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INTRODUCTION
Thalassemia is an inherited disorder of autosomal recessive gene disorder caused by
impaired synthesis of one or more globin chains. The impairment alters production of
hemoglobin (Hb) (Ridolfi et al., 2002). Thalassemia causes varying degrees of anemia, which
can range from significant to life threatening. People of Mediterranean, Middle Eastern,
African, and Southeast Asian descent are at higher risk of carrying the genes for thalassemia
(Weatherall, 1997). These hereditary anemias are caused by mutations that decrease
hemoglobin synthesis and red cell survival. These hereditary anemia caused by decreased or
absent production of one type of globin chain either or globin chain. These hematologic
disorders range from asymptomatic to severe anemia that can cause significant morbidity and
mortality. It was first recognized clinically in 1925 by Dr. Thomas Cooley, who described a
syndrome of anemia with microcytic erythrocytes. Then it was called Cooleys anemia. Later
Wipple and Bradford renamed this disease as Thalassemia. Because it was found in the
region of the Mediterranean Sea (thalasa is an old Greek word for sea) (Cooley, 1946).
Thalassemias can cause significant problems because these are inherited disorders, newborn
screening and prenatal diagnosis are important in management of patients.1
Thalassemia major (TM) originated in Mediterranean, Middle Eastern, and Asian
regions. However, because of migration, this diseases now occur globally and represent a
growing health problem in many countries.2 Thalassemia is the most common hematologic
genetic disease in Southeast Asia. The prevalences of alpha-thalassemia, beta-thalassemia,
and HbE genes in our population are 2030, 39, and 14%, respectively.3 In Indonesia,6-10%
people are carriers of thalassemia gene. 4 The -globin gene families are clustered on
chromosome 11 and are arranged over approximately 60,000 nucleotide bases. -thalassemia
is a quantitative deficiency of -globin production, and are usually due to DNA mutations of
the b-globin gene cluster and result from mutations affecting gene transcription, RNA
processing, alter splice junctions or splice consensus sequences, mutations within exons and
introns that create an alternative splice site. Majority of the mutations are point mutations and
unlike a-thalassemia deletion mutations are relatively less frequent. About the 3 % of the
worlds population carries the thalassemia gene. The bulk of this disorder is reported from
Mediterranean, African and south-east Asian populations where the incidence of gene
carriage may be as high as 10 %.5
CHAPTER II
LITERATURE REVIEW
2.1.
Definition
The thalassemias are a group of congenital anemias that have in common deficient
synthesis of one or more of the globin subunits of the normal human hemoglobins (Hbs). The
primary defect is usually quantitative, consisting of the reduced or absent synthesis of normal
globin chains, but there are mutations resulting in structural variants produced at reduced rate
(e.g., HbE, Hb Lepore) and mutations producing hyperunstable hemoglobin variants with a
thalassemia phenotype (thalassemic hemoglobinopathies). Therefore, a rigid differentiation
from
the
qualitative
changes
of
hemoglobin
structure
that
characterize
the
International occurrence
The disease is found most commonly in the Mediterranean region, Africa, and
Race-related demographics
Beta thalassemia genes are reported throughout the world, although more frequently
extraction are more likely to be anemic with thalassemia trait than Africans because they tend
to have beta-zero thalassemia rather than beta-plus thalassemia.
Age-related demographics
The manifestations of the disease may not be apparent until a complete switch from
fetal to adult Hb synthesis occurs. This switch typically is completed by the sixth month after
birth.
Etiology9
2.3.
3. A mutation in the promoter area that decreases the rate of gene expression
4. A mutation at the termination of the gene that leads to lengthening of the globin
chain with additional amino acids; the mRNA becomes unstable and causes a
reduction in globin synthesis
5. A total or partial depletion of a globin gene, probably as the result of unequal
chromosomes crossing over
2.4.
Pathophysiology
The biochemical hallmark of -thalassemia is reduced biosynthesis of the -globin
subunit of Hb A (22). In -thalassemia heterozygotes, -globin synthesis is about halfnormal (/ synthetic ratio 0.50.7). In homozygotes for
+
-thalassemia homozygotes or
+
0
/ -
released into the bloodstream as erythrocytes. The occasional erythrocytes that are formed
during erythropoiesis bear a burden of inclusion bodies. The reticuloendothelial cells in the
spleen, liver, and bone marrow remove these abnormal cells prematurely, producing a
hemolytic anemia.
