Thalassemia is a genetic blood disorder caused by an imbalance in the alpha and beta globin chains that make up hemoglobin. There are two main types - alpha thalassemia and beta thalassemia. Beta thalassemia major requires lifelong blood transfusions and iron chelation therapy to remove excess iron from the body, while beta thalassemia minor causes only mild anemia. Management of thalassemia major involves regular blood transfusions, monitoring of iron overload, and iron chelation therapy to remove excess iron and prevent organ damage. With proper treatment, patients can survive well into adulthood.

1. Thalassemia

2. Overview
• The name is derived from the Greek word “Thalasso= Sea” and
“Hemia= Blood” in reference to anemia of sea.
• Thalassemia refers to a group of genetic disorders of globin-chain
production in which there is an imbalance between the α-globin
and β-globin chain production.
• Commonest form of haemoglobinopathy.

3. Genetics
Thalassemia are autosomal recessive
disorders.
Fetal hemoglobin (HbF) = α2 γ2.
Adult hemoglobin (HbA1 ) = α2 β2 (m/c)
HbA2= α2 δ2

4. Types of thalassemia
• Based on the deficiency of either α or β chains, thalassemias are of
2 types
1. α-thalassemia
2. β-thalassemia

5. α-thalassemia
• α-globin gene deletions ,decreases alpha globin synthesis on chromosome 16.
• cis deletion -deletions occur on same chromosome,
• trans deletion -deletions occur on separate chromosome.
• Normal is αα/αα.

6. α-thalassemia
Classification Genotype No of gene
deleted
Clinical outcome
α-thalassemia minima α α/α – 1 No anemia (silent carrier)
α-thalassemia minor α –/α –; trans or
α α/– –; cis
2 Mild microcytic,
hypochromic anemia; cis
deletion may worsen
outcome for the carrier’s
offspring
Hemoglobin H disease (HbH) – –/– α 3 Moderate to severe
microcytic hypochromic
anemia
Hemoglobin Barts disease – –/– – 4 Hydrops fetalis; incompatible
with life

7. β-thalassemia: deficient synthesis of β chains
1. β Thalassemia major: They are transfusion dependent.
2. β Thalassemia minor or trait: They carry the defective gene,
completely asymptomatic and are identified incidentally.
3. β Thalassemia intermedia: Their clinical phenotype is more than
thalassemia minor but milder than thalassemia major. Their clinical
behavior is widely variable. Some of them, maintain Hb
concentration of about 7-8 gram without transfusion but some may
remain completely asymptomatic until adult life.

9. Clinical Manifestations of thalassemia major
• Age: present within first year of life ,at birth
asymptomatic and after 3 month anemia develops.
The common presentations are–
• Progressive pallor, lethargy and effort intolerance.
• Failure to thrive and growth retardation.
• Thalassemic facies (maxilla hyperplasia, flat nasal
bridge, frontal and parietal bossing, malaligned
jaw and teeth)

10. • Psychological depression.
• Recurrent infections.
• Problems in movement and abdominal discomfort because of massive spleno-
hepatomegaly.
• Sometimes, patient may present with features of complications like– Respiratory
distress due to anemic heart failure
• Gum bleeding, epistaxis etc. due to hypersplenism.
• Pathological fracture

11. Investigation
• Before 6 months of age
1. DNA analysis-based diagnostic studies
2. Rate of globin chain synthesis
3. Naked eye single tube red cell osmotic fragility test(NESTROFT)

12. After 6 months of age
Blood
• Haemoglobin: Low, (3-9 gm/d)
• TC & DC: Normal, except when associated infection (leukocytosis)
or hypersplenism (depleted)
• Platelet count: Usually normal except in hypersplenism
(Thrombocytopenia)
• Reticulocyte count: Relative reticulocytopenia , commonly <8%
• RBC indices (MCV, MCH, MCHC): Low

13. • Peripheral blood film:
Shows microcytic
hypochromic picture
with marked
anisocytosis &
poikilocytosis.
• Appearance of abnormal
cells like target cells, tear
drop, nucleated cells,
schistocytes, fragmented
cells.

14. • Serum iron, S ferritin and S transferin saturation: Increased
• Total iron binding capacity (TIBC): Decreased
• Bone marrow: hypercellular with erythroid hyperplasia.
• Radiological changes: medullary portion of bone is widened and bony cortex is thinned
out with coarse trabecular pattern in medulla.
• X-ray of metacarpals, ribs and vertebra shows thinning of cortex and skull shows hair on
end appearance. X-ray changes seen after 1 year.

