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ADC Online First, published on November 25, 2017 as 10.1136/archdischild-2016-311018
Paediatric Haematology,
Children’s Hospital, John
Radcliffe Hospital, Oxford, UK
Correspondence to
Dr Neha Bhatnagar, Children’s
Hospital, John Radcliffe Hospital,
Paediatric Haematology, Oxford
OX3 9DU, UK;
​neha.​bhatnagar@o​ uh.​nhs.​uk
Received 15 November 2016
Revised 13 October 2017
Accepted 18 October 2017
To cite: Bhatnagar N,
Hall GW. Arch Dis Child
Published Online First: [please
include Day Month Year].
doi:10.1136/
archdischild-2016-311018
Copyright Article author (or their employer) 2017. Produced by BMJ Publishing Group Ltd (& RCPCH) under licence.
Review
Major bleeding disorders: diagnosis, classification,
management and recent developments
in haemophilia
Neha Bhatnagar, Georgina W Hall
Abstract
In this review, we outline the standard of care for
children in the UK with the most common major
bleeding disorder, haemophilia, and how exciting new
developments in therapy have the potential for further
improvements in quality of life and clinical outcome.
The combination of comprehensive specialist medical
care, safer factor concentrates, earlier introduction of
prophylaxis and patient-specific education has allowed
the current generation of patients with haemophilia
to grow into adulthood with excellent joint function,
pursuing full-time employment with a good quality of
life. We are entering an exciting new phase in paediatric
haemophilia as potentially life-changing products appear
on the scene taking a step towards achieving better,
easier and personalised prophylaxis.
Introduction
This review article provides an overview of the
diagnosis, management and recent developments
in treatment of the two major inherited bleeding
disorders in children; haemophilia A and haemo-
philia B.
Haemophilia A is caused by a deficiency of the
coagulation protein factor VIII (FVIII) and haemo-
philia B by a deficiency of factor IX (FIX). These
two coagulation proteins have an essential role in
coagulation; their deficiency results in defects in
clot formation and can lead to spontaneous bleeds
affecting soft tissue, joints and muscles. Both
haemophilia A and B are X-linked conditions, with
a global prevalence of 1:5000 males for haemo-
philia A and 1:35 000 males for haemophilia B.1
Presentation and diagnosis
The diagnosis of children with bleeding disorders
requires an understanding of the normal physiology
of paediatric haemostasis and the common modes
of presentation in children and neonates. Although
haemophilia is an inherited bleeding disorder,
one-third of children with haemophilia A have no
family history of the condition, as it is due to a new
(de novo) genetic mutation.
Classification of severity
Haemophilia is classified into three main groups based
on residual FVIII or FIX coagulant activity in the
blood: severe, moderate or mild.2 Patients with a coag-
ulation factor level of <0.01 IU/mL (ie, <1%) normal
being 0.50–1.50 IU/mL (50%–150%) are classified as
having severe haemophilia, those with levels between
Bhatnagar N, Hall GW. Arch Dis Child 2017;0:1–5. doi:10.1136/archdischild-2016-311018
What is already known?
►► Haemophilia A and B are inherited X-linked
conditions with a prevalence of 1:5000 males
for haemophilia A and 1:30 000 males for
haemophilia B. One-third of children with
haemophilia A have no family history and
their haemophilia is a result of a new (de
novo) genetic mutation. Diagnosis is made by
measuring factor VIII levels and genetic analysis
to identify the FVIII mutation.
►► All children with haemophilia are registered
at a comprehensive care centre and receive
lifelong care from a dedicated multidisciplinary
specialist team with haemophilia expertise on a
24-hour basis.
►► Prophylaxis and treatment with recombinant
factor VIII/IX concentrate has been the standard
of care for children with severe haemophilia in
the UK for many decades.
What this study adds?
►► A number of novel recombinant factor VIII
products have been developed in recent years,
including recombinant factor VIII molecules
manufactured in human cell line and extended
half-life products. These potentially have
lower administration frequency and less
immunogenicity.
►► Plasma-derived concentrates should be
considered on an individualised basis in
those who are at risk of FVIII inhibitors.
Global controversy continues regarding the
use of plasma-derived concentrates versus
recombinant to reduce the risk of FVIII inhibitor
formation in young children.
