia intermedia than in
sickle cell disease, in which the number of
painful crises was reduced and overall health
indicators improved. The lesser benefits in
thalassaemia are perhaps due to the fact that
the cytostatic effects of hydroxyurea are
limited in the disease.
Otthheerr aaggeennttss
O
EErryytthhrrooppooeettiinnss ((EEPPOOss)) have increased
patients with thalassaemia intermedia, even
eliminating transfusion requirements in some
children. EPOs may thus be particularly
helpful in patients with relatively low levels of
endogenous erythropoietin for their degree
of anaemia (Bourantas, 1997; Nisli, 1996 and
1997; Rachmilevitz, 1998; Singer, 2003). EPO
promotes survival of red blood cells and may
counteract the rapid cell death (apoptosis)
caused by precipitation of excess ·-globin
chains in ‚-thalassaemia (review Silva, 1996;
Perrine, 2005).
SSh
hoorrtt cchhaaiinn ffaattttyy aacciidd ddeerriivvaattiivveess
Short chain fatty acid derivatives induce
activity from the foetal globin gene
promoter, resulting in two-to-six-fold higher
foetal globin mRNA in some patients,
especially those who have at least one ‚0-
thalassaemia mutation and EPO levels >140
mU/ml (review Collins and Perrine, 2005).
Their acceptable toxicity profiles add to their
potential as long-term therapeutic agents.
Several preliminary trials with intravenous
butyrate and oral phenylbutyrate compounds
have shown increases in foetal and total
haemoglobin levels in patients with
thalassaemia intermedia, while a few
previously transfusion-dependent
thalassaemia major patients have been
maintained transfusion-independent on
home therapy for 5-7 years. Isobutyramide
has induced foetal globin and reduced
transfusion requirements in thalassaemia
intermedia and major (Cappellini, 2000;
Reich, 2000).
The most effective compound thus far is
arginine butyrate, although this has the
disadvantage of requiring intravenous
infusion due to its rapid metabolism. Oral
derivatives that persist for many hours after
a single dose and which also stimulate
erythroid cell proliferation and survival,
similar to EPO, will enter clinical trials soon
137
(e.g. sodium 2,2-dimethybutyrate) (Boosalis,
2001; review Perrine, 2005). Select
hydroxamic acid derivatives have had high
activity in transgenic mice (Cao and
Stamatoyannopoulos, 2005).
The mechanisms by which short chain fatty
acids stimulate Á-globin production are being
elucidated. Some new derivatives displace a
repressor complex and cause acetylation
specifically of the foetal globin gene
promoter (Mankidy et al, 2006).
PPhheennyyllbbuuttyyrraattee aanndd bbuuttyyrraattee cause general
histone hyperacetylation, which inhibits cell
proliferation, and are counter-productive in
thalassaemia, requiring limited exposure
(Pulse therapy). Butyrates have induced fetal
globin production in approximately two-
thirds of patients with diverse molecular
mutations and raised total haemoglobin
levels an average of 2-3 g/dl above baseline
when given intermittently to avoid anti-
proliferative effects (review Perrine, 2005).
As differences in drug metabolism contribute
significantly to responsiveness to any drug,
these will certainly apply in the highly diverse
thalassaemia syndromes (Wilkerson, 2005).
New generation agents which promote
erythroid survival, and can be given daily,
offer significantly more potential benefit
than the first generation prototypes.
Coom
C mbbiinnaattiioonn tthheerraappyy
Although pharmacological induction of fetal
haemoglobin in transfusion-dependent
patients with thalassaemia will require high-
potency induction of foetal globin, weaning
of transfusions to allow renewal of patients’
own erythropoiesis, adequately high EPO
levels to promote eyrthroid cell survival and
iron availability for erythropoiesis, there is
expectation that some of the agents, used in
combination or properly scheduled, could
result in complimentary effects and render
even severe patients transfusion-
independent. For example, a demethylating
agent and butyrate had synergistic activity,
much higher than additive effects, in
experimental studies (Constantoulakis, 1989).
Such combinations offer excellent potential
for patients with diverse syndromes.

An approach to rational
combinations can now be based
on a patient’s baseline HbF,
total haemoglobin and EPO
levels (review Perrine, 2005).
Clinical trials should be planned
to find optimal drug
combinations for different
patient subsets.

138
Gene Therapy: Current
Status and Future Prospects
The idea of using gene therapy to treat the
haemoglobinopathies (thalassaemia and sickle
cell disease) is, in principle, straightforward.
Red blood cells (RBC) are continuously
replenished by bone marrow haematopoietic
stem cells (HSC). Therefore, the stable
transfer of a normal functioning copy of a ‚-
globin therapy gene unit into the patient’s
own HSC would result in the generation of
normal rather than diseased RBC for life.
(Note: no donor bone marrow is needed).
A number of major discoveries
and technical advances in gene
therapy over the last 20 years,
particularly since 2000, mean
that, at long last, gene therapy
for the haemoglobinopathies
looks a serious possibility in the
not too distant future.
In 1987, a group led by Prof Frank Grosveld
discovered the master regulator of the ‚-
globin gene family, known as the ‘locus
control region’ (LCR). It was found that
linking the LCR to a ‚-globin gene unit
enables the gene to be efficiently and
reproducibly switched on, and to produce a
sufficiently high level of ‚-globin protein to
be of therapeutic benefit, if reproduced in a
gene therapy context (Levings and Bungert,
2002; Stamatoyannopoulos, 2005).
The stable introduction of the LCR-‚-globin
therapy gene unit into the patient’s HSC is
via a retrovirus delivery vector, resulting in
the permanent splicing or integration of the
therapy gene into the HSC DNA, which is
then retained for life. Overall, the gene
therapy protocol employs an ‘ex vivo’
procedure. HSC are isolated from the
patient’s bone marrow and infected or
transduced with the LCR-‚-globin retroviral
139
vector. The corrected cells are then returned
to the patient, who in the meantime has
undergone chemotherapy (as in a donor-
derived bone marrow transplant) to partially
or completely destroy their diseased bone
marrow (Persons and Tisdale, 2004).
Early studies with LCR-‚-globin gene
retroviral vectors based on the mouse MoLV
virus and using an ex vivo procedure in
animal models, provided good proof of
principle. However, it proved very difficult to
accommodate LCR-‚-globin gene units within
MoLV retroviral vectors and manufacture
them. In addition, the LCR-‚-globin therapy
gene units that could be incorporated into
this vector system were ineffective at
producing a consistent and sufficiently high
level of ‚-globin protein to be of therapeutic
value (Antoniou and Grosveld, 1999).
However, a major breakthrough occurred in
2000, when the laboratory of Prof Michel
Sadelain reported work involving the testing
of an LCR-‚-globin therapy gene unit within a
class of retrovirus known as an HIV lentiviral
(LV) vector (Figure 1; May et al, 2000). Prof
Sadelain showed for the first time that the LV
vector can readily accommodate a larger and
more efficient version of the ‚-globin
therapy gene linked to the three most
powerful LCR elements (HS2, HS3, HS4), and
that application of this vector in an ex vivo
bone marrow transplant procedure could
completely cure or rescue the ‚-thalassaemia
condition in mouse models of this disease
(May et al, 2000; Rivella et al, 2003).
Since then, a number of groups in the US
and Europe have built their own versions of
the LCR-‚-globin gene LV vector (Persons and
Tisdale, 2004; von Kalle C et al, 2004;
Sadelain et al, 2006). The smallest version of
the LCR-‚-globin gene LV vector has included
only LCR elements HS2 and HS3 in its design,
Figure 1: IIlllluussttrraattiioonn ooff hhooww aa lleennttiivviirraall vveeccttoorr ccoonnttaaiinniinngg aa bb--gglloobbiinn tthheerraappyy ggeennee uunniitt iiss ccoonnssttrruucctteedd ffrroom
m
tthhee nnoorrm maall ((wwiilldd--ttyyppee)) HHIIVV vviirruuss..
AA.. Structure and gene organisation of wild-type HIV virus.
BB.. Replacement of the normal genes of the wild-type HIV virus with the Locus Control Region-‚-
globin therapy gene unit produces the lentiviral vector.
NNoottee:: combinations of locus control region elements HS2/HS3/HS4 or HS2/HS3 have been
employed.

which has significantly improved the ease of gene LV vector include: (i) reproducibility of
vector manufacture (Miccio et al, 2006). function of the vector; at present there is
significant variability in the expression of the
In all these cases, researchers have shown LCR-‚-globin therapy gene (including its
good efficacy in rescuing disease in mouse complete switching off), which is dependent
models of ‚-thalassaemia or of sickle cell upon the site where the LV vector has
disease. In addition, some groups have integrated within the HSC DNA (e.g. see May
shown that, under laboratory conditions, et al, 2000; Miccio et al, 2006; Han et al,
transduction of human HSC derived from 2007); (ii) insertional mutagenesis: the
bone marrow of severe ‚-thalassaemia major integration of the LCR-‚-globin gene LV
patients with the LCR-‚-globin gene LV vector into the HSC DNA has the potential to
vector can correct the globin chain disrupt host cell gene function causing, in
imbalance in resulting RBC (Persons and the extreme situation, a leukaemia-type
Tisdale, 2004; Sadelain et al, 2006; von Kalle condition (von Kalle C et al, 2004), as has
C et al, 2004; Roselli et al, 2006). been observed in clinical trials using retroviral
vectors for gene therapy of X-linked severe
Remaining problems that need to be combined immune deficiency (SCID-X1; see
addressed in order to improve both the Nienhuis et al, 2006), which also targets the
effectiveness and safety of the LCR-‚-globin HSC of the patient. Some researchers have

140
therefore included the chicken b-globin LCR
element cHS4 in their LV vector design to try
and ‘insulate’ the LCR-‚-globin gene unit,
which has led to some improvement in the
reproducibility of functioning (Persons and
Tisdale, 2004; von Kalle C et al, 2004;
Sadelain et al, 2006). In addition, it has been
suggested that the cHS4 element may act to
shield host genes within the HSC from
interference by the LCR-‚-globin therapy
gene unit and therefore promote safety,
although this has yet to be formally
demonstrated.
These studies led to the commencement of
the first Phase I/II gene therapy clinical trial
for the haemoglobinopathies in 2006. The
trial is led by Prof Philippe Leboulch in Paris
and aims to treat five ‚-thalassaemia and five
sickle cell disease patients within the age
range of 5-35 years. The protocol, as
expected, involves an ‘ex vivo’ approach,
with patients receiving a full chemotherapy-
conditioning programme with Busulfex to
destroy their diseased bone marrow (Bank et
141
al, 2005). Up to the end of 2006, two
patients with ‚-thalassaemia had been
treated. It is too early in the trial to know if
any benefit has been derived.
The trial has not been without controversy,
mainly related to the use of a high-risk full
chemotherapy-conditioning programme as
part of a protocol whose success is still far
from certain, let alone in relation to what is
currently achievable with a sibling-donor
bone marrow transplant.
We eagerly await the outcome
of these studies, as well as the
commencement of future trials
with LV vector designs with
higher efficacy and safety
profiles.
Psychological Support
in Thalassaemia
Why is psychological
support so
important?
It is now universally recognised that
thalassaemia, like other chronic diseases, has
important psychological implications. The way
in which the family and the patient come to
terms with the disease and its treatment will
have a critical effect on the patient’s survival
and quality of life. Without an understanding
and acceptance of the disease and its
implications, the difficulties of lifelong
transfusion and chelation therapy will not be
faced, leading to an increased risk of disease
complications and poorer survival. A key role
for treating physicians and other health care
professionals is to help patients and families
to face up to the difficult demands of
treatment, while maintaining a positive role.
Adherence to treatment is a basic goal, but a
general acceptance by the patient of his/her
own condition constitutes the key to normal
development from childhood to adulthood.
Monthly contact with a local thalassaemia
centre from the first years of life allows
doctors and other members of the team to
act as a reference point for the patient’s
overall state of health, including general
attitude and well-being. In addition, this
regular interaction provides to the whole
staff, and in particular to the treating
physician a good opportunity to promote the
patient’s physical, emotional and social
development, taking on several
characteristics of the traditional ‘family
doctor’ as guardian of the patient’s overall
wellness.
142
The success of management of thalassaemia
is based, to a great extent on the
establishment of a therapeutic alliance
between caring staff and the patient
throughout the course of the disease.
Because of the disease-oriented emphasis of
medical education, many health professionals
find it difficult to come to terms with the
psychological demands of treating chronic
inherited diseases. This can be made more
difficult in thalassaemia because patients
often express strong negative feelings, which
can hamper communication. Furthermore,
after many years of treatment, patients and
family may be better informed about the
illness than non-skilled health professionals—
a factor that can undermine the health
professionals’ perceived role. Taken together,
these factors can make honest, in-depth
communication, which is vital to successfully
coping with thalassaemia, extremely difficult
to maintain.
The psychology of
inherited chronic
disease
Every genetic disease, regardless of its
aetiology, implies a sense of guilt that may
interfere with the primary parent-infant
relationship. As its clinical manifestations
develop in the first year of life, the disease
can have also a negative impact on the
parent-child relationship. Moreover, the
treatment is emotionally demanding, as
transfusion and chelation therapy require
repeated invasive procedures and hospital
visits.
Chronicity is a powerful source of emotional
problems that intensify at each significant
developmental stage of the patient’s life.
Patients can feel that they are different,
limited or isolated. Their state of mind can
shift rapidly from depression to anger and
vice versa. Health workers must be prepared
to accept this shift and to help patients deal
with these feelings, finding a way to their
own ‘normalisation’ that implies different
individual styles in adult life.
Overall, good treatment facilitates personal
development and achievement of targets in
life, while poor care makes such
development difficult or unpredictable.
Communication:
healthcare
professionals with
patients
H e a l t h c a re p r o f e s s i on a l s s h o ul d s e e k ,
H crucial questions about the duration of care
ass far as possible, to:
a and possibilities of a cure. These should be
ñ Listen – to be interested in the patient’s
emotional and real experiences
ñ Accept – to respect the patient’s point of
view and be sensitive to the timing of
personal communication
ñ Share – to be consistently close to the
patient’s positive and negative feelings
ñ Understand – at an emotional and not
simply an intellectual level
ñ Maintain boundaries – to give help and
relief, but keeping in mind his/her role as
a physician
Good communication with healthcare
professionals can be extremely beneficial for
the patient, helping him/her to cope better
with thalassaemia and to maintain a sense of
143
balance. It can also be extremely rewarding
for the healthcare professional, both in
medical and emotional terms. Where a
healthcare professional manages to maintain
a constant dialogue with his/her patients,
s/he will often discover in patients with
thalassaemia skills that greatly surpass those
of their peers when facing the great
challenges of life such as birth/death,
love/loneliness, opportunities/limits.
Caring for a ‘normal’
development
Settings and methodology for discussion are
important all along the course of the disease,
but are mandatory at crucial milestones in
the patient’s and parents’ experience:
At the onset and during the first period,
communication work is carried out with
parents, but the child has to be included as
soon as possible. From as early as three to
five years of age, young patients begin to ask
dealt with sensitively and honestly. Separate
interviews with patient and with parents are
recommended in the approach to
adolescence, while in adulthood individual
interviews with the patient are essential.
Communication of
diagnosis
As exemplification, it is useful to focus on
communication of diagnosis, because it is the
natural starting point of the whole course of
disease and may mark permanently
(positively or negatively) the therapeutic
relationship.
In trying to establish an ideal setting, the
following points should be considered:
ñ The room chosen and time allocated aim
to provide an atmosphere that will sustain
hope and optimism; and not make the
patient feel depressed or misled.
ñ The diagnosis should be discussed with
both parents together, allowing ample
time to listen to their concerns and to
respond to their questions, worries and
concerns.
ñ Information must be sincere, complete
and repeated as often as needed. The
weight of negative emotions may be so
great that parents may appear confused
even after complete information has
been given more than once.
ñ In the months following diagnosis, the
discussion must be renewed, with the
same attention given to the setting, and
preferably with the same doctor to
preserve continuity.
The same attention to setting must be
provided at any significant step, in order to
better support patient/parents in coping with
distressing information.
Psychological impact
of anaemia and
transfusion
Serious anaemia will cause the patient to feel
weak and vulnerable. Maintaining an
adequate haemoglobin level through optimal
transfusion therapy (see Chapter 2: Blood
Tranfusion Therapy in ‚-thalassaemia Major)
eliminates these symptoms and reduces the
patient’s anxiety about death. However, the
decrease in haemoglobin during the
144
transfusion interval may allow these
symptoms to recur. This gives the patient the
experience of instability and doubt about
his/her physical capabilities. Moreover,
because of the risk of transfusion-
transmitted diseases, fears of being
contaminated are ever-present and may be
intense for real reasons (high risk of
transmission) or due to the patient’s
emotional state. This fact helps to sustain
ambivalence towards therapy.
In any case, the need for periodic
transfusions testifies that vital energy comes
from other people, implying a dependence at
the physical level that can invade the mental
level, limiting personal development. In
addition, transfusion therapy does not cure;
it merely provides a monthly “patch” for the
anaemia, giving life and well-being but also
(even if safe from infection) causing iron
overload, which necessitates additional
treatment that is also lifelong.
This combination of advantages and
disadvantages of transfusion finds a parallel
in patients’ psychological reactions to their
treatment.
Regularly transfused patients
can experience positive feelings,
such as gratitude for receiving
life, and negative ones such as
fear and anger at being ‘ruined’.
Psychological aspects
of chelation therapy
Treating staff should be very familiar with the
emotional aspects of chelation, as
compliance with therapy determines
prognosis (see Table 1).
 P s y c h o l o g i c a l a s p e c ts S u b c u t a n e o u s c h e l a ti o n O ra l c h e l a t i o n
Aggression + -
‘Patch’ + +
Body image damage + -
Daily reminder + +
Feeling different ++ +
Lack of check + +
Constant commitment + +

Table 1

In general, chelation is a psychologically Time and movement restrictions related to

demanding therapy, because: the use of the pump generate feelings of
being different and restricted.
ñ Iron chelation does not cure but rather
treats the main complication of the basic Parents may:
therapy (transfusion), as ‘the patch of ñ Not yet have overcome the shock of
another patch’. diagnosis. Administering the infusion can
ñ Like transfusion, it is a reminder of one’s be painful since they feel responsible for
illness, and even more on a daily basis. their child’s discomfort.
ñ Optimal chelation starts during the first ñ Use chelation as a control tool when the
years of life. child reaches adolescence.
ñ Effectiveness of the drug cannot be
checked quickly and directly by the Patients may:
patient. So compliance is a function of ñ Adopt attitudes of out-and-out refusal,
trust; that is to say, it reflects the quality feeling ‘tortured’ instead of cared for.
of the treating staff-patient relationship ñ Exploit any opportunity or excuse to skip
and a belief in long-term benefits. a day’s infusion.
ñ Repeatedly select the same sites for
S ub c ut a n e o us c h e l a t i on needle insertion, so trying to reduce the
Parenteral treatment implies a small act of body image damage.
aggression, either self-directed or inflicted by
the patient’s loved ones. Skin punctures from Physicians may:
the needles cause body image damage. The ñ ‘Bargain’ with the patient, under-
patient may feel ‘as full of holes as a prescribing desferrioxamine, more for
colander’. psychological reasons than on the
rationale of iron balance.