Defective -globin synthesis exerts at least three distinct yet interrelated effects on the
generation of oxygen-carrying capacity for the peripheral blood: (a) ineffective
erythropoiesis, which impairs production of new red blood cells; (b) hemolytic anemia, which
shortens the survival of the few red blood cells produced; and (c) hypochromic with
microcytosis, which reduces the oxygen carrying capacity of those few red blood cells that do
survive. In the most severe forms of the disorder, these three factors conspire to produce a
catastrophic anemia, complicated by the effects of exuberant hemolysis. The profound deficit
in the oxygen-carrying capacity of the blood stimulates production of high levels of
erythropoietin in an attempt to promote compensatory erythroid hyperplasia. Unfortunately,
the ability of the marrow to respond positively is markedly impaired by ineffective
erythropoiesis. Massive bone marrow expansion does occur, but very few erythrocytes are
actually supplied to the circulation. The marrow becomes packed with immature erythroid
precursors, which die from their burden of precipitated -globin chains before they reach the
reticulocyte stage. Profound anemia persists, driving erythroid hyperplasia to still higher
levels. In some cases, erythropoiesis is so exuberant that masses of extramedullary
erythropoietic tissue form in the chest, abdomen, or pelvis.
Figure 2.3. Pathophysiology of severe forms of -thalassemia. The diagnosis outlines the
pathogenesis of clinical abnormalities marking from the primary defect in -globin chain synthesis,
RBCs, and blood cells.
2.5.
Diagnosis11
2.5.1 Clinical Diagnosis
Thalassemia major is usually suspected in an infant younger than two years of age
with severe microcytic anemia, mild jaundice and hepatosplenomegaly. Thalassemia
intermedia presents at a later age with similar but milder clinical findings. Carriers are
usually asymptomatic, but sometimes may have mild anemia.
2.5.2 Hematologic Diagnosis
RBC indices show microcytic anemia. Thalassemia major is characterized by reduced
Hb level ( 50 < 70 fl and mean corpuscolar Hb (MCH) > 12< 20 pg. Thalassemia intermedia
is characterized by Hb level between 7 and 10 g/dl, MCV between 50 and 80 fl and MCH
between 16 and 24 pg. Thalassemia minor is characterized by reduced MCV and MCH, with
increased Hb A2 level.
2.5.3
anisocytosis, poikilocytosis (spiculated tear-drop and elongated cells)], and nucleated RBC
(i.e., erythroblasts). The number of erythroblasts is related to the degree of anemia and is
markedly increased after splenectomy.
Carriers have less severe RBC morphologic changes than affected individuals.
Erythroblasts are normally not seen.
2.5.4
facilitated molecular genetic testing. Commonly occurring mutations of the beta globin gene
are detected by PCR-based procedures. The most commonly used methods are reverse dot
blot analysis or primer-specific amplification, with a set of probes or primers complementary
to the most common mutations in the population from which the affected individual
originated.
If targeted mutation analysis fails to detect the mutation, beta globin gene sequence
analysis can be used to detect mutations in the beta globin gene.
Differential Diagnosis11
2.6.
shows microcytosis (low MCV) and reduced content of Hb per red cell (low MCH), and by
qualitative and quantitative Hb analysis, which displays the increase of HbA2. Pitfalls in
carrier identification by hematologic testing are:
Treatment12
Transfusion therapy
The goals of transfusion therapy are the correction of anemia, suppression of
below), have been excluded. For patients maintaining a pretransfusion Hb of 9.5 g/dL, the
increase in transfusion requirement is represented by a consumption of more than 200 mL of
RBC/kg/year (assuming that the Hct of the unit of red cells is 75%).
Table 2.1 Indications for splenectomy
Blood consumption > 200-220 mL/kg/year
Symptoms of splenic enlargemen
Leukopenia and/or thrombocytopenia
Increasing iron stores despite good chelation
Growth is usually normal until the age of 9 and afterwards there is a decrease of growth rate
which leads to a final height lower than that expected on a genetic basis. The factors
contributing to stunted growth are not completely understood but include chronic anemia,
hypersplenism, folate deficiency, direct iron toxicity, endocrine disorders such as
hypogonadism, hypothyroidism and growth hormone (GH) insufficiency, chronic liver
disease and deferoxamine toxicity. In regularly transfused and well-chelated patients,
deferoxamine at high doses or at therapeutic doses in patients with hypersensitivity, can be
toxic to osteogenesis, collagen synthesis and bone turnover, leading to reduced growth
(especially of the trunk), protrusion of the sternum, valgus deformity of knees and elbows,
swelling of wrists and knees and sliding of the femoral head. Radiologically, platyspondylisis
and rachitic-like lesions in the metaphyses of the long bones are present (Figure 2.4).