►► Management options may radically change in
the future as novel agents currently in clinical
trials become available such as FVIII mimetics,
molecules targeting anti-thrombin and
thrombin activatable fibrinolysis inhibitor;
however, further data are awaited.
0.01 and 0.05 IU/mL (ie, 1%–5%) as moderate and
0.05 and 0.40 IU/mL (ie, 5%–40%) as mild. Patients
with severe haemophilia are at risk of spontaneous and
life-threatening bleeding episodes, while those with
moderate or mild haemophilia will usually only suffer
abnormal bleeding after trauma or surgery.
   1
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Review
The diagnosis of a severe deficiency can be made immediately
after birth by measuring the FVIII or FIX activity in the cord
blood. However, levels of vitamin K-dependent factors including
FIX are reduced at birth making it difficult to diagnose mild
haemophilia B by measuring FIX levels alone in a new born;
thus, FIX levels need to be repeated after 6 months of age. If
the family mutation is known, genetic analysis of the cord blood
sample may be used to confirm the suspected diagnosis. Where
there is a positive family history and the mutation is known,
genetic analysis may also be performed antenatally.
In de novo cases, affected children present with symptoms
of excessive bleeding and easy bruising. Bleeds can be due to
trauma or apparently occur spontaneously.3 A child with severe
haemophilia can present during the first year of life with bleeding
following surgical intervention such as circumcision, intramus-
cular immunisations or rarely ‘spontaneously’ with intracranial
haemorrhage4 Often the child will have no problems until they
start to mobilise around 18–24 months when ‘pea-sized’ lumpy
bruises are commonly seen. The classical presentation of sponta-
neous haemarthrosis can be difficult to recognise in very young
children particularly if the hip or ankle joints are involved.5 A
toddler who refuses to weight bear, with a hot, swollen knee
is easier to diagnose than a young baby with a hip bleed and a
normal looking leg which is not moving normally. As soon as a
boy is suspected of having a problem with bleeding, then haemo-
philia must be excluded.
The laboratory investigation of suspected haemophilia typi-
cally shows an isolated prolonged activated partial thrombo-
plastin time (APTT) with a normal prothrombin time. A 50:50
mix, mixing normal plasma with the patient factor deficient
plasma, results in correction of the prolonged APTT. Measure-
ment of FVIII or FIX clotting activity is necessary to confirm
the diagnosis and establish the severity. Molecular genetic testing
may then be performed to identify the mutation in de novo cases
or to confirm known family mutations.
Genetics
Many hundreds of genetic defects causing factor VIII and IX
deficiency have been identified. The Worldwide Factor VIII
variant database (www.​factorviiii-​db.​org) describes more than
2000 unique molecular defects in the factor VIII gene, mainly
point mutations, small insertions, deletions and inversions.
One thousand and ninety-five FIX genetic variants have been
described (www.​factorix.​og); likewise mainly point and frame-
shift mutations with only 3% being large deletions.
Genetic analysis is an important part of specialist haemophilia
care as the genetic defect is a prognostic factor for inhibitor
development. Mutations are registered on the national haemo-
philia database. Knowing the genetic defect in the index case
is important so that female relatives who might be carriers
can be identified, as their factor levels may be normal and not
informative.
Management
Organisation of care
As with all chronic lifelong disorders, children with haemophilia
need regular specialist follow-up. In the UK, this is provided by
a comprehensive care centre (CCC) with a dedicated multidis-
ciplinary specialist team providing expert care 24 hours a day,
7 days a week funded by specialist commissioning. The centres
provide specialist nurses, regular joint assessments by trained
physiotherapists, psychological, surgical and dental support.
There are 22 CCCs in the UK caring for both children and adults
2 Bhatnagar N, Hall GW. Arch Dis Child 2017;0:1–5. doi:10.1136/archdischild-2016-311018
and 7 CCCs just for children. The United Kingdom Haemophilia
Centre Doctors’ Organisation (UKHCDO) is an association of
UK medical practitioners with a specialist interest in the care
of patients with haemophilia. It advances education, promotes
research and conducts national audits of care and service
delivery. It established a national haemophilia database in 1978
that generates an annual report from the data captured to better
understand epidemiology and complication rates and allow for
healthcare planning. The UKHDCO leads on the management
of patients with haemophilia by producing national guidelines
establishing standards of care and creating a network of CCCs.