145
ñ Tacitly encourage non-compliers to
treatment in order to avoid the
development of negative psychological
states.
While the underlying motivation for all the
above reactions or attitudes is generally a
desire to provide relief from the patient’s
discomfort and to make him/her feel better,
the long-term effects of such behaviour are
harmful for the patient’s physical health and
emotional well-being.
Orraall cchheellaattiioonn
O ñ Remember that long-term high
Oral administration simplifies significantly
many practical aspects of chelation
management with Deferrioxamine.
For some patients (and some healthcare
professionals), a shift to oral chelation may
seem ‘the solution to every problem’. In fact,
however, oral chelation only helps with the
issues of daily ‘holes’ to the skin and
consequent damage to body image. Patients
taking oral chelators must still face the daily
feeling of being different and will still lack
the means to immediately and quickly assess
the impact of treatment and in this context
it will remain difficult for some patients even
on oral chelation to maintain adequate
compliance.
Reeccoom
R mmmeennddaattiioonnss::
ñ Define and resolve the practical aspects
of optimal chelation (see Chapter 3: Iron
Overload).
ñ Avoid judging, reprimanding or
threatening the patient.
ñ Pay due attention to the psychological
aspects of the disease, as
underestimating these undermines the
effectiveness of the treating staff-patient
relationship with an increased risk of
treatment failure.
ñ Be involved in supporting, instead of
simply insisting or prescribing.
146
ñ Promote the shift from parent to patient
management as early as possible. Many
patients with thalassaemia can begin to
take control of their medication regimen
from six years of age. The early initiation
of self-management limits overprotection
and stimulates autonomy in the young
patient. It also gives relief to parents and
ultimately improves the quality of life of
the whole family.
ñ Encourage patients to feel a sense of
reward for achieving mutually agreed
therapeutic goals.
compliance fosters good capability and
self-reliance and is a key positive factor in
maintaining emotional well-being.
Psychological impact
of complications
During adolescence or young adulthood
various complications may occur. The
psychological implications of such
complications lie in their degree rather than
their onset. In general, asymptomatic
complications do not require medication and
do not interfere heavily with quality of life.
However, when a serious complication such
as heart disease or diabetes appears, the
patient undergoes a period of psychological
readjustment. S/he has to integrate the
hopes, enthusiasm and wishes typical of
youth with a damaged physical state and
medical features typical of old age. In such a
situation, the inadequately supported patient
may feel ‘hopelessly ruined’, giving up on
health and continued therapy.
Table 2 outlines the impact of the most
common complications (at moderate/severe
stage) on patient emotional balance.
 Coom
C mpplliiccaattiioonn TTrreeaattmmeenntt IIn
nfflluueennccee FFeeeelliinngg ooff Deeppeennddeennccee
D FFeeeelliinngg ooff Deeaatthh
D
bbuurrddeenn oonn ddaaiillyy lliiffee ddiiffffeerreennccee ddaam
maaggee aannxxiieettyy
Hypogonadism +++ ++ +++ + ++ -
Hypothyroidism + - + - ++ -
Hypoparathyroidism ++ ++ + + ++ -
Osteoporosis ++ ++ ++ + ++ -
Diabetes +++ +++ +++ +++ ++ +
Heart disease +++ +++ +++ ++ +++ +++
Hepatitis -/+++ ++ ++ + +++ +

Table 2

In contrast to the past, recent advances in Beginning a new job or an important loving
iron chelation therapy have led to a dramatic relationship can increase feelings of
progress in survival, in saving patients from inadequacy and fragility. Sometimes an
acute life-threatening heart failure, and emotional crisis occurs and psychological
generally in improving quality of life. support may be required.
Treating staff must maintain a positive
perspective and support a patient’s sense of Treating staff should accompany the patient
hope. along his/her life path, while respecting
Even in very serious cases, it is still possible his/her fragilities, sensitivity, and supporting
to deal with suffering by sharing and working resources. The most common mistakes on
together to find ways of accepting new limits the part of healthcare professionals is that
inherent to a given situation. they are being overprotective or
disinterested. On the other hand, special care
should be taken in preventing intrusions into
Challenges for the the patient’s privacy.

adult patient
Summary of
If the disease is fully compensated, physical
conditions allow the patient with psychological goals
thalassaemia to make his/her choices of adult
life without any restrictions or limitations. In terms of the psychological care of the
Even in this ideal state, however, at a patient, healthcare professionals should aim
psychological level young adults with to:
thalassaemia can run into more difficulties ñ Provide information that promotes
than peers in coping with the tasks of adult understanding of the illness
life, particularly those implying independence ñ Help patient and parents to talk and to
and responsibility. express feelings about the illness

147
ñ Help the patient to accept the illness and
to take care of him/herself
ñ Maintain realistic hopes
ñ Facilitate a ‘normal’ lifestyle and
encourage self-esteem
ñ Support the full development of an adult
life
Putting these goals into practice requires
health professionals to be:
ñ Open-minded about psychological aspects
of having and treating inherited disease
ñ Trained in normal psychosocial
development from childhood to
adulthood
ñ Sensitised to the special issues of this
chronic hereditary disease
ñ Available to accompany and support the
patient throughout his/her life path
148
It is clearly not possible for a health
professional to provide all the above support
if the organisation of his/her healthcare
system does not provide him or her with the
opportunity to work with patients on a long-
term basis. The ‘rotation’ of experienced
professionals to different wards can seriously
undermine a patient’s psychological well-
being, treatment and prognosis. Appropriate
psychological support therefore not only
requires motivated and able clinicians, but
also presupposes an organisational structure
that allows for the successful delivery of
optimal and comprehensive care.
General Health Care and
Lifestyle in Thalassaemia
Lifestyle
If the disease is fully
compensated by ideal
treatment, an individual with
thalassaemia major can enjoy a
near-normal lifestyle and
experience regular physical and
emotional development from
childhood to adulthood,
including parenthood.
Treating staff should promote such a
progression by trying to reduce as far as
possible the degree to which the disease
interferes with the patient’s personal and
social life. Where the disease cannot be fully
compensated with proper transfusional
schemes, the obstacles to a normal lifestyle
should be taken into account with a realistic
but positive approach, based on informing
and encouraging the patient, and reviewing
limitations on time and treatment schedule.
From a practical point of view, treating staff
should:
ñ Manage treatment and monitoring
schedules so as to minimise any
unnecessary impact on normal daily
activity
ñ Be aware of the particular psychological
aspects of health care for this chronic
condition (see Chapter 15: Psychological
Support in Thalassaemia)
Confidentiality vs.
openness
The patient should have the
right to decide if, when and
with whom to talk about the
disease.
149
This right should be considered before other
points of view (i.e. those of parents,
relatives, school, hospital and official bodies).
Staff should:
ñ Assure confidentiality of patient identity
and data in all circumstances, trying to be
compliant with local, International laws
and rules on privacy, if not against
patient’s rights.
ñ Help parents to be aware of disease-
related issues early on in the patient’s life
(e.g. teaching parents to decide with the
child, from the age of 6, if and how to
communicate with the school about
thalassaemia)
ñ Help the patient to build up a realistic
and balanced position between being
open and being secretive about the
disease
School
If the patient’s haemoglobin levels are
maintained close to the values recommended
in this book, no relevant interference with
academic performance should be seen.
Where the haemoglobin level is allowed to
fall too low, the patient may have difficulty in
school. However, individual variability is wide.
Although normal transfusion and follow up
schedules many require a number of
absences, these should not be to the extent
where the patients’ school performance is
negatively affected.
Home
Splenectomised patients should be warned
about the risk of having pets at home, due
to the possibility of bites and this increased
risk of septicaemia (Capnocytophaga
canimorsus-associated). Additional care in
preventive measures may be required in
some areas due to specific infection risk (see
the example of Pythiosis in Thailand in
Chapter on Infections). Patients with active
viral hepatitis or other viral infections should
take general measures to minimize or
prevent the risk of transmission to the family.
Work
In general, it is important for
patients to have a positive
attitude towards their ability to
work.
In chronic diseases a shift to overprotection
is a frequent problem for all people involved
(parents, treating staff, patient association
and patients themselves). This may be
partially useful when treatment possibilities
are scarce and the physical conditions of the
patient are poor. However, well-treated
patients generally do not face difficulties in
performing work as a direct result of their
disease.
Depending on the country, thalassaemia may
be recognised as causing a certain degree of
disability, with resulting benefits and special
employment facilities. While these may help
the family and the patient from a practical
viewpoint, care should be taken that these
entitlements do not interfere with a positive
attitude to normality, self-esteem and the
ability to work (see Chapter 15: Psychological
Support in Thalassaemia).
Symptomatic heart disease and osteoporosis
may cause difficulties for patients in
performing certain physical tasks and specific
advice in limiting at-risk activities should be
provided.
150
Sexual and
reproductive life
Differences in appearance (facial
features, height, and skin
colour) may affect self-
confidence and participation in
social life. In adolescence, the
absence or delay of sexual
development is regarded by
patients as particularly
stigmatising. Timely optimal
treatment of hypogonadism
limits these effects. Carriers of a
viral infection must also address
additional uncertainties as
regards safe sexual behaviour.
The general improvement in the health of
patients with thalassaemia, particularly in
industrilized high income (HDI) countries,
means it is now possible for them to have
children spontaneously or by induction of
pregnancy. Patient attitudes to parenthood
may range from unnecessary feelings of
psychophysical inadequacy to an
underestimation of the risks and difficulties
involved. Treating staff should help the
patient and his/her partner to achieve a
balanced position. The decision as to whether
to induce pregnancy medically can be
difficult, and the patient’s and partner’s
expectations, the risks of pregnancy and the
long-term prognosis of the patient must be
seriously taken into consideration. Exhaustive
counselling is necessary to explore these
issues in a sensitive but thorough manner.

Routine Health Care
Vaacccciinnaattiioonnss
V
There is no reason for patients
with thalassaemia to skip or
delay standard recommended
vaccinations.
Additional vaccinations for patients with
thalassaemia are discussed in the Chapter on
Infections.
Deennttaall ccaarree
D
Patients who are untransfused, under-
transfused or who begin transfusion at a
later stage in the disease may have some
malformations of the facial bones due to
marrow expansion. This can affect growth of
the teeth and cause malocclusion.
Orthodontic care may be successful in
improving masticatory function and/or
correcting unaesthetic dental appearances.
Orthodontic schedule must take account of
the peculiar characteristics of bone disease in
thalassaemia in order, to prevent tooth
instability or loss. The degree of osteoporosis
of maxillary bone should guide the treatment
schedule.
TTrraavve
elllliinngg
Travel carries a degree of risk, which
increases if the patient cannot receive expert
local treatment. If a patient is travelling to a
remote country, it is vital that adequate
travel insurance is obtained so that if serious
complications develop, s/he can be flown
home immediately, with provision of any
necessary medical assistance. If the patient
plans a trip, treating staff should, as far as
possible, give information about the closest
hospital with services and experience in the
management of thalassaemia. As for any
traveller, detailed advice about infection risks
151
in the country to be visited should be
obtained, and appropriate vaccination and
prophylaxis obtained in advance. Particular
attention should be paid to the prevalence of
malaria (see below).
Blloooodd
B
Ideally, a patient should always receive blood
transfusions at the same place. Travel plans
should be coordinated with the patient’s
transfusion schedule, in order to avoid
receiving transfusions elsewhere, particularly
if visiting areas where blood supplies carry a
high risk of infection.
Chheellaattiioonn
C
Travelling and holidays should be organised
so as not to interfere with regular chelation
and treating staff should not indulge the
‘poor guy’ attitude. However, requests to
comply with adjustments in the chelation
schedule to minimise interruptions must also
take into account some practical aspects
(e.g. an adolescent planning the first camp
holidays with peers), and relational aspects
(i.e. secrecy or open communication about
the disease).
SSp
plleenneeccttoom
myy
The splenectomised patient should always
travel with antibiotics, to assure prompt
medication in case of fever, sepsis or animal
bites. Treating staff should discourage travel
where the risk of malaria is significant, as this
disease may be more serious in
splenectomised subjects.
Nutrition
Geenneerraall
G
Patients with thalassaemia do
not have specific dietary
requirements, unless they have special
prescriptions. In general, a restrictive diet is
easy to be prescribed but difficult to be
maintained over the long term. In
thalassaemia, the patient already has a heavy
treatment schedule and it is
counterproductive to add further restrictions
without the likelihood of clear benefit.
During growth, a normal energy intake with
normal fat and sugar content is
recommended. During adolescence and adult
life, a diet low in highly refined
carbohydrates (sugar, soft drinks, snacks)
may be useful in preventing or delaying the
onset of impaired glucose tolerance or
diabetes.
There is no clear evidence that a diet is
beneficial in preventing or managing liver
disease, unless at late stages.
IIrro
onn
Increased iron absorption from the intestinal
tract is characteristic of thalassaemia. The
amount depends on the degree of
erythropoiesis, the haemoglobin level and
other potential independent factors. Drinking
a glass of black tea with meals reduces iron
absorption from food, particularly in
thalassaemia intermedia (de Alarcon, 1979).
However, there is no evidence that iron-poor
diets are useful in thalassaemia major; only
foods very rich in iron (such as liver and
some ‘health drinks’ or health vitamin
cocktails) should be avoided. Patients with
thalassaemia should never be given iron
supplements. Many baby foods, breakfast
cereals and multivitamin preparations contain
added iron, along with other vitamin
supplements. The patient should therefore
make a habit of reading labels carefully,
seeking expert advice if necessary.
152
Caallcciiuum
C m
Many factors in thalassaemia
promote calcium depletion. A
diet containing adequate
calcium (e.g. milk, cheese, dairy
products and kale) is always
recommended.
However, nephrolithiasis is seen in some
adults with thalassaemia major, and calcium
supplements should not be given unless
there is a clear indication, instead a low
oxalate diet should be considered.
Vitamin D may also be required to stabilise
calcium balance, particularly if
hypoparathyroidism is present. In case of
liver disease, the activated form should be
preferred. However, if supplements are used,
careful monitoring is required in order to
prevent toxicity.
Patients with thalassaemia should not take
additional calcium or vitamin D unless
prescribed by their medical practitioner.
FFo
olliicc aacciidd
Patients with thalassaemia who remain
untransfused or are on low transfusion
regimens have increased folate consumption
and may develop a relative folate deficiency.
Supplements (1mg/day) may be given if this
occurs. Patients on high transfusion regimens
rarely develop this condition, and usually
have no need for supplements.
Viittaam
V miinn CC
Iron overload causes vitamin C to be oxidised
at an increased rate, leading to vitamin C
deficiency in some patients. Vitamin C may
increase the ‘chelatable iron’ available in the
body, thus increasing the efficacy of
chelation with desferrioxamine. However,
there is currently no evidence supporting the
use of vitamin C supplements in patients on
deferiprone, deferasirox or combination
treatment. Indeed, vitamin C ingestion may
increase iron absorption from the gut, labile
iron and hence iron toxicity. Therefore,
supplements should only be considered for
patients on desferrioxamine (see Chapter on
Iron Overload).
Some drugs, such as aspirin and throat
lozenges, as well as certain ‘health foods’,
may contain vitamin C and should be
avoided. A diet rich in fresh fruits, including
citrus fruits and vegetables, is recommended.
Viittaam
V miinn EE
Vitamin E requirement is high in
thalassaemia. Treating staff should
recommend a regular intake of vegetable oils
as part of a balanced diet. However, the
effectiveness and safety of vitamin E
supplementation in thalassaemia major has
not been formally assessed and it is not
possible to give recommendations about its
use at this time.
ZZiin
ncc
Zinc deficiency may occur during chelation,
depending on the chelator, dose and
duration. Zinc supplementation requires close
monitoring.
Substance abuse
Allccoohhooll
A associated risks.
Patients with thalassaemia
should be discouraged from
consuming alcohol, as it can facilitate
the oxidative damage of iron and aggravates
the effect of HBV and HCV on liver tissue.
Where all three factors are present, the
probability of developing cirrhosis and
153
hepatocarcinoma is significantly raised.
Excessive alcohol consumption also results in
decreased bone formation and is a risk factor
for osteoporosis. In addition, alcoholic drinks
may have unexpected interactions with
medication.
SSm
mookkiinngg
Cigarette smoking may directly affect bone
remodelling which is associated with
osteoporosis and is related to adverse effects
on the general health.
Drruugg aabbuussee
D
In many countries, drug abuse is common
among adolescents and young adults. For an
individual with a chronic disease, drug abuse
can be a serious threat to an already
challenging condition, upsetting the delicate
balance of factors affecting physical and
mental health. Treating staff should aim to
help the patient maintain such a position,
bearing in mind the challenges an adolescent
patient is likely to face. A key danger is that—
as with many adolescents—drug abuse may
be seen as a compensatory way to be
popular among peers or to ‘fit in’. For young
people with thalassaemia, feelings of
dependence, difference and anxiety can
push patients to seek ‘normality’ through an
abuse habit.
A transparent discussion of
these issues may help the
patient to gain insight into the
Recreational activities
Phhyyssiiccaall aaccttiivviittyy
P
In general, physical activity must always be
encouraged in patients with a chronic
disease. Patients with thalassaemia should
have a quality of life and range of life
experiences as much like those of others as
possible. There is no reason to prevent
patients from engaging in physical activity to
the limits of what they are capable of and
interested in doing, unless there is a precise
secondary medical condition.

Conditions requiring special attention

include:
S p l e n om e g a l y :
ñ Splenomegaly: the more enlarged the
spleen, the more rigorous treating staff
must be in recommending avoidance of
those sports and physical activities with
significant risk of abdominal trauma.
H e ar t d i s e as e :
ñ Heart disease: moderate physical
activity is beneficial, if is matched to the
clinical condition and its treatment.
O s t e op or os i s
ñ Osteoporosis or back pain in adults may
limit physical activity. Osteoporosis carries
an increased fracture risk and contact
sports should therefore be avoided if
osteoporosis is present.