The effective treatment of growth disorders depends on an accurate assessment of
their cause. Studies evaluating the secretion of GH have yielded contradictory results,
limiting the therapeutic use of GH to those patients proven to have GH deficiency, the only
ones to show a satisfactory response to treatment. In the case of signs of deferoxamine
toxicity, a reduction in deferoxamine dose or its substitution with an oral chelator, can prevent
progression of bone lesions and improve growth. In the most severe cases, surgery can be
necessary to correct valgus deformity of the knees or sliding of the femoral head.
Figure 2.4. Abnormalities of metaphyseal growth and platospondylisis in patients with thalassemia
major
Complications of Transfusion12,13
2.8.
Although red cell transfusions are lifesavers for patients with thalassemia, they are
responsible for a series of complications and expose the patients to a variety of risks. Adverse
events associated with red cell transfusions are iron overload, infections, and immunisations
(allergic reactions, alloimmunisation).
2.8.1
Iron overload
Iron overload is the most relevant complication associated with transfusion therapy.
The timing of appearance of signs or symptoms depends on the rate of iron overload. In
severe conditions such as thalassemia major, they may appear in childhood, with skin
hyperpigmentation, growth impairment, delayed puberty, cardiac arrhythmias and the onset
of overt organ dysfunction, including congestive heart failure or diabetes. Otherwise, as in
genetic hemochromatosis, signs and symptoms may be very late and non-specific: weakness,
fatigue, loss of libido, and/or arthralgia. If the iron burden progresses and is not treated, all
the clinical features may become manifest, with heart disease, diabetes, hypothyroidism,
hypoparathyroidism, hypogonadism, and cirrhosis. A clear association with the risk of
developing hepatocellular carcinoma has been established, at least for thalassemia.
Serum ferritin is the most widely used and the least expensive parameter for assessing
iron status. A positive correlation exists between serum ferritin concentration and iron stores,
but independent conditions may falsely elevate ferritin levels (cancer, hepatitis, inflammation,
Deferoxamine
A single excellent drug, deferoxamine (DFO) has been available for many years.
DFO displays a strong and specific affinity for iron with a theoretically capability of binding
8.5 mg ferric iron every 100 mg of DFO. The subcutaneous slow infusion has been the
standard iron chelation choice since the end of the seventies. In thalassemia major, the regular
use of DFO resulted in an impressive improvement in life expectancy and a reduction in the
prevalence and severity of iron-related clinical complications. With experience and skill it is
possible to limit side effects and optimize compliance in most patients. The standard
prescription is a slow subcutaneous infusion over 8-12 hours of a 10% DFO solution by an
infusion pump at a standard dose of 20-40 mg/kg for children and up to 50-60 mg/kg for
adults. Alternatives in treatment modalities, such as s.c. bolus injection or i.v. continuous
infusion enable DFO to be used in a wide range of conditions and special needs.
Symptomatic heart disease can be reversed by high dose intravenous treatment. Recent data
show that a significant proportion of patients on long-term s.c. DFO still have evidence of
cardiac iron load despite low serum ferritin levels. With a single i.v. infusion it is possible to
obtain a significant iron excretion lasting up to several days, with limited side effects.
During the past few years the body of advances on iron chelation research has been
impressive, leading to the development of new oral chelators. Deferiprone (DFP) (Apotex,
Toronto, ON, Canada) also known as L1, CP20, Ferriprox and Kelfer, is a 1,2 dimethyl-
3hydroxypyrid-4-one, was initially synthesised in 1982, but its development did not follow a
systematic design.
Recent data on patients with beta-thalassemia demonstrate that daily through levels of
DFX suppress LPI for 24 hours. In regularly transfused MDS patients, DFX is also efficient
in reducing LIC. In this condition there is a higher rate of adverse events and more frequent
discontinuation of therapy. Indications are only based on an expert consensus, additional data
are required for a better definition of patients with the best risk-benefit ratio. In a recent study
on MDS patients DFX may reduce transfusion requirement. The hypothesis that there is a
direct effect of DFX on the neoplastic clone is under investigation. At high doses DFX shows
a positive effect on heart iron. A systematic review on DFX analyses also its economic
aspects. Table 2.2. shows the properties of available iron chelators.