15. Haemoglobin electrophoresis and HPLC
• HbA2 and HbF raised.
• This test should be done before blood transfusion, as the formation
of HbF is suppressed by blood transfusion.
• This test helps to distinguish between normal individuals, carriers
and people with thalassemia

16. Features Thalassaemia major Thalassemia
intermedia
Thalassemia minor
Genetics Homozygous form-two
muted genes
Homozygous or
heterozygous-2 muted
gens
Heterozygous –one
muted genes
Age of presentation Early infancy(6-8 m) Second year of life Adolescence
Clinical feature Progressive pallor
Hepatosplenomegaly
Bony changes
Anemia
Hepatosplenomegaly
Bony changes
Mild persistent anemia
Hb electrophoresis HbF (10-50%)
,HbA2>4%, HbA(30%)
HbA2>/=3.5%
Requirement of blood
transfusion
By 6 months Rarely needed.by 2
years Hb falls to about
7 g/dl
By adolescence
complication Hypersplenism
Iron overload
Iron overload,
recurrent leg
ulcers,Cholelithiasis
Iron overload
Prognosis Fetal in first year of life Normal lifespan Normal lifespan

17. Management and Treatment of Thalassemia
• β-thalassemia major is a clinical diagnosis that requires the
integration of laboratory findings and clinical features.
• The long-term observation of the clinical characteristics, such as
growth, bony changes, and hemoglobin, are necessary to determine
chronic transfusion therapy.

18. Transfusion therapy
Transfusions should generally be given at intervals of 3-4 wk, with the
goal being to maintain a pretransfusion Hb level of 9.5-10.5 g/ dL and
post transfusion level should not be more than 16gm/dl.
Amount and rate of transfusion:
• Fresh blood -20ml/kg , Packed RBC-10 ml/kg
• Transfusion rate 5-7 ml/kg/hr
• In presence of cardiac failure, rate of transfusion should be decreased.
• Hb should increase by 3.5 g/dl
• Average annual blood requirement is 180-200 ml/kg, in patients with
hypersplenism or antired cell antibodies, requirement is more.

19. Iron Overload and Chelation Therapy
• Iron overload is a major cause of morbidity
• Exceesive overload of iron is due to increased gastrointestinal iron absorption as well
as repeated transfusion
• Patient show signs of endocrinopathy affecting pancreas, thyroid & parathyroid
glands.
• Screening with serial serum ferritin level and quantitative measurement of iron by
MRI.
• The liver iron results will help guide the chelation regimen.
• Iron overload occurs after 1 yr of transfusion therapy and correlates with the serum
ferritin >1,000 ng/ mL and/or a liver iron concentration of >5,000 µg/g dry weight.
• Iron chelation is not currently labeled for use in children <2 years.

20. • There are 3 available iron chelators:
1. Deferoxamine : sc infusion pump/iv (25 -60 mg/kg/day.)
2. Deferasirox : oral chelating agent (20-40mg/kg)
3. Deferiprone- oral chelating agent (75-99 mg/kg/day PO TDS)
• Vitamin –C 2-3 mg/kg/day helps in excretion of iron.
• Vitamin E should be supplemented as an antioxidant to reduce iron
induced oxidative damage of cells.

21. Hydroxyurea
• A DNA antimetabolite, increases HbF production.
• Studies in β-thalassemia major are limited.
• mean increase in Hb of 1 g/dL.
• Hydroxyurea therapy in thalassemia intermedia is associated with a reduced
risk of leg ulcers, pulmonary hypertension, and extramedullary hematopoiesis.
• 10-20 mg/kg.

22. Hematopoietic Stem Cell Transplantation
• Most success has been in children <14yr without excessive iron
stores and hepatomegaly who undergo sibling HLA- matched
allogenic transplantation.
• In low-risk HLA-matched sibling patients, there is at least a 90%
survival and an 80% event-free survival

23. Splenectomy
• Should be postponed for at least up to age of 6 years to avoid the risk of
infection.
• Indications
1. Transfusion requirement PRBC>200ml/kg/year.
2. Hypersplenism(leucopenia, thrombocytopenia).
3. Massive splenomegaly
• Child should be immunized with pneumococcal, Haemophilus influenza, and
meningococcal vaccine 4-6 weeks prior to splenectomy.
• Life long penicillin prophylaxis and prophylaxis for malaria should be given.

24. Prevention
• Carrier detection: among the general population through Lab assessment of
blood CBC, PBF, MCV, MCHC & Hemoglobin electrophoresis. DNA analysis
in confirmatory
• Pre-marital counseling: among the population, specially among the carriers,
how the disease is transmitted from one generation to the next and
Antenatal detection how to prevent .
• When a carrier mother becomes pregnant, the status of the fetus whether
having thalassemia major, carrier or normal can be detected by chorionic
villus sampling (CVS) and DNA analysis during 8-11th weeks of pregnancy

25. Follow up
Monthly Complete Blood Count
Every three months S. ferritin, RBS, SGPT, albumin, creatinine
Every six months Cardiac evaluation e.g. echocardiography,
ECG
yearly Screening for infection: HBV, HCV, HIV
Screening for endocrinopathy: FT4, TSH,
LH, Testosterone, Estradiol, GTT
Assessment of vision and hearing
Other investigations to assess iron
deposition in vital organs
e.g. MRI of heart, liver, endocrine glands

26. Prognosis
• The outcome depends on the severity of disease .
• Life expectancy is normal for people with β-thalassemia or thalassemia minor.
• If the child has thalassemia major he requires frequent blood transfusion and
chelation therapy and can survive for up to 30 years of age.
• Death usually occurs from cardiac complications, post-splenectomy sepsis, multi-
organ failure secondary to hemochromatosis.

27. References
• Ghai Essential Pediatrics, 9th edition.
• Nelson textbook of Pediatrics, 21st edition.

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