Drriivviinngg
D
No special attention is needed. In some
countries, the presence of diabetes mellitus
requires special checks and limitations.

154
Organisation and
Programming of a
Thalassaemia Centre
The importance of a
dedicated
thalassaemia unit
Unless the number of patients is minimal,
organisation of a thalassaemia unit is useful
both in terms of functionality and cost.
Attempting to manage many patients with
thalassaemia in big multi-purpose units (such
as paediatrics, oncohaematology and
transfusion centres) without dedicated
facilities is often counterproductive, as most
resources are used for the main activity of
the unit (acute patient, oncology patients,
transfusion, etc).
In a dedicated thalassaemia unit, a treating
physician specially trained in thalassaemia
oversees all aspects of treatment, referring
to specialists when indicated. Staff most
commonly involved are:
ñ Nurse specialist(s)
ñ Cardiologist
ñ Endocrinologist
ñ Diabetes specialist
ñ Reproduction endocrinologist
ñ Andrologist or gynaecologist
ñ Psychiatrist/psychologist
ñ Social worker
ñ Hepatologist
ñ Transplant specialist
The unit should be dedicated but not
isolated. The staff requires a career structure
with promotion possibilities and regular
contact with other branches of medicine;
otherwise, doctors and nurses can be afraid
of losing skills and missing promotion
opportunities, and as a result they may be
unwilling to work in the unit. It is essential
that staff turnover of the unit is kept as low
155
as possible, in order to provide continuity of
care. The staff must include a charge
nurse/nurse practitioner who supervises the
nursing staff.
The thalassaemia unit should operate on an
outpatient basis: facilities for evening, night,
and overnight transfusion help minimise
inconvenience to the patient’s social life.
P a e d i at r i c v s . ad u l t c ar e
The choice between a paediatric or adult
medicine setting may be crucial. Paediatric
centres, mainly in thalassaemia major,
accumulate more experience and are closer
to prevention of genetic disease. As
treatment opportunities improve, more
patients reach adulthood (Figure 1), with a
growing number of risk factors and
complications. This requires an approach
more like that of adult internal medicine.
Each patient’s transition from paediatric to
adult care must be accurate and smooth:
ñ transmission of complete clinical records
ñ shared discussion of past and current
clinical problems
ñ Ideally, a clinician with continued care as
patients progress from paediatric to adult
stages
Programming of
treatment
Transfusion therapy is ideally conducted
according to the procedure outlined in
Chapter 2: Blood Tranfusion Therapy in ‚-
Thalassaemia Major. The day of transfusion
should be utilised as effectively as possible –
ideally providing all treatment and other
medical services the patient needs during
one visit. This often includes:
 Figure 1: Changing pattern of age distribution in patients with thalassaemia
ñ Physical examination
ñ Clinical and laboratory tests, scheduled by
the treating physician on the basis of
guidelines and individual need.
ñ Clinical discussion of the case record
ñ Individual conversation to set goals,
renew critical information, and listen to
the patient (see Chapter 15: Psychological
Support in Thalassaemia)
ñ Ideally the patient should leave the
hospital after every transfusional event
with updated documentation.
Several programmes for thalassaemia patient
data have been set up. Some of them have
been computerised and can be distributed to
the interested centres upon request (TIF’s
website: www.thalassaemia.org.cy).
156
Interaction of the
thalassaemia unit
with other hospital
facilities
The unit must be closely connected with:
ñ A blood bank
ñ A general laboratory
ñ If available, a special laboratory unit,
which runs all specific procedures used in
the diagnosis, follow-up and monitoring
treatment of thalassaemia,
ñ The clinical resources of the departments
of paediatrics, internal medicine and
haematology/oncology critical for
thalassaemia (see specialists).
 Figure 2: An example of organisational interaction of the thalassaemia unit with other hospital
facilities [Kattamis 1989]
The well-functioning blood bank is of primary
importance for the management of
thalassaemia. Its functions are not only to
find the huge amount of blood needed for
the treatment of thalassaemia, but also to
secure the ideal blood for the patient, in
order to minimise the risks involved in
transfusion (e.g. alloimmunisation and
infections). The doctor from the Thalassaemia
Unit must keep blood bank staff sensitised to
the needs of chronically transfused patients
The supervising physician should schedule
regular meetings of the staff for the purpose
of:
157
ñ Updating staff on new aspects of
thalassaemia and its treatment
ñ Discussing and resolving organisational
aspects of the unit’s activities
ñ Renewing staff motivation to work in the
field of thalassaemia, so as to prevent
professional burnout
The organisation of a
Thalassaemia Unit
The organisation of the Thalassaemia Unit in
this fashion optimises treatment, while
ensuring the greatest possible level of
comfort and convenience for patients with
thalassaemia and their families. It is essential
that patients with thalassaemia feel that the
unit is their own place, and that the medical
staff have the patients’ best interests as top
priority. Long-term management implies
collaboration of the patient and the family
with the well-organised thalassaemia unit
team, to ensure continuous, appropriate
treatment and a long and productive life for
the patient with thalassaemia.
A Thalassaemia Unit is expected to be a
centre of expertise for the management of a
chronic disorder. As such, it should be in a
position to provide multidisciplinary
knowledge, as described above, with the aim
of improving both survival and quality of life.
In addition, the centre will provide support to
local physicians treating patients with limited
access to expert centres, mainly due to
distance.
The European Union has established criteria
for such centres of expertise (Rare Disease
Task Force Criteria), which could be used as a
standard in organising or running an expert
or Reference Centre, such as:
158
ñ Capacity for expert diagnosis
ñ Expert clinical management
ñ The use of outcome measures and quality
control, including survival and
complication rates, quality of life
measures and other measures of patient
interest
ñ Sufficient activity – which means a
minimum number of patients to ensure
adequate staff experience for quality care
ñ High level expertise and experience of
staff
ñ Epidemiological surveillance, including
patient registers
ñ Collaboration with national and
international centres
ñ Close links with patient associations
In such a system, the patient is fully
supported for self-management and is
considered a partner in the decisions
affecting his/her treatment, a fact that may
assist in patient adherence to long-term
treatment protocols.
Outline of Diagnostic
Dilemmas in Thalassaemia

II -- IIn
nccrreeaasseedd ttrraannssffuussiioonn rreeqquuiirreem
meennttss VIIII -- W
V Woorrsseenniinngg jjaauunnddiiccee
A - Hypersplenism A - Gilberts
B - Alloantibody B - Increased haemolysis
C - Autoantibody C - Drug Reaction
D - Infection with HPV-B19 virus D - Liver failure

IIII -- FFe
evveerr VIIIIII -- LLeegg ccrraam
V mppss
A - Infection due to Bacterial A - Hypocalcaemia
B - Yersinia B - Hypoparathyroidism
C - Klebsiella
D - Delayed transfusion reaction
Diagnostic Dilemmas
IIIIII -- B
Baacckk PPaaiinn
in Thalassaemia
A - Osteoporosis and microfractures
B - Prolapse in disc Thalassaemia is an extremely demanding
C - End plate degeneration disease. Patients must commit themselves to
D - Prolapse a lifetime of transfusion and chelation
therapy, with all its attendant side effects. At
IIV
V -- UUnneexxppllaaiinneedd AAbbddoom
miinnaall PPaaiinn the same time, thalassaemia poses
considerable challenges to treating
A - Cholelythiasis physicians, who often struggle to resolve
B - Pancreatitis competing complaints that together pose
C - Portal vein thrombosis diagnostic dilemmas. The following chapter
D - Renal stones addresses some of those dilemmas, including
E - Hepatic capsule distension increased transfusion requirements, fever,
F - Yersinia back pain, abdominal pain, chest pain,
dyspnoea, worsening jaundice and leg
V -- CChheesstt PPaaiinn
V cramps.

II.. IInnccrreeaasseedd ttrraannssffuussiioonn

A - Pericarditis and myocarditis

rreeqquuiirreemmeennttss
B - Rib fracture (extramedullary expansion)
C - Pulmonary embolism

VII -- DDyyssppnnooeeaa
V The recommended treatment for
A - Dysrhythmia thalassaemia major involves regular blood
B - Delayed Transfusion reaction transfusions, usually administered every two
G - Pump failure to five weeks, to maintain the pre-
D - Pulmonary hypertension transfusion haemoglobin level above 9-10.5
g/dl. This transfusion regimen promotes
normal growth, allows normal physical
activities, adequately suppresses bone
marrow activity and minimises transfusional
iron accumulation. While shorter intervals
between transfusions may reduce overall