The goal in haemophilia care is to provide safe, effective,
non-immunogenic easily administered prophylaxis with the aim
of preventing joint damage and life-threatening complications
associated with excessive, repetitive bleeding through long-term
prophylaxis. Patient education is an essential part of haemophilia
care to gain independence in the management of haemophilia
before transition to adult care.
Management of patients with severe haemophilia
Recombinant factor concentrates have been the treatment of
choice for children with haemophilia in the UK6 7 since 1990 to
avoid the potential for transfusion transmitted infections (TTI).
Prior to this, children in the UK received virucidally treated
donor screened plasma-derived (PD) factor concentrate. There
have been no TTIs in PD products since 1985.
Prophylaxis
Prophylaxis has been the standard of care in children with
severe haemophilia in the UK for many decades. This is usually
commenced by or before the second joint or significant soft
tissue bleed. Prophylaxis involves routine administration of
factor concentrate. There are many different prophylaxis regi-
mens. For a patient with severe haemophilia A prophylaxis
would optimally be on alternate days, while for a patient with
severe haemophilia B prophylaxis would optimally be twice or
three times per week. Prophylaxis aims to prevent recurrent
‘spontaneous’ haemoarthroses and hence chronic joint damage
although it will not prevent traumatic bleeds. The frequency of
dosing will depend on clinical symptoms of bleeding in combina-
tion with maintaining the factor through levels (just prior to the
next dose) above 1%. In patients with short factor half-lives that
might mean more frequent, sometimes daily, dosing.
The greatest challenge when starting prophylaxis in a baby or
young child is venous access. Central venous access devices may
be necessary but carry a risk of bleeding during initial surgery,
infection and thrombosis. The role of the haemophilia centre
is to teach carers and then boys to administer treatment so that
safe-independent prophylaxis can be given at home (figure 1).
Boys on adequate prophylaxis have an excellent quality of
life with virtually normal levels of activity, fewer joint bleeds,
reduced arthropathy and improved quality of life.8
Management of bleeds
Patients on regular prophylaxis will still require treatment doses
of factor concentrate after injury or before surgery to provide
an increase in factor level dependent on the nature of bleed, site
of injury or surgery. An on-demand dose aiming for a level of
50% is given for joint or muscle bleeds, often one dose is suffi-
cient with full supportive measures to stop and resolve the bleed.
A head injury or life-threatening bleed requires a higher dose
which aims for a level of 100%9 for several hours.
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Figure 1  A young boy with severe haemophilia A preparing for self-
administration of FVIII concentrate by peripheral venous access.
Complications of treatment and management of inhibitors
Inhibitory antibodies may develop in approximately 25% of
children with severe haemophilia A and 3% of children with
haemophilia B following exposure to factor concentrate. These
are neutralising antibodies to the procoagulant activity of FVIII
or FIX. Patients with a FVIII inhibitor also present with break-
through bleeds while on adequate prophylaxis or may stop
responding to previously effective treatment doses of factor
concentrate during a bleeding episode. Patients with a FIX inhib-
itor may present with anaphylaxis or symptoms of an allergic
reaction. Routine screening for the presence of inhibitors should
be part of the regular follow-up at least every third exposure day
(ED) until the 20th ED. If the inhibitor screening test is posi-
tive, a Bethesda assay should be performed to quantify the inhib-
itor in Bethesda units (BU). The inhibitor screening test should
be done every 3–6 months up to 150 exposure days. Inhibitor
testing should continue one to two times per year thereafter.
The UKHCDO recommends early institution of immune toler-
ance induction (ITI) as soon as a FVIII inhibitor is confirmed.10
Inhibitor may be low titre (<5 BU) or high titre (>5 BU). High-
titre inhibitors often require high doses of factor VIII adminis-
tered daily for months. ITI is successful in approximately 90% of
patients with low-titre FVIII antibodies, but only 50% of high-
risk patients with high-titre FVIII antibodies.
Treatment of FIX inhibitors is extremely challenging due
to the relative poor response rate and risk of anaphylaxis and
nephrotic syndrome. Successful tolerisation has been reported
with the addition of immunosuppressive agents to the ITI
regimen. ITI should be conducted under the supervision of a
haemophilia CCC.