Table 2.2. Comparison of iron chelators
iron-dependent physiological pathways. Age, high doses of chelator and low level of iron
overload are the main risk factors, whereas certain side effects are characteristic of each drug.
For detecting early iron chelation toxicity and minimising its consequences, a close
monitoring schedule should be individually tailored. This may include: auxological
assessment (weight, body fat, standing and sitting height, pubertal stages, radiological
assessment of bone age and the main metaphyses), bone densitometry, liver function tests,
ophthalmological examination, audiometry, plasma zinc, rheumatological assessment are
recommended. For DFO specific attention must be paid to early signs of infection for
diagnosis and treatment of iron related complications as Yersinia enterocolitica septicaemia.
For DFP weekly check of absolute neutrophil count is required. For DFX regular renal
2.8.2 Infections
The risk of infections is one of the most relevant potential complications of blood
transfusion. Blood-borne infections can be viral, bacterial or protozoa. The hepatotropic
viruses include hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis G virus.
Transmission of these viruses in multitransfused patients varies widely in different parts of
the world and is directly correlated with their frequency in each population. Administration of
recombinant HBV vaccine is recommended for all non-infected patients.
The prevalence of HIV positivity in patients from Mediterranean countries is 1.6%.
The implementation of nucleic acid testing (NAT) together with the existing
antigen/antibody-based assays for donor screening has further reduced the residual risk of
recipients viral infection by shortening the window period that is the temporal gap spanning
from the time of infection to seroconversion.
Fever, shivers, nausea, vomiting, dyspnoea and hypotension are the most common
symptoms occurring during or shortly after transfusion. Differential diagnosis includes
haemolytic and non-haemolytic reactions. Supportive and antibiotic therapy should be
initiated as required. In US death from transfusion-transmitted infections is the second
leading cause of death. In countries where it is endemic, malaria can be acquired from
transfusions.
CHAPTER III
CASE REPORT
3.1 Objective
The objective of this paper is to report a case of 10 years old girl with a diagnosis of
Thalassemia Major + Moderate Mitral Regurgitation + Mitral Prolapse.
3.2 Case
VR, a 10 years old girl, with 10 kg of BW and 118 cm of BH, is a new patient of noninfection unit in PediatricDepartment in Central Public Hospital Haji Adam Malik Medan on
May 5th 2015 at 17.30. Her chiefcomplaint was pale.
History of disease:
VR, a girl, 10 years old, came to Haji Adam Malik Hospital at May, 5 th 2015 with pale
as the chief complaint. The pale symptom have been experienced by patient since a month
ago, and become paler in recent week. The patient has no history of spontaneous bleeding,
nosebleed, melena, and fever. Urination and defecation of the patient within normal limits.
History of previous illness: The patient is an old patient of Hematology Unit with
Thalassemia and got routine transfusions.
History of medication:Vitamins : C 1x1 tab, E 1x1 tab; Folic acid 1x1 tab; Exjade 2x1 tab.
History of family:No family history of thalassemia and other diseases.
History of parents medication: unclear
History of pregnancy:The gestation age was 36 weeks. No history of complication, neonate
and maternal problem.
History
of
birth:
Birth
assisted
by
midwife
spontaneously.
The
baby
was
Neck
Thorax
Abdomen : Supple, normal peristaltic, liver was palpated3 cm below the right
clubbing finger(-).
Working diagnosis
: Thalassemia Major
Laboratory finding
Result
5.30
2.29
12.98
157
17.30
2.40
1.200
46.20
42.40
7.80
6.00
5.51
1.01
0.31
0.15
75.50
23.10
30.60
26.40
Unit
g%
106/mm3
103/mm3
103/mm3
%
%
%
%
%
%
103/L
103/L
103/L
103/L
103/L
fL
pg
g%
%
Referral
12.0-14.4
4.40-4.48
4.5-13.5
150-450
37-41
1-6
0-1
37-80
20-40
2-8
2.4-7.3
1.7-5.1
0.2-0.6
0.10-0.30
0-0.1
81-95
25-29
29-31
11.6-14.8
Morphology:
normal
Trombocyte: normal
Clinical Chemistry
Test
Carbohydrate Metabolism
Blood Glucose
Electrolite
Natrium
Kalium
Cloride
Other Test
Therapy
Result
Unit
Referral
119.00
mg/dL
< 200
131
3.8
107
mEq/L
mEq/L
mEq/L
135-155
3.6-5.5
96-106
Planning Assesment:
- Hand bone age (May 6th, 2015)
- PRC Transfusion = PRC needed = (Hb target Hb actual) x Constants x BW
= (12 5,3) x 4 x 20 = 536 cc 540 cc
PRC capability = 20 x 5 cc = 100 cc
Follow Up
06 May 2015
S
O
Pale(+)
Sensorium: Compos Mentis, Temp: 36,7oC.