159
blood requirements, the choice of interval
must take into account other factors, such as
the patient’s work or school schedule.
Reasons for increased consumption include
hypersplenism, new alloantibodies, infection
and changes in the haematocrit of
transfused units.
II--A
A.. HHyyppeerrsspplleennssiissm
m
Throughout the care of the patient with
thalassaemia, the size of the spleen should
be carefully monitored on physical
examination and, as needed, by
ultrasonography. Physicians should be on the
look out for hypersplenism with stasis,
trapping and destruction of red blood cells in
an enlarged spleen.
Splenectomy should be considered when
annual blood requirements exceed 1.5 times
those of splenectomised patients, provided
that they are on the same transfusion
scheme and have no other reasons for
increased consumption. (Reasons for
increased blood requirements include new
alloantibodies, infection and changes in the
haematocrit of transfused units.)
Enlargement of the spleen is accompanied by
symptoms such as left upper quadrant pain
or early satiety, or when massive
splenomegaly causes concern about possible
splenic rupture.
II--B
B.. AAllllooaannttiibbooddyy
The development of one or more specific red
cell antibodies (alloimmunisation) is a
common complication of chronic transfusion
therapy. Thus it is important to carefully
monitor patients for the development of
new antibodies and to eliminate donors with
corresponding antigens. Anti-E, anti-C and
160
anti-Kell alloantibodies are most common.
However, 5-10% of patients present with
alloantibodies against rare erythrocyte
antigens or with warm or cold antibodies of
unidentified specificity.
Autoimmune haemolytic anaemia is a very
serious complication of transfusion therapy
usually combined with underlying
alloimmunisation. Even red cells from
seemingly compatible units may have
markedly shortened survival, and
haemoglobin concentration may fall well
below the usual pre-transfusion level.
Destruction both of the donor red cells and
of the recipient’s red cells occurs. Steroids,
immunosuppressive drugs and intravenous
immunoglobulin are used for the clinical
management of this situation, although they
may give little benefit. Autoimmune
haemolytic anaemia may occur more
frequently in patients beginning transfusion
therapy later in life.
II--C
C.. AAuuttooaannttiibbooddyy
Autoimmune haemolytic anaemia (AIHA)
refers to a collection of disorders
characterised by the presence of
autoantibodies that bind to the patient's own
erythrocytes, leading to the premature
destruction of red cells. Specific
characteristics of the autoantibodies
(especially the type of antibody), its optimal
binding temperature, and whether
complement is fixed, constitute factors that
influence the clinical picture. However, in all
cases of AIHA the autoantibody leads to a
shortened red blood cell survival (i.e.,
haemolysis) and, when the rate of haemolysis
exceeds the ability of the bone marrow to
replace the destroyed red cells, to anaemia
and its attendant signs and symptoms.
II--D
D.. IIn
nffeeccttiio
onnw
wiitth
hHHP
PVV--B
B1199
Parvovirus B 19 - In patients with an already
shortened red cell lifespan (15-20 days) and a
low haemoglobin level due to haematological
disorders such as spherocytosis, sickle-cell
anaemia, autoimmune haemolytic anaemia
and thalassaemia, B 19 infection may cause
an acute, life-threatening red cell aplasia,
commonly referred to as “transient aplastic
crisis”. The cessation of erythropoiesis lasts
for 5-7 days and haematologically
complicates chronic haemolytic anaemia.
Attention must thus be given not only to
aplastic crises, but also to other clinical
problems such as myocarditis, which may
indicate infection with the virus.
IIII.. FFe
evveerr
Fever is an elevation of body temperature
that exceeds the normal daily variation. A
wide differential exists, spanning all types of
infections from bacterial to viral to fungal,
along with a multitude of syndromes and
organic diseases leading to fever.
IIII--AA.. IIN
NFFEEC
CTTIIO
ONND
DUUEE TTO
O chelation should not be restarted until the
B
BA AC CTTEERRIIA
A patient has been asymptomatic for over a
In patients with thalassaemia, the causes may
include other infections with Klebsiella and
Yersinia, or other bacterial pathogens and
delayed transfusion reactions. Iron overload
and infection are common causes of death.
Hence clinical experience mandates that
fever and infection, even in the non-
splenectomised patient, be thorough;y
investigated and treated swiftly and
aggressively. It is recommended that iron
chelation be stopped while the cause of
unidentified fever is investigated.
161
IIII--B
B.. YYeerrssiin
niiaa
Unlike most other bacteria, Yersinia
enterocolitica makes no siderophores of its
own and therefore lives most efficiently in an
iron-rich environment such as that found in
unchelated patients with thalassaemia or
uses the DFO in chelating patients which is a
siderophore to obtain iron and thrive. The
Yersinia organism is most commonly
transmitted by the ingestion of
contaminated food, meat, milk or water,
although it is commensal in healthy
individuals. It can also be transmitted
through blood.
Fever is the most common presenting
feature, often associated with abdominal
pain and diarrhoea or vomiting. Extra
gastrointestinal manifestations, such as
arthralgia and skin rashes, are sometimes
seen. Complications may include abdominal
abscess (right iliac fossa), nephritis or splenic
abscess.
Generally antibiotics are continued for at
least two weeks after proven infection. Iron
week. Relapse after restarting
desferrioxamine has been noted in some
cases. If this occurs, a longer period of oral
antibiotics may be necessary to eradicate the
infection. Iron chelation can be
recommenced after the infection has been
eliminated.
IIII--C
C.. KKlleeb
bssiieellllaa
Of the multitude of bacteria described in
association with iron overload, Klebsiella
species should be addressed as a potential
pathogen. In vitro Klebsiella species have
been shown to have increased virulence in
the presence of excess iron. Infection with
Klebsiella can be fatal in patients with
thalassaemia.
Although there is evidence of altered host
immunity in thalassaemia syndromes, only
limited information is available regarding the
effects or functions of mononuclear
phagocytes in relation to micro-organisms
and the influence of iron overload and iron
chelation on their activity and pathogenicity.
IIII--D
D.. DDeellaayyeed
d ttrraan
nssffu
ussiio
onn
rreeaaccttiio
onn
Delayed transfusion reactions occur 5-10
days after transfusion and are characterised
by anaemia, malaise and jaundice. These
reactions may be due to an alloantibody that
was not detectable at the time of transfusion
or to the development of a new antibody. A
sample should be sent to the blood bank to
look for a new antibody and to re-
crossmatch the last administered units.
IIIIII.. B
Baacckk P
Paaiin
n abnormal. Marrow expansion causes dramatic
Back symptoms are the most common cause
of disability in patients and account for a
huge portion of primary care physician visits.
The differential spans congenital anomalies
of the lumbar spine (spondylolysis,
spondylolisthesis), trauma with sprains and
strains, lumbar disk disease and organic
causes such as osteoporosis.
Patients with thalassaemia experience myriad
bone complications. The differential diagnosis
includes osteoporosis, microfarctures, disc
prolapse and end plate degeneration.
162
IIIIII--A
A.. O
Osstteeo
oppo
orro
ossiiss
There is a high incidence of osteoporosis of
the spine and hip in both sexes in
thalassaemia, with severity increasing with
age. Even young patients exhibit a spinal
bone mineral density far below that of age-
matched controls.
IIIIII--B
B,, IIIIII--C
C&& IIIIII--D
D..
Miiccrro
M offrraaccttuurreess,, ddiisscc p
prro
ollaap pssee
aan nd de en nd dp pllaatte
ed de eg
geen neerraattiio
onn
Patients with thalassaemia may exhibit
dramatic skeletal abnormalities, frequently
leading to marked changes in the facial
structure and body habitus and delayed
skeletal maturation. Skeletal changes are due
largely to the expansion and invasion of
erythroid bone marrow, which widen the
marrow spaces, attenuate the cortex and
produce osteoporosis.
The skull and facial bones are often strikingly
widening of the diploic spaces and produces
a characteristic ‘hair-on-end’ radiographic
appearance of the skull. In addition, there is
prominent frontal bossing, delayed
pneumatisation of the sinuses and marked
overgrowth of the maxillae. As a result, the
upper incisors are ‘jumbled’ and the malar
eminences are especially prominent,
producing malocclusion and the
characteristic faces. The ribs and bones of
the extremities become box-like and
eventually convex, due to expansion of the
bone marrow. Premature fusion of the
epiphyses can result in characteristic
shortening of the limbs, particularly the
arms. Of equal concern is the thinning of the
cortices due to marrow expansion, which
often results in pathologic fractures.
Compression fractures of the spine, often
with spinal cord compression and neurologic
deficits, have been reported in children with
thalassaemia. Compression fractures and
paravertebral expansion of extramedullary
masses often become particularly prominent
in the second decade of life.
IIVV.. UUnneexxppllaaiinneedd aabbddoom
miinnaall
ppaaiinn
Correctly interpreting abdominal pain
constitutes a particular challenge in
thalassaemia. The list includes pain
originating in the abdomen (peritoneal,
mechanical obstruction, vascular, abdominal
wall), pain referred from extra abdominal
sites (thorax, spine, genitalia), metabolic
causes (uremia, porphyria) and neurogenic
causes.
Of the multiple complaints patients with
thalassaemia present with, unexplained
abdominal pain spans a wide differential
diagnosis including chloelythiasis,
pancreatitis, portal vein thrombosis, hepatic
capsule distention and kidney stones.
IIV
V--AA.. CChhoolleellyytthhiiaassiiss
A prominent feature of children with chronic
haemolytic anaemia is the development of
premature bilirubin gallstone disease and
biliary tract inflammation. This is particularly
true of children with ‚-thalassaemia, two-
thirds of which have multiple calcified
bilirubin stones by the age of 15.
Fortunately, true episodes of cholecystitis or
cholangitis are rare. In the absence of clear-
cut symptoms, gall bladder removal is thus
rarely indicated.
163
IIV
V--BB.. PPaannccrreeaattiittiiss
Acute pancreatitis is an inflammatory
condition of the pancreas characterised
clinically by abdominal pain and elevated
levels of pancreatic enzymes in the blood. A
number of conditions are known to induce
this disorder with varying degrees of
certainty. However, the pathogenesis of this
disorder is not fully understood.
Although a number of situations can
precipitate acute pancreatitis in humans, only
a small fraction of patients with these
predisposing factors develop the diseases—3
to 7 percent with gallstone, 10 percent of
alcoholics and a few patients with
hypercalcemia.
With regard to patients with thalassaemia,
pancreatitis is caused by myriad factors. First
and foremost is increased transfusion
requirement, leading to increased turnover
of red blood cells and hence further
precipitation of gallstones.
IIV
V--CC.. PPoorrttaall vveeiinn tthhrroom
mbboossiiss
Venous thrombo-embolism (VTE) is
increasingly recognised in paediatrics as a
complication of improved treatment
strategies for previously lethal childhood
diseases. The basic pathological process
underlying VTE is Virchow's triad (stasis,
endothelial injury and hypercoagulability).
Central venous catheters (CVCs), which
present a foreign intravascular surface,
damage vessel walls and disrupt blood flow,
are responsible for approximately 60 percent
of VTEs in children. In patients with
thalassaemia, CVCs are resorted to when
frequent transfusions are required.
Thrombosis of the hepatic venous system
usually occurs within the portal venous
system. Older children may develop portal
vein thrombosis (PVT) secondary to liver
transplantation, infections, splenectomy,
sickle cell disease or the presence of
antiphospholipid antibodies. PVT may
manifest acutely with symptoms of an acute
abdomen, particularly in adolescents, or be
asymptomatic for long periods of time until
symptoms reflecting chronic vascular
obstruction (portal hypertension) occur (e.g.,
splenomegaly or gastrointestinal bleeding
secondary to oesophageal varices). In
addition, the debris released from
intravascular destruction of red blood cells
may accumulate and plug the portal vein,
particularly after spelenctomy.
IIV
V--DD.. RReennaall ssttoonneess
The kidneys are frequently enlarged in
thalassaemia, due to the presence of
extramedullary haematopoiesis. Less well
understood is the tendency for the renal
tubules to be dilated. The urine is frequently
dark, due to increased concentrations of bile
pigments; large amounts of urate, uric acid
and oxalate are also seen.
IIVV--EE.. HHeeppaattiicc ccaappssuullee
ddiisstteennssiioonn
Hepatomegaly is prominent early on in
thalassaemia, due to increased red cell
destruction as well as extramedullary
erythropoiesis in the liver. Liver enlargement
tends to be somewhat more prominent in
children with thalassaemia than in those with
congenital haemolytic anaemia. Later in the
first decade of life, hepatomegaly becomes
fixed and non-reducible by blood transfusion,
due to development of cirrhosis secondary to
increased iron deposition. Even in the
164
absence of transfusion, the accelerated rate
of iron turnover enhances dietary iron
absorption from the gut, resulting in a
chronic state of iron overload. In the liver,
iron first infiltrates Kupffer cells and then
engorges hepatocytes, ultimately provoking
fibrosis and, potentially, end-stage liver
disease, in a manner analogous to that seen
in idiopathic haemochromatosis.
V.. CChheesstt ppaaiinn
V
Chest discomfort is one of the most common
challenges faced by physicians treating
thalassaemia patients. The differential
diagnosis includes conditions affecting
organs throughout the thorax and abdomen,
with prognostic implications that vary from
benign to life-threatening. Failure to
recognise potentially serious conditions such
as acute ischemic heart disease, aortic
dissection, tension pneumothorax or
pulmonary embolism can lead to serious
complications, including death. In
thalassaemics, the differential diagnosis spans
pericarditis and myocarditis, extramedullary
causes and pulmonary embolism.
VV--AA.. PPeerriiccaarrddiittiiss aanndd
myyo
m occaarrddiittiiss
Cardiac symptoms and premature death from
cardiac causes are still major problems in
thalassaemia. Heart complications are the
leading causes of death and one of the main
causes of morbidity. In the absence of
effective iron chelation therapy, many
patients develop evidence of iron-induced
myocardial damage with cardiac failure,
cardiac arrhythmia, sudden death or a
distressing slow death from progressive
congestive cardiac failure.
The regular assessment of cardiac status can
identify the early stages of heart disease,
enabling prompt intervention.
The characteristic lesion in the heart is
caused by iron deposition in the myofibres,
with associated myofibrillar fragmentation
and diminished mitochondrial volume per
myocyte. Classically, it has been suggested
that there is a poor correlation between
myocardial iron content, fibrosis and cardiac
functional impairment. Iron distribution in
the heart is relatively uneven. It has also
been suggested that viral myocarditis is a
contributing factor to acute cardiac
deterioration.
VV--BB.. RRiibb ffrraaccttuurree
((eexxttrraam
meedduullllaarryy eexxppaannssiioonn))
Extramedullary haematopoiesis (EMH) is a
compensatory mechanism where bone
marrow activity increases in an attempt to
overcome the chronic anaemia of
thalassaemia intermedia (TI), leading to the
formation of erythropoietic tissue masses
that primarily affect the spleen, liver and
lymph nodes. These masses can be detected
by magnetic resonance imaging (MRI). They
may cause neurological problems such as
spinal cord compression and paraplegia, and
intrathoracic masses. Extramedullary
haematopoiesis can be managed by
radiotherapy, since haematopoietic tissue is
highly radiosensitive, as well as transfusion
therapy and hydroxyurea.
V--CC.. PPuullm
moonnaarryy eem
mbboolliissm
m
V work up to reach a diagnosis. However,
Patients with TI have an increased risk of
thrombosis compared with a normal age and
sex-matched population and with
thalassaemia major patients, especially
following splenectomy. In TI patients,
165
pulmonary embolism occurs as part of the
full picture of thrombosis. Data indicate that
thrombotic events primarily occur in the
venous system, comprising deep vein
thrombosis (DVT) (40%), portal vein
thrombosis (19%), stroke (9%), pulmonary
embolism (12%) and others (20%). Moreover,
splenectomised patients have been shown to
have a higher risk of thrombosis than non-
splenectomised patients. There are several
possible reasons for this, including the
procoagulant activity of circulating damaged
red blood cells, as it is thought that RBC
remnants expose negatively charged
phosphatidyl-serine through the ‘flip-flop’
phenomenon and subsequently initiate
thrombosis.
Deep vein thrombosis, pulmonary
thromboembolism and recurrent arterial
occlusion have been described in patients
with TI, mostly occurring without any other
risk factors. It is important to be aware of
these complications since thromboembolism
plays an important role in cardiac failure.
VII.. DDyyssppnnooeeaa
V
A cardinal symptom of diseases affecting the
cardiorespiratory system is dyspnoea, defined
as an abnormally uncomfortable awareness
of breathing. The differential covers general
topics of obstructive disease of airways,
diffuse parenchymal lung diseases,
pulmonary vascular occlusive diseases,
diseases of the chest wall or respiratory
muscles, and heart diseases. Such an
extensive differential necessitates meticulous
dysrhythmia, pump failure, pulmonary
hypertension and delayed transfusion
reaction lead the list of probable causes of
dyspnoea in thalassaemia.
VII--AA.. DDyyssrrhhyytthhm
V miiaa
Significant cardiac disease from iron overload
typically occurs in the absence of symptoms.
However, when symptoms do occur, they
include palpitations, syncopes, shortness of
breath, epigastric pain, decreased exercise
tolerance and peripheral oedema. The
development of symptoms of heart failure
implies advanced disease with a poor
prognosis.
Once the ventricles have enlarged, cardiac
arrhythmias are more common. These tend
to be of atrial origin, but ventricular
tachycardia is also occasionally seen. Sudden
death is likely to be arrhythmic in origin and
is more likely to be due to ventricular
arrhythmia than atrial.
The decision to treat arrhythmias in patients
with thalassaemia must be carefully
considered, bearing in mind that iron toxicity
is the primary cause of this complication.
Intensive chelation treatment has been
demonstrated to reduce arrhythmias. In the
majority of instances, the arrhythmias are
supraventricular, although ventricular
tachycardia may occur in seriously ill
individuals. The development of arrhythmia
may be associated with a deteriorating
ventricular function and can be improved by
addressing the latter problem. Arrhythmias
require very careful assessment. For most
supraventricular arrhythmias, reassurance of
the patient is generally appropriate, whereas
patients with ventricular arrhythmias should
be warned as to the potential severity of
their condition.
VVII--BB.. DDeellaayyeedd ttrraannssffuussiioonn
rreeaaccttiioonn
Delayed haemolytic transfusion reactions
(DHTRs) are due to an anamnestic antibody
166
response occurring after re-exposure to a
foreign red cell antigen previously
encountered by transfusion, transplantation
or pregnancy. The antibody, often of the
Kidd or Rh system, is undetectable on
pretransfusion testing but increases rapidly in
titer following the transfusion.
These delayed reactions are seen generally
within 2 to 10 days after transfusion.
Haemolysis is usually extravascular, gradual
and less severe than in the case of acute
reactions, but rapid haemolysis can occur. A
falling hematocrit, slight fever, mild increase
in serum unconjugated bilirubin, and
spherocytosis on the blood smear may be
noted. The diagnosis is often made by the
blood bank when ordering more blood for
another transfusion, the direct antiglobulin
test and antibody screen which were
previously negative, now have become
positive.
VII--CC.. PPuum
V mpp ffaaiilluurree
The characteristic lesion in the heart is
caused by iron deposition in the myofibres,
with associated myofibrillar fragmentation
and diminished mitochondrial volume per
myocyte. Classically, it has been suggested
that there is a poor correlation between
myocardial iron content, fibrosis and cardiac
functional impairment. Iron distribution in
the heart is relatively uneven. It has also
been suggested that viral myocarditis is a
contributing factor to acute cardiac
deterioration.
An important distinguishing feature of
cardiac dysfunction due to iron overload is
the capacity of patients, if detected early, to
make a complete recovery with appropriate
chelation therapy. This fact may not be
widely appreciated by physicians and
cardiologists unaccustomed to dealing with
patients with thalassaemia. It must be
emphasised that supporting the failing
circulation in these patients for several weeks
may be required in order to achieve
recovery.
VII--DD.. PPuullm
moonnaarryy hhyyppeerrtteennssiioonn
V the following: unconjugated
Pulmonary hypertension (PHT) is prevalent in
patients with TI (59.1%), and is thought to be
the primary cause of congestive heart failure
(CHF) in this patient population. The
mechanism underlying PHT in TI is unclear,
although evidence indicates a local
pathophysiological response in the
pulmonary vascular bed that is independent
of thromboembolism due to DVT. Suggested
mechanisms include endothelial dysfunction
with increased inflammation and apoptosis,
decreased nitric oxide and nitric oxide
synthase production, pulmonary
haemosiderosis and local thrombosis. Several
echocardiographic studies have confirmed
that cardiac ejection fraction is rarely
affected in TI. Nevertheless, patients with TI
often have an increased cardiac output and
left ventricular wall dimensions proportional
to the dilutional volume overload secondary
to chronic anaemia.
As anaemia and iron overload are uncommon
in well-transfused and chelated patients with
thalassaemia major, they are likely to be at
the heart of the pathophysiology of PHT.
Regular transfusion and iron chelation
therapy is, therefore, indicated in TI patients
who are well-stratified according to the early
detection of PHT indices. Sildenafil has also
been successfully used to treat PHT, although
large-scale data for TI patients are lacking.
VIIII.. W
Woorrsseenniinngg jjaauunnddiiccee
V bilirubin production.
Jaundice, or icterus, is a yellowish
discoloration of tissue resulting from the
167
deposition of bilirubin. Tissue deposition of
bilirubin occurs only in the presence of
serum hyperbilirubinemia and is a sign of
liver disease or, less frequently, a haemolytic
disorder. Of the many diseases presenting
with icterus, physicians should suspect any of
hyperbilirubinemia, haemolytic, Crigler-Najjar
type II, Gilbert's syndrome, conjugated
hyperbilirubinemia, hepatocellular conditions,
cholestatic conditions and drugs. Malignant
causes should not be missed, including
pancreatic, gallbladder, ampullary and
cholangiocarcinoma.
In patients with thalassaemia, worsening
jaundice is another way of presenting to the
clinic. Hence the following discussion will
shed light on the differential of worsening
jaundice in thalassaemics.
VIIII--AA.. GGiillbbeerrtt’’ss ssyynnddrroom
mee
V
The most common inherited disorder of
bilirubin glucuronidation is Gilbert's
syndrome, which has also been called
"constitutional hepatic dysfunction" and
"familial nonhaemolytic jaundice". Although
many patients present as isolated cases, the
condition is known to run in families.
Gilbert's syndrome is usually diagnosed in
young adults who present with mild,
predominantly unconjugated
hyperbilirubinemia. It is rarely diagnosed prior
to puberty when alterations in sex steroid
concentrations affect bilirubin metabolism,
leading to increased plasma bilirubin
concentrations. The disorder is more
commonly diagnosed in males, possibly due
to their relatively higher level of daily
The physical examination is usually
unrevealing, except for icterus. However
situations that exaggerate hyperbilirubinemia
may bring the patient to medical attention
and have corresponding physical findings.
Thalassaemia patients with inherited Gilbert’s
syndrome are at increased risk for haemolysis
and, as a result, would present with clinical
manifestations of icterus and elevated
bilirubin.
VIIII--BB.. IInnccrreeaasseedd hhaaeem
moollyyssiiss
V more pronounced in patients who are G6PD
Patients with thalassaemia are more
susceptible to haemolysis, whether
intracorpuscular (intrinsic) or
extracorpuscular (a distinction made here
because the causes of intrinsic RBC defects
are all hereditary). Injury to the RBC
membrane due to the production of excess
·- or ‚-globin genes in thalassaemia is an
example of an intrinsic defect leading to
haemolysis. Extracorpuscular causes of
haemolysis, on the other hand, are almost
always acquired conditions that lead to the
accelerated destruction of otherwise normal
RBCs. Examples include antibodies directed
against RBC membrane components, such as
autoimmune haemolytic anaemia,
alloimmune haemolytic anaemia, delayed
(haemolytic) transfusion reaction, and some
drug-induced haemolytic anaemias.
Hypersplenism, which includes stasis,
trapping and destruction of RBC in an
enlarged spleen, is also part of
extracorpuscular haemolysis.
VIIII--CC.. DDrruugg rreeaaccttiioonnss
V One-third of patients with thalassaemia major
A variety of drugs have been implicated as
causes of drug-induced oxidant haemolysis.
Although any defect in the antioxidant
defence mechanisms, such as G6PD
deficiency, substantially increases
susceptibility to haemolysis, the drugs
referred to below can produce oxidative
168
haemolysis even in normal subjects, usually
within hours to days after the onset of
exposure to the agent.
Amyl nitrite and butyl nitrite, primarily via
inhalation, have been used to increase sexual
arousal. Nitrites bind to haemoglobin,
producing methemoglobinemia that may be
so profound as to induce coma. The resulting
methemoglobinemia and haemolysis may be
deficient. The possible presence of the latter
disorder should be suspected if methylene
blue infusion does not quickly turn the
chocolate colour of blood back to normal.
VIIII--DD.. LLiivveerr ffaaiilluurree
V
Hepatitis due to viral (B and C) infections is
less frequent in TI than in patients with
thalassaemia major, since blood transfusions
are much less common in TI. Abnormal liver
enzymes (e.g., increased alanine and
aspartate aminotransferase) are frequently
observed in TI patients, primarily due to
hepatocyte damage resulting from iron
overload. Normalisation of liver enzyme levels
is often observed during appropriate
chelation therapy.
VIIIIII.. LLeegg ccrraam
mppss
V
Electrolyte disturbances such as
hypocalcemia, endocrine deficiencies and
neuromuscular and vascular issues may all
result in leg cramps.
suffer from leg cramps, muscle wasting and
weakness. The differential diagnosis includes
hypocalcemia and hypoparathyroidism.
VIIIIII--AA.. HHyyppooccaallccaaeem
miiaa
V
Several acquired causes of
hypoparathyroidism have been identified in
children, including thyroid surgery and iron
deposition in the parathyroid gland as a
result of frequent transfusions (as in ‚-
thalassaemia major).

VIIIIII--BB.. HHyyppooppaarraatthhyyrrooiiddiissm
V m
In the past two decades, several cases of
hypoparathyroidism (HPT) in ‚-thalassemia
major have been observed. HPT is thought to
be mainly the consequence of iron
deposition in the parathyroid glands. The
onset of HPT was preceded or followed in
most patients by other endocrine and/or
cardiac complications. No clear relationship
between HPT and serum ferritin levels was
established, suggesting either an individual
sensitivity to iron toxicity or early damage of
the parathyroid gland before chelation.
Furthermore, the fact that no new cases of
HPT have been diagnosed at a time when
improved chelation therapy regimes have
been introduced suggests that chelation may
have helped to prevent the development of
HPT.