Table 1  Extended half-life factor VIII products—manufacturing characteristics and pharmacokinetics
Product Company Cell line
rFVIII-Fc (Elocta) Biogen Human embryonic kidney
BAX 855 (Adynovate) Baxalta Chinese hamster ovary
Bay 94–9027 Bayer Baby hamster kidney
N8-GP Novo-Nordisk Chinese hamster ovary
Bhatnagar N, Hall GW. Arch Dis Child 2017;0:1–5. doi:10.1136/archdischild-2016-311018
Review
In the presence of inhibitors, bleeding episodes require treat-
ment with bypassing agents such as recombinant activated FVII
concentrate (rFVIIa), NovoSeven or factor VIII inhibitor by
passing agent (FEIBA) or occasionally large doses of FVIII/IX
in patients with low-titre inhibitors. Eradication of inhibitors
(tolerance) is extremely invasive, costly and time intensive.
Management of patients with moderate/mild haemophilia
For children with moderate/mild haemophilia, on-demand factor
concentrate infusions at the time of a bleeding episode and prior
to surgery or dental procedures are appropriate. Desmopressin
(DDAVP) may also be given to children with mild haemophilia
A instead of factor concentrate as a subcutaneous injection,
intravenously or as a nasal spray for treatment of bleeds, prior
to minor surgery or for dental procedures. However, not all
children achieve an adequate sustained rise in their FVIII level
following DDAVP administration and it is therefore important to
perform a DDAVP challenge prior to its clinical use. Traexamic
acid may also be used in combination with factor concentrate or
DDAVP.
Supportive management
Acute joint bleeds should be managed with supportive measures
such as protection, rest, ice, compression and elevation in addi-
tion to factor administration. Childhood immunisations should
be given subcutaneously and not intramuscularly to prevent deep
muscle. Non-steroidal medicines such as ibuprofen and aspirin
should be avoided as these increase the risk of bleeding.
Recent developments in treatment
Recombinant factor replacement therapy is the mainstay of
haemophilia treatment in the UK; however, the main limita-
tion with existing products is their short half-lives (8–12 hours
for FVIII and 18–24 hours for FIX) resulting in the need for
frequent intravenous infusions.11
Recombinant factor concentrate development
First/second/third generation
In order to manufacture recombinant coagulation factors, the
gene is inserted into a cell line such as animal cell lines (Chinese
hamster ovary or baby hamster kidney). The cells are cultured
and the secreted factor is purified from the culture medium. The
factor must be stable throughout the production process and in
the final form. If human and animal products are used in the
culture media, trace amounts may appear in the final product. A
viral inactivation/removal step is used to enhance safety.
First-generation recombinant coagulation factors used human
albumin as a stabiliser of the final product and are no longer
available for use in the UK. Second-generation recombinant
coagulation factors are stabilised without the addition of human
albumin and include Kogenate and Refacto. Third-generation
Currently in
Modification Clinical benefit use in UK
B-domain-deleted rFVIII fused with human IgG1 1.8-fold increase T1/214 Yes
Fc domain
Full-length rFVIII with lysine PEGylation 1.5-fold increase T1/215 No
B-domain-deleted with site-specific PEGylation 1.7-fold increase T1/216 No
B-domain-truncated rFVIII with site-specific 1.5-fold increase T1/217 Yes
PEGylation
3
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Review
Table 2  Extended half-life factor IX products—manufacturing characteristics and pharmacokinetics
Product Company Cell line Modification
rFIX-Fc (Alprolix) Biogen Human embryonic kidney rFIX fused with human IgG1 Fc domain
rFIX-FP (Idelvion) CSL Behring Chinese hamster ovary rFIX fused with recombinant human
albumin
N9-GP Novo-Nordisk Chinese hamster ovary rFIX with site-specific PEGylation
recombinant coagulation factors in which animal products are
not used in the culture media are Advate and BenefIX. The
recombinant FVIII products currently available in the UK are
either full-length or B-domain-deleted FVIII molecules.
Human cell line recombinant FVIII products
Recently, recombinant FVIII products have been manufactured
in human cell lines, the potential advantage being ‘human-like’
post-translational modifications resulting in improved binding
affinity to von Willebrand factor (vWF) and thus conceivably
an increase in half-life and a reduction in immunogenicity.12 A
recombinant FVIII-single chain product has also been shown to
have an improved binding affinity for vWF.13
Fourth generation/extended half-life recombinant factor
concentrates
Extended half-life (EHL) products with their potential for
reduced frequency of administration are especially attractive
for children and their parents. Two molecular strategies have
been used to engineer modified clotting factor glycoproteins and
thereby prolong their half-lives:
1. PEGylation involves covalently binding a polyethylene glycol
polymer to the factor protein to extend the survival in the
circulation.