Head :
-
Eye : light refleks (+/+), isochoric pupil, pale was found in inferior
conjunctiva palpebral(+/+)
Ear : within normal range
Nose : within normal range
Mouth : pale mucous +/+
A
P
Extremities : pulse 111 bpm, reguler, p/v adequate, warm acral, CRT < 3
Thalassemia Mayor
Exjade 2x1 tab
Vit C 1x1 tab
Vit E 1x1 tab
Folic acid 1x1 tab
R/ Transfusion
R/ Echocardiography
7 May 2015
S
O
Pale(+)
Sensorium: Compos Mentis, Temp: 36,7oC.
Head :
-
Eye : light refleks (+/+), isochoric pupil, pale was found in inferior
conjunctiva palpebral(+/+)
Ear : within normal range
Nose : within normal range
Mouth : pale mucous +/+
A
P
Extremities : pulse 110 bpm, reguler, p/v adequate, warm acral, CRT < 3
Thalassemia Mayor
Exjade 2x1 tab
Vit C 1x1 tab
Vit E 1x1 tab
Folic acid 1x1 tab
Echocardiography
Mitral Valve Prolapse; Moderate MR
Hand bone age (Left manus)
Retarded girls [norm. range bone age: 8-12 y.o.; actual bone age: 7 years 10 months]
8 May 2015
S
O
Pale(+)
Sensorium: Compos Mentis, Temp: 36,7oC.
Head :
-
Eye : light refleks (+/+), isochoric pupil, pale was found in inferior
conjunctiva palpebral(+/+)
Ear : within normal range
Nose : within normal range
Mouth : pale mucous +/+
A
P
Extremities : pulse 110 bpm, reguler, p/v adequate, warm acral, CRT < 3
Thalassemia Mayor + Moderate MR + Mitral Valve Prolaps
Exjade 2x1 tab
Vit C 1x1 tab
Vit E 1x1 tab
Folic acid 1x1 tab
9 May 2015
S
O
Pale (-)
Sensorium: Compos Mentis, Temp: 37oC, BW: 20 kg,
Head :
-
Eye : light refleks (+/+), isochoric pupil, pale inferior conjungtiva palpebra (+/
+)
Ear : within normal range
Nose : within normal range
Mouth :within normal range
Thorax : symmetrical fusiform, retraction (-)
HR: 92 bpm, reguler, murmur (-)
RR : 22 bpm, reguler, wheezing (-/-)
Abdominal : supple, peristaltic (+)N,liver was palpated 3 cm below the right
costal arches and spleen was palpable (Schuffner II)
A
P
Extremities : pulse 92 bpm, reguler, p/v adequate, warm acral, CRT < 3
Thalassemia Mayor + Moderate MR + Mitral Valve Prolaps
Exjade 2x1 tab
Vit C 1x1 tab
Vit E 1x1 tab
Folic acid 1x1 tab
Laboratory finding (May 9th 2015)
Hb/Ht/L/T = 13/4.94/8.51/39
MCV/MCH/MCHC/RDW = 78.9/26.5/33.6/21.0
Difftel = N/L/M/E/B = 35.4/49.1/10.2/4.2/1.10
R/outpatient
CHAPTER IV
DISCUSSION
Case
Theory
Patients mother had a history of diabetes Type 1 DM is the result of interactions of
mellitus
genetic,
environmental,
and
immunologic
Patient was admitted to the hospital with a Natural history of Type 1 DM is marked by
chief complaint history of unconsiousnes partial/total remission which is known as
after an injection of Novorapid.
enuresis
secondary
to
= (50 60) x 35 kg
= 50 gr
25 gr
snack night.
CHAPTER V
SUMMARY
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