169
REFERENCES
A Thalassaemia heart disease: a comparative
Aessopos A, Stamatelos G, Skoumas V,
Vassilopoulos G, Mantzourani M, Loukopoulos
D. Pulmonary hypertension and right heart
failure in patients with beta-thalassemia
intermedia.
Chest 1995;107:50-3.
Aessopos A, Farmakis D, Karagiorga M,
Voskaridou E, Loutradi A, Hatziliami A, Joussef
J, Rombos J, Loukopoulos D. Cardiac
involvement in thalassemia intermedia: a
multicenter study.
Blood 2001;97:3411-6.
Aessopos A, Farmakis D, Deftereos S, Tsironi
M, Tassiopoulos S, Moyssakis I, Karagiorga M.
Thalassemia heart disease: a comparative
evaluation of thalassemia major and
thalassemia intermedia.
Chest 2005;127:1523-30.
Aessopos A, Farmakis D. Pulmonary
hypertension in beta-thalassemia.
Ann N Y Acad Sci 2005;1054:342-9.
Aessopos A, Kati M, Farmakis D. Heart disease
in thalassemia intermedia: a review of the
underlying pathophysiology.
Haematologica 2007;92:658-65.
Aessopos A, Farmakis D, Taktikou H,
Loukopoulos D. Doppler-determined peak
systolic tricuspid pressure gradient in persons
with normal pulmonary function and
tricuspid regurgitation.
J Am Soc Echocardiogr 2000;13:645-9.
Aessopos A, Kati M, Meletis J. Thalassemia
intermedia today: should patients regularly
receive transfusions?
Transfusion 2007;47:792-800.
170
Aessopos A, Farmakis D, Deftereos S et al.
evaluation of thalassaemia major and
thalassaemia intermedia.
Chest. 2005;127:1523-1530
Aessopos A, Farmakis D, Karagiorga M et al.
Cardiac involvement in thalassaemia
intermedia: a multicentre study.
Blood. 2001:97;3411-3416
Aessopos A, Karabatsos F, Farmakis D,
Katsantoni A, Hatziliami A, Youssef J,
Karagiorga M. Pregnancy in patients with
well-treated beta-thalassaemia: outcome for
mothers and newborn infants. Am J Obstet
Gynecol. 1999 Feb;180(2 Pt 1):360-5
Agarwal, M.B., Gupte, S.S., Viswanathan, C.,
Vasandani, D., Ramanathan, J., Desai, N.,
Puniyani, R.R. & Chhablani, A.T. (1992) Long-
term assessment of efficacy and safety of L1,
an oral iron chelator, in transfusion
dependent thalassaemia: Indian trial.
Br J Haematol, 82, 460-466.
Al-Refaie, F.N., Wonke, B., Hoffbrand, A.V.,
Wickens, D.G., Nortey, P. & Kontoghiorghes,
G.J. (1992) Efficacy and possible adverse
effects of the oral iron chelator 1,2-
dimethyl-3-hydroxypyrid-4-one (L1) in
thalassemia major [see comments].
Blood, 80, 593-599.
American Association of Blood Banks
Technical Manual, 15th Edition, Brecher M,
Editor, 2005, Bethesda, MD. Anderson LJ,
Westwood MA, Prescott E, Walker JM, Pennell
DJ, Wonke B. Development of thalassaemic
iron overload cardiomyopathy despite low
liver iron levels and meticulous compliance to
desferrioxamine.
Acta Haematol. 2006;115(1-2):106-8
Anderson LJ, Westwood MA, Holden S et al.
Myocardial iron clearance during reversal of
siderotic cardiomyopathy with intravenous
desferrioxamine: a prospective study using
T2* cardiovascular magnetic resonance. Br J
Haematol.
2004 November;127(3):348-55
Anderson LJ, Wonke B, Prescott E, Holden S,
Walker JM, Pennell DJ. Comparison of effects
of oral deferiprone and subcutaneous
desferrioxamine on myocardial iron
concentrations and ventricular function in
beta-thalassaemia. Lancet.
2002 August 17;360(9332):516-20
Anderson LJ, Holden S, Davis B et al.
Cardiovascular T2-star (T2*) magnetic
resonance for the early diagnosis of
myocardial iron overload. Eur Heart J.
2001 December;22(23):2171-9
Andreani M, Nesci S, Lucarelli G, Tonucci P,
Rapa S, et al. 2000. Long-term survival of ex-
thalassemic patients with persistent mixed
chimerism after bone marrow
transplantation.
Bone Marrow Transplant 2000;. 25: 401-4
Angastiniotis M, Modell B. Global
epidemiology and haemoglobin disorders.
Ann NY Acad Sci. 1998;850:251-269
Angelucci E, Muretto P, Nicolucci A et al.
Effects of iron overload and HCV positivity in
determining progression of liver fibrosis in
thalassaemia following bone marrow
transplantation.
Blood. 2002;100:17-21
Angelucci E, Lucarelli G. Bone marrow
Transplantation for Thalassemia. In Disorders
of Hemoglobin – Genetics, pathophysiology,
and clinical managements. Edited by Martin H
Steinberg, Bernard G. Forget, Douglas R
171
Higgs and Ronald L. Nagel. Cap 39, pag 1052-
1072.
2001 Cambridge University Press
Angelucci E, Brittenham GM, McLaren CE, et
al. Hepatic iron concentration and total body
iron stores in thalassaemia major. N Engl J
Med.
2000 Aug 3;343(5):327-31
Angelucci, E., Giovagnoni, A., Valeri, G., Paci,
E., Ripalti, M., Muretto, P., McLaren, C.,
Brittenham, G.M. & Lucarelli, G. (1997)
Limitations of magnetic resonance imaging in
measurement of hepatic iron.
Blood, 90, 4736-4742.
Angelucci E, Muretto P, Lucarelli G, Ripalti M,
Baronciani D, Erer B, Galimberti M, Giardini C,
Gaziev D, Polchi P. Phlebotomy to reduce
iron overload in patients cured of thalassemia
by bone marrow transplantation. Italian
Cooperative Group for Phlebotomy
Treatment of Transplanted Thalassemia
Patients.
Blood 1997; 90: 994-8
Angelucci E, Baronciani D, Lucarelli G et al.
Needle liver biopsy in thalassaemia: analyses
of diagnostic accuracy and safety in 1184
consecutive biopsies.
Br J Haematol. 1995;89:757-61
Anie KA, Massaglia P. Psychological therapies
for thalassaemia. Cochrane Database Syst
Rev. 2001;(3):CD002890
Antoniou M and Grosveld F. (1999) Genetic
approaches to therapy for the
haemoglobinopathies. In: Blood Cell
Biochemistry, Volume 8: Hematopoiesis and
Gene Therapy, Fairbairn and Testa (eds).
Kluwer, New York. 219-242
Ansari S, Kivan AA, Tabaroki A. Pregnancy in
patients treated for beta thalassaemia major
in two centres (Ali Asghar Children's Hospital
and Thalassaemia Clinic): outcome for
mothers and newborn infants. Pediatr
Hematol Oncol. 2006;23:33-7
Arden, G.B., Wonke, B., Kennedy, C. &
Huehns, E.R. (1984) Ocular changes in
patients undergoing long term
desferrioxamine treatment.
British Journal of Ophthalmology, 68, 873-
877.
Aswapokee P, Aswapokee N, Fucharoen S,
Sukroongreung S, Wasi P. “Severe infection in
thalassaemia: a prospective study.”
Birth Defects 1988a;23:521-6
B
Bank A, Dorazio R and Leboulch P. A phase I/II
clinical trial of b-globin gene therapy for b-
thalassaemia.
Ann N Y Acad Sci. 2005;1054:308-316
Bhanu NV, Trice TA, Lee YT, Miller JL. A
signalling mechanism for growth-related
foetal haemoglobin.
Blood. 2004;103:1929-1933
Blake, D.R., Winyard, P., Lunec, J., Williams,
A., Good, P.A., Crewes, S.J., Gutteridge,
J.M.C., Rowley, D., Halliwell, B., Cornish, A. &
Hider, R.C. (1985) Cerebral and ocular toxicity
induced by desferrioxamine.
Quarterly Journal of Medicine, 56, 345-355.
Bohacek R, Boosalis MS, McMartin C, Faller
DV, Perrine SP. Identification of novel small
molecule inducers of foetal haemoglobin
using pharmacophore and “pseudo” receptor
models. Chemical Biology & Drug Design.
2006;67:318-328
172
Boone KE, Watters DA. The incidence of
malaria after splenectomy in Papua New
Guinea. Br Med J. 1995;311(7015):1273
Boosalis MS, Castaneda SA, Faller DV, Perrine
SP. Expression of Bcl-family proteins in beta-
thalassaemia [abstract].
Blood. 2003;102:517a
Boosalis MS, Bandyopadhyay R, Bresnick EH,
et al. Short-chain fatty acid derivatives
stimulate cell proliferation and induce STAT-5
activation. Blood. 2001;97:3259-3267
Borgna-Pignatti, C., Cappellini, M.D., De
Stefano, P. et al. Cardiac morbidity and
mortality in Desferrioxamine or Deferiprone-
treated patients with thalassaemia major.
Blood (2006), 107(9): 3733-3737.
Borgna-Pignatti C. Thalassaemia. A few new
tiles in a large mosaic. Haematologica.
2006 Sep;91(9):1159-61. Review
Borgna-Pignatti C, Rigon F, Merlo L et al.
Thalassaemia minor, the Gilbert mutation,
and the risk of gallstones.
Haematologica. 2003;88:1106-1109
Borgna-Pignatti C, Rugolotto S, De SP et al.
Survival and complications in patients with
thalassemia major treated with transfusion
and deferoxamine. Haematologica 2004
October;89(10):1187-93.
Borgna-Pignatti C, et al. “Survival and disease
complications in thalassaemia major.” Annals
of the New York Academy of Sciences.
1998 Jun 30;850:227-31
Bosquet, J., Navarro, M., Robert, G., Aye, P. &
Michel, F.B. (1983) Rapid desensitisation for
desferrioxamine anaphylactoid reaction.
Lancet, 2, 859-860.
Bourantas K, Economou G, Georgiou J.
Administration of high doses of recombinant
human erythropoietin to patients with beta-
thalassaemia intermedia: a preliminary trial.
Eur J Haematol. 1997;58:22-25
Braunwald E, Ingram R H. Dyspnea and
pulmonary oedema. (2005) In: Kasper D,
Braunwald E. Harrison's Principles of Internal
Medicine, 16th Edition. McGraw-Hill.
Ch 29:201-4
Brecker M, ed Technical Manul, 14TH ed
Bethesda, MD: American Association of Blood
Banks, 2003: 162
Brecker M, ed Technical Manul, 14TH ed
Bethesda, MD: American Association of Blood
Banks, 2003: 183
Brittenham G M, Griffith PM, et al. Efficacy of
deferoxamine in preventing complications of
iron overload in patients with thalassaemia
major.”
New Eng J Med. 1994;331(9):567-73
Brittenham, G.M., Cohen, A.R., McLaren, C.E.,
Martin, M.B., Griffith, P.M., Nienhuis, A.W.,
Young, N.S., Allen, C.J., Farrell, D.E. & Harris,
J.W. (1993) Hepatic iron stores and plasma
ferritin concentration in patients with sickle
cell anemia and thalassemia major.
Am J Hematol, 42, 81-85.
Buchholz DH, AuBuchon JP, Snyder EL,
Kandler R, Edberg S, Piscitelli V, Pickard C,
Napychank P. “Removal of Yersinia
enterocolitica from AS-1 red cells.”
Transfusion. 1992;32:667-72
Butwick A, Findley I, Wonke B. Management
of pregnancy in a patient with beta
thalassaemia major.
Int J Obstet Anesth. 2005;14:351-4
173
C
Camaschella C, Cappellini MD. Thalassaemia
intermedia. Haematologica. 1995;80:58-68
Cao H, Jung M, Stamatoyannopoulos G.
Hydroxamic acid derivatives induce g globin
gene expression in vivo [abstract].
Blood Cells Mol Dis. 2005;34:80
Cao H, Stamatoyannopoulos G, Jung M.
Induction of human gamma globin gene
expression by histone deacetylase inhibitors.
Blood. 2004;103:701-709
Cappellini, M.D., Cohen, A., Piga, A., Bejaoui,
M., Perrotta, S., Agaoglu, L., Aydinok, Y.,
Kattamis, A., Kilinc, Y., Porter, J., Capra, M.,
Galanello, R., Fattoum, S., Drelichman, G.,
Magnano, C., Verissimo, M., Athanassiou-
Metaxa, M., Giardina, P., Kourakli-Symeonidis,
A., Janka-Schaub, G., Coates, T., Vermylen, C.,
Olivieri, N., Thuret, I., Opitz, H., Ressayre-
Djaffer, C., Marks, P. & Alberti, D. (2006) A
phase 3 study of deferasirox (ICL670), a
once-daily oral iron chelator, in patients with
beta-thalassemia. Blood, 107, 3455-3462.
Cappellini MD. Overcoming the challenge of
patient compliance with iron chelation
therapy. Semin Hematol. 2005;42:S19-S21
Cappellini MD, Cerino M, Marelli S, Fiorelli G.
Thalassaemia intermedia: clinical aspects and
management. Haematologica.
2001;86(Suppl 1):194-196
Cappellini MD, Graziadei G, and Ciceri L, et al.
Oral isobutyramide therapy in patients with
thalassemia intermedia: Results of a phase II
open study. Blood Cells Mol Dis.
2000;26:105-111
Cappellini MD, Robbiolo L, Bottasso BM et al.
Venous thromboembolism and
hypercoagulability in splenectomised patients
with thalassaemia intermedia.
Br J Haematol. 2000;111:467-473
Carmina E, Di Fede G, Napoli N, et al.
Hypogonadism and hormone replacement
therapy on bone mass of adult women with
thalassaemia major.
Calcif Tissue Int. 2004;74:68-71
Castaneda SA, Faller DV, Perrine SP.
Alterations in Bcl-family proteins in _-
thalassaemic erythroid progenitors by novel
SCFADs.
Blood Cells Mols Dis. 2005;35(2):217-26
Castelli R, Graziadei G, Karimi M, Cappellini
MD. Intrathoracic masses due to
extramedullary haematopoiesis.
Am J Med Sci. 2004;328:299-303
Cabantchik, Z.I., Breuer, W., Zanninelli, G. &
Cianciulli, P. (2005) LPI-labile plasma iron in
iron overload. Best Pract Res Clin Haematol,
18, 277-287.
Cazzola M, Borgna-Pignatti C, et al. A
moderate transfusion regimen may reduce
iron loading in beta-thalassaemia major
without producing excessive expansion of
erythropoiesis.
Transfusion. 1997;37(2):135-40
Cazzola M, DeStrfano P, Ponchio L, Locatelli F,
Beguin Y, Dessi C, Barella S, Cao A, Galanello
R. Relationship between transfusion regimen
and suppression of erythropoiesis in _-
thalassaemia major. Br J Haem. 1995;89:473-
8 transfusional iron overload. Clin Endocrinol
Ceci, A., Baiardi, P., Catapano, M., Felisi, M.,
Cianciulli, P. et al. Risk factors for death in
174
patients with b-thalassaemia major: results of
a case-control study.
Haematologica (2006), 91(10): 1420-1.
Ceci, A., Baiardi, P., Felisi, M., Cappellini, M.D.,
Carnelli, V., De Sanctis, V., Galanello, R.,
Maggio, A., Masera, G., Piga, A., Schettini, F.,
Stefano, I. & Tricta, F. (2002) The safety and
effectiveness of deferiprone in a large-scale,
3-year study in Italian patients.
Br J Haematol, 118, 330-336.
Centis F, Tabellini L, Lucarelli G, et al. The
importance of erythroid expansion in
determining the extent of apoptosis in
erythroid precursors in patients with beta-
thalassemia major.
Blood. 2000;96:3624-3629.
Chan YL, Pang LM, Chik KW, Cheng JC, Li CK.
Patterns of bone diseases in transfusion-
dependent homozygous thalassaemia major:
predominance of osteoporosis and
desferrioxamine-induced bone dysplasia.
Pediatr Radiol. 2002;32:492-497
Chandcharoensin-Wilde C, Chairoongruang S,
Jitnuson P, Fucharoen S, Vathanopas C.
Gallstones in thalassaemia. Birth Defects.
1988;23:263-7
Chatterjee R GM, Helal MA. Hypogonadism is a
key contributor to the severity of
osteoporosis in thalassaemic patients. 10th
International Federation Conference (TIF)
October 18-21, 2001
Chatterjee R, Katz M. Reversible
hypogonadotrophic hypogonadism in sexually
infantile male thalassaemic patients with
(Oxf). 2000 Jul;53(1):33-42
Chehal A, Aoun E, Koussa S et al.
Hypertransfusion: a successful method of
treatment in thalassaemia intermedia
patients with spinal cord compression
secondary to extramedullary haematopoiesis.
Spine. 2003;28:E245-E249
Cherchi GB, Cossellu S, Pacifico L, Gallisai D,
Ranucci A, Zanetti S, Fadda G, Chiesa.
Incidence and outcome of Yersinia
enterocolitica infection in thalassaemic
patients. Contrib Microbiol Immunol.
1995;13:16-8
Chiodo, A.A., Alberti, P.W., Sher, G.D.,
Francombe, W.H. & Tyler, B. (1997)
Desferrioxamine ototoxicity in an adult
transfusion-dependent population. J
Otolaryngol, 26, 116-122.
Choudhry, V.P., Pati, H.P., Saxena, A. &
Malaviya, A.N. (2004) Deferiprone, efficacy
and safety. Indian J Pediatr, 71, 213-216.
Chung BH, Ha SY, Chan GC, Chiang A, Lee TL,
Ho HK, Lee CY, Luk CW and Lau YL. Klebsiella
infection in patients with thalassaemia. Clin.
Infect. Dis. 2003; 36 (5): 575-579.
Cohen, A., Masera, G., Zoumbos, N., Uysal, Z.,
Boulet, D., Watman, N., Loggetto, S., Opitz,
H., Gathmann, I. & Alberti, D. (2005) Effect of
iron intake on control of body iron in
patients with thalassemia major treated with
deferasisox. Blood, 106, Abstract 622.
Cohen, A.R., Galanello, R., Piga, A., De
Sanctis, V. & Tricta, F. (2003) Safety and
effectiveness of long-term therapy with the
oral iron chelator deferiprone. Blood, 102,
1583-1587.
Cohen, A.R., Galanello, R., Piga, A., Dipalma,
A., Vullo, C. & Tricta, F. (2000) Safety profile
175
of the oral iron chelator deferiprone: a
multicentre study. Br J Haematol, 108, 305-
312.
Cohen A, Markenson AL, Schwarz E.
“Transfusion requirements and splenectomy
in thalassaemia major.” Journal of Paediatrics.
1980;97:100-2
Collins AF, Pearson HA, Giardina P, McDonagh
KT, Brusilow SW, Dover GJ. Oral sodium
phenylbutyrate therapy in homozygous beta
thalassaemia: a clinical trial. Blood.
1995;85:39-43
Colombo M, de Franchis R, Del Ninno E, et al.
Hepatocellular carcinoma in Italian patients
with cirrhosis. N Engl J Med. 1991;325:675-
80
Constantoulakis P, Knitter G,
Stamatoyannopoulos G. On the induction of
foetal haemoglobin by butyrates: in vivo and
in vitro studies with sodium butyrate and
comparison of combination treatments with
5-AzaC and AraC. Blood. 1989;74:1963-1971
D
Daar, S., Taher, A., Pathare, A., Krahn, U.,
Gathmann, I., Nick, H. & Hadler, D. (2005)
Plasma LPI in Thalassemia Patients before and
after Treatment with Deferasirox (Exjade®,
ICL670). Blood, 106, Abstract 2697.
Das PM, Singal R. DNA methylation and
cancer. J Clin Oncol. 2004;22:4632-4642
Daskalakis GJ, Papageorgiou IS, Antsaklis AJ,
Michalas SK. Pregnancy and homozygous
beta thalassaemia major. Br J Obstet
Gynaecol. 1998;105:1028-32
Davies, S.C., Marcus, R.E., Hungerford, J.L.,
Miller, H.M., Arden, G.B. & Huehns, E.R.
(1983) Ocular toxicity of high-dose
intravenous desferrioxamine.
Lancet, 2, 181-184.
Davis, B.A., O'Sullivan, C., Jarritt, P.H. &
Porter, J.B. (2004) Value of sequential
monitoring of left ventricular ejection
fraction in the management of thalassemia
major. Blood, 104, 263-269.
Davis, B.A. & Porter, J.B. (2002) Results of
long term iron chelation treatment with
deferoxamine.
Adv Exp Med Biol, 509, 91-125.
Davis, B.A. & Porter, J.B. (2000) Long-term
outcome of continuous 24-hour
deferoxamine infusion via indwelling
intravenous catheters in high-risk beta-
thalassemia. Blood, 95, 1229-1236.
Deech R. Legal and ethical responsibilities of
gamete banks. Hum Reprod. 1998;May;13
Suppl 2:80-3;discussion 84-9. Review
De Luca, C., Filosa, A., Grandinetti, M.,
Maggio, F., Lamba, M. & Passi, S. (1999)
Blood antioxidant status and urinary levels of
catecholamine metabolites in beta-
thalassemia.
Free Radic Res, 30, 453-462.
De Virgillis, S., Congia, M., Frau, F., Argiolu,
F., Diana, G., Cucca, F., Varsi, A., Sanna, G.,
Podda, G. & Fodde, M. (1988)
Desferrioxamine-induced growth retardation
in patients with thalassaemia major. Journal
of Pediatrics, 113, 661-669.
Del Vecchio, G.C., Schettini, F., Piacente, L.,
De Santis, A., Giordano, P. & De Mattia, D.
(2002) Effects of deferiprone on immune
176
status and cytokine pattern in thalassaemia
major. Acta Haematol, 108, 144-149.
Dettelbach HR, Aviado DM. Clinical
pharmacology of pentoxifylline with special
reference to its haemorrheologic effect for
the treatment of intermittent claudication. J
Clin Pharmacol. 1985;25:8-26
Dinarello C A, Gelfand J A. Fever and