2. Fusion to the Fc region of human Ig G1 or to recombinant
human albumin by covalent bonds, thus taking advantage of
the neonatal Fc receptor-mediated recycling which delays
lysosomal degradation of the fusion proteins and recycles
them back into circulation.
The most impressive results are seen with EHL-FIX with half-
lives of three to six times longer than existing products. The
results with EHL-FVIII are less impressive only increasing the
half-life by 1.5 times largely due to the dependence of FVIII on
the half-life of vWF in the circulation. Tables 1 and 2 summarise
the EHL-FVIII and FIX products currently available.14–20
PD factor concentrates
PD-FVIII is made from pooled human plasma; thus, there is a
potential risk of TTIs. Despite stringent procedures designed to
reduce the risk of TTIs, this risk cannot be totally eliminated. One
recent international randomised-control study (Survey of Inhib-
itors in Plasma Product Exposed Toddlers—SIPPET) compared
the incidence of FVIII inhibitors among previously untreated
patients (PUPs) treated with PD-FVIII or rFVIII. The study
was conducted mostly from non-European countries with very
different practices and identified an increased risk of inhibitor
occurrence with rFVIII products at a rate of 44.5% compared
with 26.8% in PD-FVIII concentrates.21 In contrast, a retrospec-
tive UKHCDO study conducted between 2000 and 2011 looked
at the inhibitor rates for the complete UK cohort of PUPs. All
407 study patients received rFVIII in keeping with the UK policy,
and an overall inhibitor rate of 29% was identified.22
In light of the SIPPET data discussions regarding choice of either
PD FVIII concentrate or recombinant FVIII concentrate should
4 Bhatnagar N, Hall GW. Arch Dis Child 2017;0:1–5. doi:10.1136/archdischild-2016-311018
Currently in use
Clinical benefit in UK
Threefold increase T1/218 Yes
Fourfold to fivefold increase T1/219 Yes
Fourfold to fivefold increase T1/220 No
be held with the family balancing the theoretical risk of TTIs
and potential immunogenicity of each product. The UKHCDO
recommends that recombinant FVIII concentrates remain an
acceptable standard of care for PUPs in the UK, with PD concen-
trates considered on an individual basis particularly for those
with a strong family history of inhibitor formation.
Novel therapies: non-factor approaches
Improving haemostasis without replacing the deficient factor
is a potentially exciting concept for patients with haemophilia
particularly those with persistent inhibitors who have limited
treatment options other than rVIIa and FEIBA. There are a
number of such agents currently in various stages of clinical trials
and include FVIII mimetics, molecules targeting anti-thrombin
and thrombin activatable fibrinolysis inhibitor .
One published study of emicizumab (ACE910), a recombi-
nant humanised bispecific antibody that promotes thrombin
generation by binding to and bridging activated FIX and FX,
thus mimicking the co-factor activity of FVIII,23 has shown
once weekly subcutaneous usage may be possible which would
completely revolutionise prophylaxis for children though further
trial data are awaited.
Gene therapy for FVIII and FIX deficiencies is now progressing
through clinical trials with promising results in adults. Trans-
lating this to paediatric practice is likely to be a considerable
time away.
Summary
The lives of children with haemophilia and their families have
been transformed in the last few decades due to earlier prophy-
laxis, specialised and dedicated care overseen by the UKHCDO.
Feedback and support for families via the Haemophilia Society
(UK) and the World Federation of Haemophilia helps to promote
high-quality care. Safer and better products are now available
but we look to the future to novel agents currently in clinical
trials, which show great promise in being able to radically alter
the management of children with haemophilia particularly those
with persistent inhibitors.
Competing interests  None declared.
Provenance and peer review  Commissioned; externally peer reviewed.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
article) 2017. All rights reserved. No commercial use is permitted unless otherwise
expressly granted.
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5
 Downloaded from http://adc.bmj.com/ on November 26, 2017 - Published by group.bmj.com

Major bleeding disorders: diagnosis,

classification, management and recent
developments in haemophilia
Neha Bhatnagar and Georgina W Hall

Arch Dis Child published online November 25, 2017

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References This article cites 23 articles, 3 of which you can access for free at:
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