hyperthermia. (2005) In: Kasper D, Braunwald
E. Harrison's Principles of Internal Medicine,
16th Edition. McGraw-Hill. Ch 16:104-8
Dixit A, Chatterjee TC, Mishra P et al.
Hydroxyurea in thalassaemia intermedia-a
promising therapy. Ann Hematol.
2005;84:441-446
Dodd RY, Notari EP, Stramer SL. Current
prevalence and incidence of infectious
disease markers and estimated window-
period risk in the American Red Cross donor
population. Transfusion 42: 975-70, 2002.
Dunbar C, Travis W, Kan YW, Nienhuis AW. 5-
Azacytidine treatment in a beta (0)-
thalassemic patient unable to be transfused
due to multiple allo-antibodies. Br J
Haematol. 1989;72:467-468
Dzik WH. Leukoreduction of blood
components. Current Opinion in Hematology.
9:521-6, 2002.
E
Eldor A, Rachmilewitz EA. The
hypercoagulable state in thalassaemia. Blood.
2002;99:36-43
Engstrom J W. Back and neck pain. (2005) In:
Kasper D, Braunwald E. Harrison's Principles
of Internal Medicine, 16th Edition. McGraw-
Hill. Ch 15:94-104
Evered DC, Ormston BJ, Smith PA, Hall R, Bird
T. Grades of hypothyrodism. BMJ 1973;
I:657-662
F R., Leoni, G., Ladis, V., Voi, V., Lund, U. &
Fathallah H and Atweh GF. Induction of foetal
haemoglobin in the treatment of sickle cell
disease. Hematology, Am Soc Hematol Educ
Program. 2006; 58-62
Fiorelli G, Fargion S, Piperno A et al. Iron
metabolism in thalassaemia intermedia.
Haematologica. 1990;75(Suppl. 5);89-95
Fischer, R., Longo, F., Nielsen, P., Engelhardt,
R., Hider, R.C. & Piga, A. (2003) Monitoring
long-term efficacy of iron chelation therapy
by deferiprone and desferrioxamine in
patients with beta-thalassaemia major:
application of SQUID biomagnetic liver
susceptometry. Br J Haematol, 121, 938-948.
Freeman, A.P., Giles, R.W., Berdoukas, V.A.,
Walsh, W.F., Choy, D. & Murray, P.C. (1983)
Early left ventricular dysfunction and
chelation therapy in thalassemia major. Ann
Intern Med, 99, 450-454.
Friedman DF, Jawad AF, Martin MB, Horiuchi
K, Mitchell CF, Cohen AR:
Erythrocytapheresis to reduce iron loading in
thalassemia. Blood. 102:121a, 2003.
Fucharoen S, Siritanaratkul N, Winichagoon P,
et al. Hydroxyurea increases HbF levels and
improves the effectiveness of erythropoiesis
in beta thalassaemia/HbE disease. Blood.
1996;87:887-892
177
G
Gabutti, V. & Piga, A. (1996) Results of long-
term iron-chelating therapy. Acta Haematol,
95, 26-36.
Galanello, R., Kattamis, A., Piga, A., Fischer,
Tricta, F. (2006a) A prospective randomized
controlled trial on the safety and efficacy of
alternating deferoxamine and deferiprone in
the treatment of iron overload in patients
with thalassemia. Haematologica, 91, 1241-
1243.
Galanello, R., Piga, A., Forni, G.L., Bertrand, Y.,
Foschini, M.L., Bordone, E., Leoni, G.,
Lavagetto, A., Zappu, A., Longo, F., Maseruka,
H., Hewson, N., Sechaud, R., Belleli, R. &
Alberti, D. (2006b) Phase II clinical evaluation
of deferasirox, a once-daily oral chelating
agent, in pediatric patients with beta-
thalassemia major. Haematologica, 91, 1343-
1351.
Galanello, R., Piga, A., Alberti, D., Rouan,
M.C., Bigler, H. & Sechaud, R. (2003) Safety,
tolerability, and pharmacokinetics of ICL670,
a new orally active iron-chelating agent in
patients with transfusion-dependent iron
overload due to beta-thalassemia. J Clin
Pharmacol, 43, 565-572.
Galanello R, Piras S, Barella S et al.
Cholelithiasis and Gilbert's syndrome in
homozygous beta-thalassaemia. Br J
Haematol. 2001;115:926-928
Galanello R, Barella S, Turco MP, et al. Serum
erythropoietin levels and erythropoiesis in
high and low-foetal haemoglobin beta
thalassaemia intermedia patients. Blood.
1994; 83:561-565
Gallo E, Massero P, Miniero R, David D, Tarella
C. The importance of the clinical picture and
globin synthesis in determining the clinical
and haematological features of thalassaemia
intermedia. Blood. 1979; 41:211-221
Gambari R and Fibach E. Medicinal chemistry
of foetal haemoglobin inducers for treatment
of b-thalassaemia. Curr Med Chem.
2007;14:199-212
Gane EJ, Portmann BC, Naoumov NV, et al.
Long-term outcome of hepatitis C infection
after liver transplantation. N Engl J Med.
1996;334:815-20
Gimmon Z, Wexler WR, Rachmilewitz EA.
Juvenile leg ulceration in beta-thalassaemia
major and intermedia. Plast Reconstr Surg.
1982;69:320-325
Gane EJ, Portmann BC, Naoumov NV, et al.
Long-term outcome of hepatitis C infection
after liver transplantation. N Engl J Med
1996;334:815-20.
Global Report on Birth Defects, March of
Dimes, 24 – 25 (2006)
Gomber, S., Saxena, R. & Madan, N. (2004)
Comparative efficacy of desferrioxamine,
deferiprone and in combination on iron
chelation in thalassemic children. Indian
Pediatr, 41, 21-27.
H promoter in response to butyrate therapy.
Ha, S.Y., Chik, K.W., Ling, S.C., Lee, A.C., Luk,
C.W., Lam, C.W., Ng, I.O. & Chan, G.C. (2006)
A randomized controlled study evaluating the
safety and efficacy of deferiprone treatment
in thalassemia major patients from Hong
Kong.
Hemoglobin, 30, 263-274.
178
Haemoglobin E-beta-thalassemia. Thalassemia
International Federation, chapter 12, 2002.
Hajjar FM, Pearson HA. Pharmacologic
treatment of thalassaemia intermedia with
hydroxyurea. J Pediatr. 1994;125:490-492
Han XD, Lin C, Chang J, Sadelain M and Kan
YW. Foetal gene therapy of a-thalassaemia in
a mouse model. Proc Natl Acad Sci USA.
2007;104:9007-9011
Hershko, C. & Rachmilewitz, E. (1979)
Mechanism of desferrioxamine induced iron
excretion in thalassaemia. Brit. J. Haematol,
42, 125-132.
Hoffbrand, A.V., F, A.L.-R., Davis, B.,
Siritanakatkul, N., Jackson, B.F., Cochrane, J.,
Prescott, E. & Wonke, B. (1998) Long-term
trial of deferiprone in 51 transfusion-
dependent iron overloaded patients. Blood,
91, 295-300.
Hui L, Leung MP, Ha SY, Chau AK, Cheung YF.
Early detection of left ventricular dysfunction
in patients with beta-thalassaemia major by
dobutamine stress echocardiography. Heart.
2003;89:669-70
I
Ikuta T, Kan YW, Swerdlow PS, Faller DV,
Perrine SP. Alterations in protein-DNA
interactions in the gamma-globin gene
Blood. 1998;92:2924-2933
Inati A, Taher A, Ghorra S, Koussa S, Taha M,
Aoun E, Sharara AI. Efficacy and tolerability of
peginterferon alpha-2a with or without
ribavirin in thalassaemia major patients with
chronic hepatitis C virus infection. Br J
Haematol 2005;130:644-6
Ismail A, Campbell MJ, Ibrahim HM, Jones GL.
Health Related Quality of Life in Malaysian
children with thalassaemia. Health Qual Life
Outcomes. 2006;4:39.:39
Issargagrisil S, Piankijagum A, Wasi P. “Spinal
cord compression in thalassaemia. Report of
12 cases can recommendations for
treatment.” Archives of Internal Medicine.
1981;141:1033-6
J Koury MJ, Sawyer ST, Brandt SJ. New insights
Jensen, P.D., Jensen, F.T., Christensen, T.,
Nielsen, J.L. & Ellegaard, J. (2003)
Relationship between hepatocellular injury
and transfusional iron overload prior to and
during iron chelation with desferrioxamine: a
study in adult patients with acquired
anemias.
Blood, 101, 91-96.
K al., Myocarditis in beta-thalassaemia major: a
von Kalle C, Baum C and Williams DA. Lenti in
red: progress in gene therapy for human
haemoglobinopathies.
J Clin Invest. 2004;114:889-891
Karimi M, Darzi H, Yavarian M. Hematologic
and clinical responses of thalassaemia
intermedia patients to hydroxyurea during 6
years of therapy in Iran. J Pediatr.
Hematol. Oncol. 2005;27:380-385
Kattamis, A., Ladis, V., Berdousi, H., Kelekis,
N.L., Alexopoulou, E., Papasotiriou, I., Drakaki,
K., Kaloumenou, I., Galani, A. & Kattamis, C.
(2006) Iron chelation treatment with
combined therapy with deferiprone and
deferioxamine: a 12-month trial.
Blood Cells Mol Dis, 36, 21-25.
179
Kaul S, Tei C, Hopkins JM, Shah PM.
Assessment of right ventricular function
using two-dimensional echocardiography.
Am Heart Jour. 1984;107:526-31
Kontoghiorghes, G., Sheppard, L., Barr, J. &
al, e. (1988) Iron Balance studies with the
oral chelator 1,2,dimethyl-3-hydroxypyridin-
4-one. British Journal of Haematology, 69,
129(abstract).
into erythropoiesis. Curr Opin Hematol.
2002;9:93-100
Krajaejun T, Sathapatayavongs B, Pracharktam
R, Nitiyanant P, Leelachaikul P,
Wanachiwanawin W et al. Clinical and
epidemiological analyses of human pythiosis
in Thailand.
Clin Infect Dis. 2006;43(5):569-576
Kremastinos D, Tiniakos G, Theodorakis G et
cause of heart failure.
Circulation. 1995;91:66-71
Kuo HT, Peng CT, Tsai MY. Pilot study on
parental stress and behavioural adjustment
to the thalassaemia major disease process in
children undergoing iron-chelation in western
Taiwan. Hemoglobin. 2006;30(2):301-309
L
Landgren O, Bjorkholm M, Konradsen HB,
Soderqvist M, Nilsson B, Gustavsson A et al. A
prospective study on antibody response to
repeated vaccinations with pneumococcal
capsular polysaccharide in splenectomised
individuals with special reference to
Hodgkin's lymphoma. J Intern Med.
2004;255(6):664-673
Lasco A, Morabito N, Gaudio A, et al.
Osteoporosis and beta-thalassaemia major:
role of the IGF-I/IGFBP-III axis. J Endocrinol
Invest. 2002;25:338-344
Lasco A, Morabito N, Gaudio A, Buemi M,
Wasniewska M, Frisina N. Effects of hormonal
replacement therapy on bone metabolism in
young adults with beta-thalassaemia major.
Osteoporos Int. 2001;12:570-575
Leandros E et al. Hand-assisted laparoscopic
surgery with a Pfannenstiel incision in beta-
thalassaemia patients: initial experience.
World J Surg. 2006;30:1216-20
Lefrere JJ, Maniez-Montreuil M, Morel P,
Defer C, Laperche S. Safety of blood products
and B19 parvovirus. Transfus Clin Biol.
2006;13(4):235-241
Leung CF, Lao TT, Chang AM. Effect of folate
supplement on pregnant women with beta-
thalassaemia minor. Eur J Obstet Gynecol
Reprod Biol. 1989;33:209-13
Levings PP and Bungert J. The human b-
globin locus control region. Eur J Biochem.
2002;269:1589-1599
Ley TJ, DeSimone J, Anagou NP, et al. 5-
Azacytidine selectively increases g-globin
synthesis in a patient with beta+-
thalassaemia. N Eng J Med. 1982;307:1469-
1475
Li CK, Chan PK, Ling SC, Ha SY. Interferon and
ribavirin as frontline treatment for chronic
hepatitis C infection in thalassaemia major.
Br J Haematol. 2002;117:755-8
Lindsay KL. Management of chronic hepatitis
in special populations. Am J Med
1994;96:57S-60S.
180
Locatelli F, Rocha V, Reed W, Bernaudin F,
Ertem M, et al. Related umbilical cord blood
transplantation in patients with thalassemia
and sickle cell disease.
Blood 2003; 101: 2137 - 2143
Loukopoulos D, Voskaridou E, Stamoulakatou
A, et al. Hydroxyurea therapy in thalassaemia.
Ann N Y Acad Sci. 1998;850:120-128
Lowrey C. Epigenetic modifications of the
human b-globin LCR core elements and g-
globin gene promoters [abstract].
Blood Cells Mol Dis. 2005;34:104-105
Lowrey CH, Nienhuis AW. Brief report:
treatment with azacitidine of patients with
end-state b-thalassaemia.
N Eng J Med. 1993;329:945
Lucarelli G, Galimberti M, Polchi P, Angelucci
E, Baronciani D, Giardini C, Politi P, Durazzi
SM, Muretto P, Albertini F. Bone marrow
transplantation in patients with thalassemia.
N Engl J Med. 1990; 322:417-21.
M
Maggio, A., D'Amico, G., Morabito, A., Capra,
M., Ciaccio, C., Cianciulli, P., Di Gregorio, F.,
Garozzo, G., Malizia, R., Magnano, C.,
Mangiagli, A., Quarta, G., Rizzo, M., D'Ascola,
D.G., Rizzo, A. & Midiri, M. (2002) Deferiprone
versus deferoxamine in patients with
thalassemia major: a randomized clinical trial.
Blood Cells Mol Dis, 28, 196-208.
Mahachoklertwattana P. Zoledronic acid for
the treatment of thalassaemia-induced
osteonecrosis. Haematologica. 2006
Sep;91(9):1155A
Mahachoklertwattana P, Chuansumrit A,
Sirisriro R, Choubtum L, Sriphrapradang A,
Rajatanavin R. Bone mineral density,
biochemical and hormonal profiles in
suboptimally treated children and
adolescents with beta-thalassaemia disease.
Clin Endocrinol (Oxf). 2003;58:273-279
Miano M, Labopin M, Hartmann O, Angelucci
E, Cornish J, Gluckman E, Locatelli F, Fischer
A, Egeler RM, Or R, Peters C, Ortega J, Veys P,
Bordigoni P, Iori AP, Niethammer D, Rocha V,
Dini G. Trends of Haematopoietic Stem cell
Transplantation in Children during the last 3
decades: a survey from the Paediatric
Diseases Working Party of the European
Blood and Bone Marrow Transplantation
Group.
Bone Marrow Transplant 2007; 39: 89-99.
Mankidy, R, Faller, DV, Mabaera R, Lowrey C,
Boosalis M, White G, Castaneda SC, and
Perrine SP. Dissociation of an HDAC-3/ NCoR
repressor complex is associated with high-
level induction of the gamma-globin gene
promoter by potent SCFAD. Blood.
2006;108:3179-3186
Mariotti E, Angelucci E, Agostini A, Baronciani
D, Sgarbi E, Lucarelli G. Evaluation of cardiac
status in iron-loaded thalassaemia patients
following bone marrow transplantation:
improvement in cardiac function during
reduction in body iron burden. Br J
Haematol. 1998;103: 916-21
March of Dimes (2006). Global Report on
Birth Defects
Marzano A., Angelucci E, Andreone P et al.
Prophylaxis and treatment of hepatitis B in
immunocompromised patients. Digest Liver
Dis 2007; doi:10.1016/j.dld.2006.12.017
Massaglia P, Pozzan MT, Piga A, Davico S,
181
Luzzatto L, Carpignano M. Psychological
aspects of thalassaemia. Pediatr Med Chir.
1986;8(1):27-31
May A, Choiseul M. Sickle cell anaemia and
thalassaemia: symptoms, treatment and
effects on lifestyle.
Health Visit. 1988;61(7):212-215
May C, Rivella S, Callegari J, Heller G,
Gaenslerk KML, Luzzatto L and Sadelain M.
Therapeutic haemoglobin synthesis in b-
thalassaemic mice expressing lentivirus-
encoded human b-globin.
Nature. 2000;406:82-86
Michail-Merianou V, Pamphili-Panousopoulou
L, Piperi-Lowes L, Pelegrinis E, Karaklis A.
Alloimmunization to red cell antigens in
thalassemia: comparative study of usual
versus better-match transfusion
programmes.
Vox Sanguinis. 52:95-8, 1987.
Miccio A, Cesari R, Lotti F, Rossi C, Tiboni F,
Sanvito F, Ponzoni M, Routledge S, Antoniou
M and Ferrari G. Long-term correction of b-
thalassaemia by transplantation of
transduced hematopoietic stem cells.
Mol Ther. 2006;13, Supplement 1: S30
de Montalembert M, Girot R, Revillion Y, Jan
D, Adjrad L, Ardjoun FZ, Belhani M, Najean Y.
Partial splenectomy in homozygous _-
thalassaemia. Arch Dis Child. 1990;65:304-7
Modell B. Total management of thalassaemia
major. Arch Dis Child. 1977;52(6):489-500
Morabito N, Gaudio A, Lasco A, Atteritano M,
Pizzoleo MA, Cincotta M, La Rosa M, Guarino
R, Meo A, Frisina N. Osteoprotegerin and
RANKL in the pathogenesis of thalassaemia-
induced osteoporosis: new pieces of the
puzzle. J Bone Miner Res. 2004;19:722-7
Morell A, ZLB Central Laboratory Swiss Red
Cross, Bern Switzerland, 2000. Pathogen
inactivation of labile blood products
Mork CN, Faller DV, Spanjaard RA. A
mechanistic approach to anticancer therapy:
targeting the cell cycle with histone
deacetylase inhibitors. Curr Pharm Des.
2005;11:1091-1104
Mosely J. Editorial. Transfusion. 1994;34(9)
Mourad FH, Hoffbrand AV, Sheikh-Taha M et
al. Comparison between desferrioxamine and
combined therapy with desferrioxamine and
deferiprone in iron overloaded thalassaemia
patients. Br J Haematol. 2003;121:187-189
Muretto P, Angelucci E, Lucarelli G.
Reversibility of Cirrhosis in Patients Cured of
Thalassemia by Bone Marrow Transplantation.
Ann Intern Med 2002; 136:667-72.
N chelation therapy with deferiprone for
Nash KB. A psychosocial perspective. Growing
up with thalassaemia, a chronic disorder. Ann
N Y Acad Sci. 1990;612:442-50.:442-450
Nassar AH, Usta IM, Rechdan JB, Koussa S,
Inati A, Taher AT. Pregnancy in patients with
beta-thalassaemia intermedia: outcome of
mothers and newborns. Am J Hematol.
2006;81:499-502
National Evidence-Based Clinical Guidelines
Fertility: assessment and treatment for
people with fertility problems_. February
2004. http://www.rcog.org.uk.
Nienhuis AW, Dunbar CE and Sorrentino BP.
Genotoxicity of retroviral integration in
hematopoietic cells. Mol Ther. 2006;13:1031-
1049
182
Nisbet-Brown, E., Olivieri, N.F., Giardina, P.J.,
Grady, R.W., Neufeld, E.J., Sechaud, R.,
Krebs-Brown, A.J., Anderson, J.R., Alberti, D.,
Sizer, K.C. & Nathan, D.G. (2003)
Effectiveness and safety of ICL670 in iron-
loaded patients with thalassaemia: a
randomised, double-blind, placebo-
controlled, dose-escalation trial. Lancet, 361,
1597-1602.
Nisli G, Kavakli K, Vergin C, Oztop S, Cetingul
N. Recombinant human erythropoietin trial in
thalassaemia intermedia. J Trop Pediatr.
1996;42:330-334
O
Olivieri NF. The beta-thalassaemias, N Engl J
Med. 1999;341:99-109
Olivieri, N.F., Brittenham, G.M., McLaren, C.E.,
Templeton, D.M., Cameron, R.G., McClelland,
R.A., Burt, A.D. & Fleming, K.A. (1998) Long-
term safety and effectiveness of iron-
thalassemia major [see comments]. N Engl J
Med, 339, 417-423.
Olivieri, N.F. & Brittenham, G.M. (1997) Iron-
chelating therapy and the treatment of
thalassemia. Blood, 89, 739-761.
Olivieri NF, Rees DC, Ginder GD, et al.
Treatment of thalassaemia major with
phenylbutyrate and hydroxyurea. Lancet.
1997;350:491-492
Olivieri, N.F., Brittenham, G.M., Matsui, D.,
Berkovitch, M., Blendis, L.M., Cameron, R.G.,
McClelland, R.A., Liu, P.P., Templeton, D.M. &
Koren, G. (1995) Iron-chelation therapy with
oral deferiprone in patients with thalassemia
major [see comments]. N Engl J Med, 332,
918-922.
Olivieri, N.F., Nathan, D.G., MacMillan, J.H.,
Wayne, A.S., Liu, P.P., McGee, A., Martin, M.,
Koren, G. & Cohen, A.R. (1994) Survival in
medically treated patients with homozygous
beta-thalassemia. New England Journal of
Medicine, 331, 574-578.
Olivieri, N.F., Koren, G., Harris, J., Khattak, S.,
Freedman, M.H., Templeton, D.M., Bailey, J.D.
& Reilly, B.J. (1992) Growth failure and bony
changes induced by deferoxamine. American
Journal of Pediatric Hematology Oncology,
14, 48-56.
Olivieri, N.F., Koren, G., Hermann, C., Bentur,
Y., Chung, D., Klein, J., St Louis, P.,
Freedman, M.H., McClelland, R.A. &
Templeton, D.M. (1990) Comparison of oral
iron chelator L1 and desferrioxamine in iron-
loaded patients. Lancet, 336, 1275-1279.
Olivieri, N.F., Buncie, J.R., Chew, E., Gallanti,
T., Harrison, R.V., Keenan, N., Logan, W.,
Mitchell, D., Ricci, G., Skarf, B., Taylor, M. &
Freeman, M.H. (1986) Visual and auditory
neurotoxicity in patients receiving
subcutaneous desferrioxamine infusions. New
England Journal of Medicine, 314(14), 869-
873.
Origa R, et. al. Liver Iron Concentration and
Urinary Hepcidin in Beta-Thalassemia.
Haematologica 92 2007; 583.
Origa, R., Bina, P., Agus, A., Crobu, G.,
Defraia, E., Dessi, C., Leoni, G., Muroni, P.P. &
Galanello, R. (2005) Combined therapy with
deferiprone and desferrioxamine in
thalassemia major. Haematologica, 90, 1309-
1314
Origa R, Fiumana E et al. Osteoporosis in
beta-thalassaemia: Clinical and genetic
aspects. Ann N Y Acad Sci. 2005;1054:451-6
183
Orr D. Difficult intubation: a hazard in
thalassaemia. A case report. Br J Anaesth.
1967;39:585-6
P
Pace BS and Zein S. Understanding
mechanisms of g-globin gene
regulation to develop strategies for
pharmacological foetal haemoglobin
induction. Developmental Dynamics.
2006;235:1727-1737
Pace BS, White GL, Dover GJ, Boosalis MS,
Faller DV, Perrine SP. Short-chain fatty acid
derivatives induce foetal globin expression
and erythropoiesis in vivo. Blood.
2002;100:4640-4648
Pakbaz Z, Treadwell M, Yamashita R, Quirolo
K, Foote D, Quill L et al. Quality of life in
patients with thalassaemia intermedia
compared to thalassaemia major. Ann N Y
Acad Sci. 2005;1054:457-61:457-461
Pakbaz Z, et. al. Serum Ferritin
Underestimates Liver Iron Concentration in
Transfusion Independent Thalassemia Patients
as Compared to Regularly Transfused
Thalassemia and Sickle Cell Patients. Pediatr
Blood Cancer 00 2004;1-4.
Pedersen FK. Post-splenectomy infections in
Danish children splenectomised 1969-1978.
Acta Ped Scand. 1983;72:589-95
Pennell, D.J., Berdoukas, V., Karagiorga, M.,
Ladis, V., Piga, A., Aessopos, A., Gotsis, E.D.,
Tanner, M.A., Smith, G.C., Westwood, M.A.,
Wonke, B. & Galanello, R. (2005) Randomized
controlled trial of deferiprone or
deferoxamine in beta-thalassemia major
patients with asymptomatic myocardial
siderosis. Blood.
Pennell, D.J., Berdoukas, V., Karagiorga, M.,
Ladis, V., Piga, A., Aessopos, A., Gotsis, E.D.,
Tanner, M.A., Smith, G.C., Westwood, M.A.,
Wonke, B. & Galanello, R. (2006) Randomized
controlled trial of deferiprone or
deferoxamine in beta-thalassemia major
patients with asymptomatic myocardial
siderosis. Blood, 107, 3738-3744.
Pepe, A., Lombardi, M., Positano, V., Cracolici,
E., Capra, M., et al. Evaluation of the efficacy
of oral Deferiprone in beta-thalassaemia
major by multislice multiecho T2*. Eur. J.
Haematol. (2006), 76(3): 183-92.
Perera D, Pizzey A, Campbell A, Katz M, Porter
J, Petrou M, Irvine DS, Chatterjee R. Sperm
DNA damage in potentially fertile
homozygous beta-thalassaemia patients with
iron overload. Hum Reprod. 2002;17:1820-5
Perrine SP, Castaneda SA, Boosalis MS, White
GL, Jones BM and Bohacek R. Induction of
foetal globin in beta-thalassaemia: Cellular
obstacles and molecular progress. Ann N Y
Acad Sci. 2005;1054:257-265
Perrine SP. Haemoglobin F-new targets, new
path. Blood. 2006;108:783-784
Perrine SP. Foetal globin induction - Can it
cure beta-thalassaemia? Hematology, Am Soc
Hem Education Programme, December 2005
Perrine SP, Boosalis MS, Emery DW,
Castaneda SA, Bohacek RA. A pharmacophore
model for screening Hb-F-inducing agents.
Blood. 2003;102:122a
Perrine SP, Yang YM, Piga A et al. Butyrate +
EPO in beta thalassaemia intermedia: interim
findings of a phase II trial [abstract]. Blood.
2002;100:47a
184
Perrine SP, Ginder G, Faller DV, et al. A short-
term trial of butyrate to stimulate foetal-
globin-gene expression in the beta-globin
disorders. N Eng J Med. 1993;328:129-131
Persons DA and Tisdale JF. Gene therapy for
the haemoglobin disorders. Semin Hematol.
2004;41:279-286
Piga, A., Galanello, R., Forni, G.L., Cappellini,
M.D., Origa, R., Zappu, A., Donato, G.,
Bordone, E., Lavagetto, A., Zanaboni, L.,
Sechaud, R., Hewson, N., Ford, J.M., Opitz, H.
& Alberti, D. (2006) Randomized phase II trial
of deferasirox (Exjade, ICL670), a once-daily,
orally-administered iron chelator, in
comparison to deferoxamine in thalassemia
patients with transfusional iron overload.
Haematologica, 91, 873-880.
Piga, A., Galggioti, C., Rogliacco, E., Tricta, F.
Comparative effects of Deferiprone and
Desferrioxamine on survival and cardiac
disease in patients with thalassaemia major: a
retrospective analysis. Haemtologica (2003),
88(5): 489-496.
Piga, A., Luzzatto, L., Capalbo, P., Gambotto,
S., Tricta, F. & Gabutti, V. (1988) High dose
desferrioxamine as a cause of growth failure
in thalassaemic patients. European Journal
Haematology, 40, 380-381.
Pippard, M., Johnson, D., Callender, S. &
Finch, C. (1982) Ferrioxamine excretion in
iron loaded man. Blood, 60, 288-294.
Pippard MJ, Callender ST, Warner GT,
Weatherall DJ. Iron absorption and loading in
beta-thalassaemia intermedia. Lancet.
1979;2:819-821
Pootrakul P, Sirankapracha P, Hemsorach S,
et al. A correlation of erythrokinetics,
ineffective erythropoiesis and erythroid
precursor apoptosis in Thai patients with
thalassaemia. Blood. 2000;96:2606-2612
Porter, J.B. (2005) Monitoring and treatment
of iron overload: state of the art and new
approaches. Semin Hematol, 42, S14-18.
Porter, J.B., A., T.M., J., P.D. & P, E. (2005)
Improved Myocardial T2* in Transfusion
Dependent Anemias Receiving ICL670
(Deferasirox). Blood, 106, Abstract 3600.
Porter, J.B., Abeysinghe, R.D., Marshall, L.,
Hider, R.C. & Singh, S. (1996a) Kinetics of
removal and reappearance of non-
transferrin-bound plasma iron with
deferoxamine therapy. Blood, 88, 705-713.
Porter, J.B., Abeysinghe, R.D., Marshall, L.,
Hider, R.C. & Singh, S. (1996b) Kinetics of
removal and reappearance of non-
transferrin-bound plasma iron with
desferrioxamine therapy. Blood, 88, 705-714.
Porter, J.B. & Davis, B.A. (2002) Monitoring
chelation therapy to achieve optimal
outcome in the treatment of thalassaemia.
Best Pract Res Clin Haematol, 15, 329-368.
Porter, J.B., Jaswon, M.S., Huehns, E.R., East,
C.A. & Hazell, J.W. (1989) Desferrioxamine
ototoxicity: evaluation of risk factors in
thalassaemic patients and guidelines for safe
dosage. Br J Haematol, 73, 403-409.
Pratt D S, Kaplan M M. Jaundice. (2005) In:
Kasper D, Braunwald E. Harrison's Principles
of Internal Medicine, 16th Edition.
McGraw-Hill. Ch 38:238-43
Premawardhena et al. HaemoglobinE-ß-
Thalassaemia: Progress Report from the
International Study Group.
Ann NY Acad Sci. 2005;1054:33-39
185
Pringle KC, Spigos DG, Tan WS, Politis C, Pang
EJ, Reyez HM et al. Partial splenic
embolisation in the management of
thalassaemia major. J Pediatr Surg.
1982;017(6):884-891
R
Rachmilewitz EA, Aker M. The role of
recombinant human erythropoietin in the
treatment of thalassaemia. Ann N Y Acad Sci.
1998;850:129-138
Rahav G, Volach V, Shapiro M, Rund D,
Rachmilewitz EA, Goldfarb A. Severe
infections in thalassaemic patients:
prevalence and predisposing factors. Br J
Haematol. 2006;133(6):667-674
RCOG clinical Green Top Guidelines.
Management of HIV in Pregnancy (39) - April
2004. http://www.rcog.org.uk.
Rebulla P, Modell B. Transfusion requirements
and effects in patients with thalassaemia
major. Lancet. 1991;337:277-80
Reich S, Buhrer C, Henze G, et al. Oral
isobutyramide reduces transfusion
requirements in some patients with
homozygous beta-thalassaemia. Blood.
2000;96:3357-3363
Report of a joint WHO/March of Dimes
Meeting, 5 – 15, May 2006
Rivella S, May C, Chadburn A, Rivière I and
Sadelain M (2003) A novel murine model of
Cooley anemia and its rescue by lentiviral-
mediated human b-globin gene transfer.
Blood. 2003;101:2932-2939
Roselli EA, Cesari R, Miccio A, Tiboni F,
Corbella P, Rossi C, Biral E, Marktel S,
Antoniou M, Andreani M, Lucarelli G and
Ferrari G. Gene Therapy for b-thalassaemia:
Preclinical studies on human cells. Mol Ther.
2006;13, Supplement 1: S257
S in the Treatment of the Thalassemias . Annu
de Sanctis V, Eleftheriou A, Malaventura C, on
behalf of the Thalassaemia International
Federation Study Group on Growth and
Endocrine Complications in Thalassaemia.
Prevalence of Endocrine Complications and
Short Stature in Patients with Thalassaemia
major: A Multicenter Study by the
Thalassaemia International Federation (TIF).
Ped Endocrinol Rev 2004; 2 (Suppl. 2):249-
255
de Sanctis V, Urso L. Clinical experience with
growth hormone treatment in patients with
_-thalassaemia major.
BioDrugs 1999; 11:79-85
de Sanctis V, Pintor C, et al., Multicentre
study on endocrine complications in
thalassaemia major.
Clinical Endocrinology. 1995;42:581-6
de Sanctis V, Atti G, Banin P, Orzincolo C,
Cavallini AR, Patti D, Vullo C. Growth in
thalassaemia major. Acta Med Auxol 1991;
23:29-36
Sadelain M. Recent advances in globin gene
transfer for the treatment of b-thalassaemia
and sickle cell anaemia. Curr Opin Hematol.
2006;13:142-148
Sambrook P, Cooper C. Osteoporosis. Lancet.
2006 Jun 17;367(9527):2010. Review
Saxon BR, Rees D, Olivieri NF. Regression of
extramedullary haemopoiesis and
186
augmentation of foetal haemoglobin
concentration during hydroxyurea therapy in
beta-thalassaemia. Br J Haematol.
1998;101:416-419
Schrier SL and Angelucci E. New Strategies
Rev Med 2005; 56: 157-71
Schrier SL. Pathobiology of thalassemic
erythrocytes. Curr Opin Hematol. 1997;4:75-
78
Sharara AI, Aoun E, Koussa S, Inati A, Taher A.
Treatment of acute hepatitis C in a child with
thalassemia major using weight-based
peginterferon alpha-2b. J Gastroenterol
Hepatol 2006;21:1221.
Sharara AI, Hunt CM, Hamilton JD. Hepatitis C.
Ann Intern Med 1996;125:658-68.
Silen W. Abdominal pain. (2005) In: Kasper D,
Braunwald E. Harrison's Principles of Internal
Medicine, 16th Edition. McGraw-Hill. Ch
13:82-5
Silva M, Grillot D, Benito A, Richard C, Nunez
G, Fernandez-Luna JL. Erythropoietin can
promote erythroid progenitor survival by
repressing apoptosis through Bcl-XL and Bcl-
2. Blood. 1996;88:1576-1582
Singer DB. Postsplenectomy sepsis. Perspect
Pediatr Pathol. 1973;1:285-311:285-311
Singer ST, Sweeters N, Vichinsky E, Wagner
AJ, Rachmilewitz EA. A dose-finding and
safety study of darbepoetin alfa
(erythropoiesis stimulating protein) for the
treatment of anaemia in patients with
thalassaemia intermedia [abstract]. Blood.
2003;102:268a
Singer ST, Kuypers FA, Coates TD, et al. The
effect of single and combination drug
therapy on previously transfused E/beta-
thalassaemia patients: Implications on
decision-making for therapy. Blood.
2002;100:119a-120a
Singer ST, Wu V, Mignacca R, Kuypers FA,
Morel P, Vichinsky EP. Alloimmunization and
erythrocyte autoimmunization in transfusion-
dependent thalassemia patients of
predominantly Asian descent.
Blood. 96:3369-73, 2000.
Singer ST, Vichinsky EP. Deferoxamine
treatment during pregnancy: is it harmful?
Am J Hematol. 1999;60:24-6
Skarpidi E, Cao H, Heltweg B, et al.
Hydroxamide derivatives of short-chain fatty
acids are potent inducers of human foetal
globin gene expression.
Exp Hematol. 2003;31:197-203
Skordis N, Christou S, Koliou M, Pavlides N,
Angastiniotis M. Fertility in female patients
with thalassaemia. J Pediatr Endocrinol
Metab. 1998;11 Suppl 3:935-43
Sodani P, Gaziev D, Polchi P, Erer B, Giardini
C, Angelucci E, Baronciani D, Andreani M,
Manna M, Nesci S, Lucarelli B, Clift RA,
Lucarelli G. A new approach for bone
marrow transplantation in class 3 thalassemic
patients aged less than 17 years.
Blood 2004; 104:1201-3
Spanos T, Ladis V, Palamidou F, Papassotiriou
I, Banagi A, Premetis E, Kattamis C. The
impact of neocyte transfusion in the
management of thalassaemia. Vox Sanguinis.
70:217-23, 1996.
Spanos T, Karageorga M, Ladis V, Peristeri J,
187
Hatziliami A, Kattamis C. “Red cell
alloantibodies in patients with thalassemia.”
Vox Sanguini 1990;58:50-5
Spoulou VI, Tsoumas DL, Ladis V, Spentzou A,
Theodoridou MC. Natural and vaccine-
induced immunity against Haemophilus
influenzae type b in patients with beta-
thalassaemia.
Vaccine. 2006;24(16):3050-3053
St Pierre, T.G., Clark, P.R., Chua-anusorn, W.,
Fleming, A.J., Jeffrey, G.P., Olynyk, J.K.,
Pootrakul, P., Robins, E. & Lindeman, R.
(2005) Noninvasive measurement and
imaging of liver iron concentrations using
proton magnetic resonance.
Blood, 105, 855-861.
Stamatoyannopoulos G (2005) Prospects for
developing a molecular cure for thalassemia.
Hematology, 10 Suppl 1:255-257
Steinberg MH, Rodgers GP. Pharmacologic
modulation of foetal haemoglobin.
Medicine. 2001;80:328-344.
Swanson K, Dwyre DM, Krochmal J, Raife TJ.
Transfusion-related acute lung injury (TRALI):
current clinical and pathophysiologic
considerations.
Lung. 184:177-85, 2006.
T
Taher A, Abou-Mourad Y, Abchee A et al.
Pulmonary thromboembolism in beta-
thalassaemia intermedia: are we aware of this
complication? Hemoglobin. 2002;26:107-112
Taher A, Ismaeel H, Cappellini MD.
Thalassaemia Intermedia: Revisited. Blood
Cells Mol Dis. 2006;37:12-20
Taher A, Ismaeel H, Mehio G, Bignamini D, et
al. The incidence of thromboembolic events
among 8,860 patients with thalassaemia
major and intermedia in the Mediterranean
area and Iran. Thromb Haemost.
2006;96:488-91
Tanner MA, Galanello R, Dessi C et al. A
randomised, placebo-controlled, double-blind
trial of the effect of combined therapy with
deferoxamine and deferiprone on myocardial
iron in thalassaemia major using
cardiovascular magnetic resonance.
Circulation. 2007 April 10;115(14):1876-84
Tanner MA, Galanello R, Dessi C et al.
Myocardial iron loading in patients with
thalassaemia major on deferoxamine
chelation. J Cardiovasc Magn Reson.
2006;8(3):543-7
Tanner JM. Growth at adolescence. 2nd Ed.
Springfield: Charles C Thomas Publisher, 1962
Telfer, P.T., Prestcott, E., Holden, S., Walker,
M., Hoffbrand, A.V. & Wonke, B. (2000)
Hepatic iron concentration combined with
long-term monitoring of serum ferritin to
predict complications of iron overload in
thalassaemia major. Br J Haematol, 110, 971-
977.
Thalassemia International Federation (2002)
Haemoglobin E-beta-thalassaemia. Chapter
12
Tondury, P., Zimmermann, A., Nielsen, P. &
Hirt, A. (1998) Liver iron and fibrosis during
long-term treatment with deferiprone in
Swiss thalassaemic patients. British Journal of
Haematology, 101, 413-415.
Tsiantis J, Xypolita-Tsantili D, Papadakou-
Lagoyianni S. Family reactions and their
management in a parents group with beta-
188
thalassaemia. Arch Dis Child.
1982;57(11):860-863
Tuck SM, Jensen CE, Wonke B, Yardumian A.
Pregnancy management and outcomes in
women with thalassaemia major. J Pediatr
Endocrinol Metab. 1998;11 (3):923-8
V
Vento S, Cainelli F, Cesario F. Infections and
thalassaemia. Lancet Infect Dis.
2006;6(4):226-233
Villeneuve, J.P., Bilodeau, M., Lepage, R.,
Cote, J. & Lefebvre, M. (1996) Variability in
hepatic iron concentration measurement
from needle- biopsy specimens.
Journal of Hepatology, 25, 172-177.
Vogel M, Anderson LJ, Holden S, Deanfield JE,
Pennell DJ, Walker JM. Tissue Doppler
echocardiography in patients with
thalassaemia detects early myocardial
dysfunction related to myocardial iron
overload.
Eur Heart J. 2003 January;24(1):113-9
Voskaridou E, Terpos E, Spina G, et al.
Pamidronate is an effective treatment for
osteoporosis in patients with beta-
thalassaemia.
Br J Haematol. 2003;123:730-737
W
Wainscoat JS, Thein SL, Weatherall DJ.
Thalassaemia intermedia. Blood Rev.
1987;1:273-279
Walker JM. The heart in thalassaemia. Eur
Heart J. 2002 January;23(2):102-5
Walter, P.B., Fung, E.B., Killilea, D.W., Jiang,
Q., Hudes, M., Madden, J., Porter, J., Evans,
P., Vichinsky, E. & Harmatz, P. (2006)
Oxidative stress and inflammation in iron-
overloaded patients with beta-thalassaemia
or sickle cell disease. Br J Haematol, 135,
254-263.
Wang SC, Lin KH, Chern JP, Lu MY, Jou ST, Lin
DT et al. Severe bacterial infection in
transfusion-dependent patients with
thalassaemia major. Clin Infect Dis.
2003;37(7):984-988
Wanless, I.R., Sweeney, G., Dhillon, A.P.,
Guido, M., Piga, A., Galanello, R., Gamberini,
M.R., Schwartz, E. & Cohen, A.R. (2002) Lack
of progressive hepatic fibrosis during long-
term therapy with deferiprone in subjects
with transfusion-dependent beta-
thalassemia. Blood, 100, 1566-1569.
Weatherall DJ. Thalassaemia intermedia:
cellular and molecular aspects, J Hematol.
2001; 86 (Suppl 1):186-188
Westwood MA, Anderson LJ, Maceira AM et al.
Normalized left ventricular volumes and
function in thalassaemia major patients with
normal myocardial iron. J Magn Reson
Imaging. 2007 June;25(6):1147-51
WHO/March of Dimes, 2006 (Report of a joint
meeting, 5-15 May)
Wittich S, Scherf H, Xie C, et al. Structure-
activity relationships on phenylalanine-
containing inhibitors of histone deacetylase:
in vitro enzyme inhibition, induction of
differentiation, and inhibition of proliferation
in Friend leukaemic cells. J Med Chem.
2002;45:3296-3309
Wolfe, L., Olivieri, N., Sallan, D., Colan, S.,
Rose, V., Propper, R., Freedman, M.H. &
189
Nathan, D.G. (1985) Prevention of cardiac
disease by subcutaneous deferoxamine in
patients with thalassemia major. N Engl J
Med, 312, 1600-1603.
Wood JC, Enriquez C, Ghugre N, Tyzka JM,
Carson S, Nelson MD, Coates TD. MRI R2 and
R2* mapping accurately estimates hepatic
iron concentration in transfusion-dependent
thalassemia and sickle cell disease patients.
Blood 2005;106:1460-5.
Worwood, M., Cragg, S.J., Jacobs, A.,
McLaren, C., Ricketts, C. & Economidou, J.
(1980) Binding of serum ferritin to
concanavalin A: patients with homozygous
beta thalassaemia and transfusional iron
overload. Br J Haematol, 46, 409-416.
Y
Yarali, N., Fisgin, T., Duru, F., Kara, A., Ecin,
N., Fitoz, S. & Erden, I. (2006) Subcutaneous
bolus injection of deferoxamine is an
alternative method to subcutaneous
continuous infusion. J Pediatr Hematol Oncol,
28, 11-16.
Yuan J, Angelucci E, Lucarelli G, et al.
Accelerated programmed cell death
(apoptosis) in erythroid precursors of
patients with severe beta-thalassaemia.
Blood. 1993;82:374-377.
Z
Zurlo MG, De SP, Borgna-Pignatti C et al.
Survival and causes of death in thalassaemia
major. Lancet. 1989 July 1;2(8653):27-30
WEBSITES
National Evidence-Based Clinical Guidelines
Fertility: assessment and treatment for
people with fertility problems_. February
2004. http://www.rcog.org.uk

RCOG Clinical Green Top Guidelines.

Management of HIV in Pregnancy (39) - April
2004. http://www.rcog.org.uk

190
191
APPENDIX A

192
193
194
195
Index

Description Page Number

A
Adefovir 101, 105
Adult Haemoglobin (Hb A) 12
Alendronate 81
Assisted reproduction techniques ART 70
Arrhythmias 84, 88, 166
Alloimmunisation 19, 20, 24, 128, 160
Allergic transfusion reactions 28
Acute haemolytic reactions 28
Autoimmune haemolytic anaemia 28, 160
Arrested pubity 65
Amenorrhoea 66
Acarbose 69
5 - Azacytidine 136
Alchohol consumption 153
Aplastic crisis 108, 161
Antioxidants 37
Agranulocytosis 50
Arthropathy 50
Anticoagulants 21, 88, 126
ACE inhibitors 87
Amiodarone 88
Abdominal pain 163

B
Blood donation 18, 93, 98
Bone marrow expansion 79, 123, 162
Back pain 162
Bisphosphonates 74, 81
Butyrates 136
Bumetanide 87
BMP 88
Beta blocking agents 88

C
Chimerism 134
Cirrhosis 93, 99
Chelaton 38, 108, 127, 144, 151
Cardiac disease 73, 76, 83, 154

196
Calcium 69, 81, 152
Circulatory overload (transfusion) 29
Calcitriol 69
Cytotoxic agents 136
Confidentiality 149
Cytomegolovirus (CMV) 111
Chagas disease 30, 115
Chemoprophylaxis 118

D
Diabetes mellitus 68, 92
Deferiprone 48, 74
DNA 12
Delayed pubity 65
Desferioxamine DFO 39, 65, 77, 108, 112
DEXA scan 74, 79
Disc prolapse 162
Diet 151-153
Deferasirox 55
Delayed transfusion reactions 28, 162, 166
Decitabine 136
Dental care 151
Drug abuse 153
Driving 154
Dengue fever 114
Digoxine 87
Diuretics 87

E
Entecavir 101, 105
Extramedullary haemopoiesis 124, 165
Echocardiography 85
Ejection fraction (LVEF) 36, 49, 54, 73
Electrocardiogram (ECG) 84
Erythropoietin (EPO) 129, 136

F
Ferritin 33, 48, 53, 55, 75
Fetal haemoglobin (Hb F) 12, 129, 136
Fractures 81, 162, 165
Fertility 70

197
Folic acid 127, 152
Filtration (Leukoreduction) 19, 20, 29
Frozen red cells 20

G
GVHD 29, 133
Growth 43, 64
Growth velocity 64
Glucose tolerance 69
Gene therapy 139
Gallstones (cholelithiasis) 124
Gilbert's syndrome 167
GM CSF 50

H
HLA 133
Hepatitis C (HCV) 74, 92, 94, 126
Hepatocellular carcinoma 93, 99
Hepatitis B (HBV) 74, 98, 128
HIV 74, 109
Hypersplenism 116, 160
Hypothyrodism 67
Heart failure 36, 126, 166
Haemoglobin E (Hb E) 16,130
Haemoglobin Lepore 16
Haemoglobin S (Hb S) 16
Haemoglobin H (Hb H) 17
Hb Constant Spring 17
Hb Bart's Hydrops Fetalis 17
Hypogonadic hypogonadism 67, 70, 78
Hormone replacement therapy (HRT) 74, 81
Hydroxyurea 121, 124, 129, 136
Hypoparathyroidism 69, 169
Hypocalcaemia 69, 169
Heart function 36, 40, 49, 54, 56, 73

I
Iron load (haemosiderosis) 26, 31, 107, 127
Interferon (pegylated) 95, 101, 105
Iron absorption 31, 151
Insulin 69

198
Insurance (travel) 150
Immune function 107
Influenza virus vaccine 118
Indwelling intravenous lines 47
Intensive chelation 46
Immunoprophilaxis 118

J
Jaundice 117

K
Klebsiella 113, 161

L
Liver fibrosis 50, 92, 132
Liver failure 93, 168
Liver biopsy 35, 94
Lamivudine 101, 105
Lifestyle 149
Liver iron concentration (LIC) 33, 39, 48, 53, 55, 92
Labile plasma iron (LPI) 37
Leg cramps 168
Leg ulcers 125

M
Matched unrelated donors (MUD) 133
MRI 36, 92
MRI cardiac 36, 40, 49, 74, 85
Malaria 114, 115
Myocarditis 36, 164

N
Neutropenia 50
Neocytes 21
Nonhaemolytic febrile transfusion reactions 27
Nephrolithiasis (kidney or renal stones) 123, 164
Non transferring bound iron (NTBI) 37

199
O
Osteoporosis 74, 79, 127, 162, 154
Ovulation 70, 71
Oxidative damage 37

P
Puberty 65
Pregnancy 45, 51, 70, 127
Pre pregnancy counselling 70, 73
Preimplantation genetic diagnosis (PGD) 71
Pubertal staging 66
Physical activity 153
Parvovirus B19 108, 161
Palpitations 84
Pericarditis 164
Pancreatitis 163
Portal vein thrombosis 163
Pulmonary embolism 165
Pulmonary hypertension 90, 120, 126, 166
Pseudoxanthoma elasticum 127
Pamidronate 81

S
Survival 40, 49
SQUID 35
Skeletal dysplasia 43
Spermatogenesis 70, 72
Splenectomy 107, 116, 124, 128
Short chain fatty acids 137
School 149
Smoking 153
Splenomegaly 124, 154
Splenic embolisation 117

T
Thrombocytopenia 50, 97, 116
Transfusion requirement 23, 25, 26, 97
Transplantation (Stem cells) 129, 132
Transfusion related acute lung injury (TRALI) 29

200
V
Vaccinations 99, 101, 118, 151
Vitamin D 69, 81
Vitamin C 33, 39, 45, 52, 152
Vitamin E 153
Vision 43, 50

W
Washed red cells 20
Work 150

Y
Yersinia enterocolitica 42, 111, 161

Z
Zolandronic acid 81
Zinc deficiency 51, 153

201
About Thalassaemia
International Federation

The Thalassaemia International Federation (TIF) was established in 1987 with the mission to
promote the establishment of national control programmes for the effective prevention and
appropriate clinical management of thalassaemia, in every affected country of the world. TIF, a
Federation “umbrella”, is comprised of 98 national thalassaemia associations from 60 countries,
representing hundreds of thousands of patients worldwide.

TIF has been in official relations with the World Health Organisation (WHO) since 1996, and has
developed an extensive network of collaboration with scientific and medical professionals from
more than 60 countries around the world, as well as with other national and international health
bodies, pharmaceutical companies and other disease-orientated patients’ organisations.

TIF’s educational programme is one of its most important and successful activities. It includes
the organisation of local, national, regional and international workshops, conferences and
seminars, and the preparation, publication, translation and free distribution of leaflets,
magazines and books for health professionals and patients/parents, to more than 60 countries.

MIISSSSIIO
M ONN:: ““EEQ
QUUAALL AAC
CCCEESSSS TTO
OQQUUAALLIITTYY H
HEEA
ALLTTH
H SSEER
RVVIIC
CEESS FFO
ORRA
ALLLL
WIITTH
W H TTH
HAALLAASSSSAAEEM
MIIA
A””

MO
M OTTTTO
O:: ““U
UNNIITTYY IISS O
OUUR
R SSTTR
REEN
NGGTTH
H””

WORLD HEALTH ORGANIZATION (WHO) RESOLUTION:

no. EB118.R1 (29 May 2006)
““TTH
HAALLA
ASSSSA
AEEM
MIIA
AAANND
DOOTTH
HEER
RHHA
AEEM
MOOG
GLLO
OBBIIN
NOOP
PAATTH
HIIEESS””

202
1. ““BBlloooodd SSaaffeettyy KKiitt”” (1999) - 8. ““AA gguuiiddee ttoo tthhee
In English eessttaabblliisshhm meenntt aanndd
pprroom mo ottiioon no off n
noonn--
ggoovveerrnnm me en ntt
ppaattiieennttss//ppaarreennttss’’
2. “GGuuiiddeelliinneess ttoo tthhee CClliinniiccaall oorrggaanniizzaattiioonn”” 2007 - In
Maan
M naaggeem meenntt ooff English
TThhaallaassssaaeem
miiaa”” 2000 -
Translated into 6 languages
9. ““GGuuiiddeelliinneess ttoo tthhee CClliinniiccaall
Maan
M naaggeem meenntt ooff
3. ““CCoom mpplliiaannccee ttoo IIrroonn TThhaallaassssaaeem
miiaa”” Second
CChheellaattiioonn tthheerraappyy wwiitthh Edition - 2007 - In English
DDeessffeerrrriiooxxaam
miin
ne e”” 2000 –
Reprint 2005 - Translated
into 4 languages 10. ““TThhaallaassssaaeem
miiaa M
Maajjoorr aanndd
Me
M e”” – Children’s Book –
2007 - In English
4. ““AAbboouutt TThhaallaassssaaeem
miiaa”” -
2003 - Translated into 11
languages
11. ““AAbboouutt -- ‚‚ -- tthhaallaassssaaeem
miiaa”” –
2007 - In English, Italian,
5. ““PPrreevveennttiioonn ooff French
TThhaallaassssaaeem
miiaass aanndd OOtthheerr
HHaaeemmo og gllo
obbiin
nooppaatthhiieess””
Volume I (2003) - 12. ““AAbboouutt -- ·· -- tthhaallaassssaaeem
miiaa””
Translated into 2 languages – 2007 - In English, Italian,
French

6. ““PPrreevveennttiioonn ooff
TThhaallaassssaaeem
miiaass aanndd OOtthheerr 13. ““AAbboouutt ssiicckkllee cceellll ddiisseeaassee”” –
HHaaeemmo og gllo
obbiio
oppaatth
hiieess”” 2007 - In English, Italian,
Volume II (2005) - In French
English

7. ““PPaattiieennttss’’ RRiigghhttss”” 2007 - In 14. EEdduuccaattiioonnaall FFoollddeerr --

English Information for the
community, the carrier of
and the patient with a
Haemoglobin disorder.

203