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Thalassemia (Ref. Hari. 18th ed., Pg- 858)

Important Points
  1. Hemoglobin consists of 2 different pairs of peptide chains (one alpha and the other beta) with the haem molecule attached to each peptide.
  2. Adults have 95% HbA (α2β2) + 5% HbA22δ2).
  3. Fetuses have HbF (α2γ2) which continues to persist in beta – thalassanemia
  4. In thalassemias, there is a reduced rate of production of one or more globin chains leading to precipitation of globin, and anemia occurs as a result of ineffective erythropoiesis and hemolysis. (LQ 2012)

(Ref. Hari. 18th ed., Pg- 61, table 99.4)



  1. Alpha thalassanemia (reduced production of alpha chains)
  2. Beta thalassanemia (reduced production of beta chains)
  3. Hemoglobin H disease
  4. Hb Barts
  5. Beta thalassemia intermedia.


Beta-thalassemia (β-thalassemia) is a form of thalassemia due to mutations in the HBB gene on chromosome 11, inherited in an autosomal recessive fashion.
The severity of the disease depends on the nature of the mutation.
  1. Alleles without a mutation that reduces function are characterized as (β).
  2. Mutations are characterized as (βo) if they prevent any formation of β chains.
  3. Mutations are characterized as (β+) if they allow some β chain formation to occur. (Note that the "+" in β+ is relative to βo, not β.)
In either case there is a relative excess of α chains, but these do not form tetramers: rather, they bind to the red blood cell membranes, producing membrane damage, and at high concentrations they form toxic aggregates
Any given individual has two β globin alleles:
Name Description Alleles
β thalassemia minor
Also called β thalassemia trait)
i. If only one β globin allele bears a mutation.
ii. There is a mild microcytic anemia.
iii. MCV a slightly decreased.
iv. The patient will have an increased fraction of Hb A2 (>3.5%) and a decreased fraction of HbA (<97.5%).
β+/β or βo
Thalassemia intermedia i. A condition intermediate between the major and minor forms.
ii. Affected individuals can often manage a normal life without need for transfusions.
β++or βo
β thalassemia major or Cooley's anemia i. If both alleles have thalassemia mutations.
ii. This is a severe microcytic, hypochromic anemia.
iii. Untreated, it causes anemia, splenomegaly, and severe bone deformities.
iv. It progresses to death before age twenty. Treatment consists of periodic blood transfusion;
v. Splenectomy if splenomegaly is present, and treatment of transfusion-caused iron overload.
vi. Cure is possible by bone marrow transplantation.
β+oor βoo or β++


Note that β°/β can be associated with β thalassemia minor or β thalassemia intermedia, and β++ with thalassemia major or intermedia.


The genetic mutations present in β thalassemias are very diverse, and a number of different mutations can cause reduced or absent β globin synthesis. Two major groups of mutations can be distinguished:
  1. Nondeletional forms: These defects generally involve a single base substitution or small deletion or inserts near or upstream of the β globin gene. 
  2. Most commonly, mutations occur in the promoter regions preceding the beta-globin genes.
  3. Less often, abnormal splice variants are believed to contribute to the disease.
  4. Deletion forms: Deletions of different sizes involving the β globin gene produce different syndromes such as (βo) or hereditary persistence of fetal hemoglobin syndromes.

Types of Beta Thalassemia

  1. Beta– Thalassanemia Major (Homozygotes)
    (Cooley’s Anemia)
    1. Anemia is very severe and the patients live only for a short time without blood transfusion. 
    2. Bone marrow hyperplasia produces frontal bossing and prominent malar eminences which is seen in the skull X – ray as ‘hair on end’ appearance. 
    3. Children develop characteristic "chipmunk" facies due to maxillary marrow hyperplasia and frontal bossing.
    4. Most types of beta thalassemia are caused by point mutations affecting one or few bases.
    5. M/C point mutation in beta thalassemia involves IVS-1 or the intron – 1
  2. Thalassemia Intermedia
    1. The patient presents with features which are intermediate between thalassemia major and thalassemia minor.
    2. The symptoms are milder than those of thalassemia major but severe than those of usually asymptomatic thalassemia minor. Important characteristic features of thalassemia intermedia are: 
    3. Conventionally the condition is considered non-transfusion dependent, the patient is capable of surviving without transfusion.
    4. The growth and development in the patient is usually normal. The common presenting features are:
      1. Anemia of mild to moderate degree (7-10 g/dl), less than 7-8 degrees indicates severe cases.
      2. Mild jaundice.
      3. Splenomegaly (the spleen is palpable from the beginning and its size increases with time).
  3. Beta– Thalassanemia Minor (Heterozygotes)
    The course is very mild and often this anemia is detected only when a therapy for a mild hypochromic anemia fails. Symptoms are minimal
​↑ HbF, ↑HBA2, usually asymptomatic S. ferritin is (n)

Thalassanemia minor: Clinical feature
  1. Mild anemia, microcytic hypochromic RBCS (total iron binding capacity, serum iron, ferritin levels are normal)
  2. Some target cells, punctate basophilia
  3. Raised HbA2 4 –6% (normal HbA2 1.5 to 3%)
  4. Family history with one parent having thalassanemia minor. 
Management of thalassemia major
  1. Regular blood transfusion to maintain hematocrit in the range of 30 – 35% or Hb in the range of 10 gm%
  2. Allogeneic bone marrow transplantation for erythropoietic failure.
  3. Avoid iron therapy. Desferrioxamine is used as an iron chelating agent.
  4. Splenectomy if hypersplenism occurs.
  5. Give folate supplementation
  6. Manipulation of globin chain expression and gene therapy.

Alpha - Thalassanemia

There are four alpha genes in chromosome 16 in normal individuals. Both sexes are affected. It may present as hydrops fetalis (all genes deleted) or hemoglobin H (3 genes deleted), or mild hypochromic microcytic anemia (2 genes deleted) or asymptomatic (1 gene deleted).
Alpha – Thalassanemia
  1. Cause:
    1. Failure of production of hemoglobin alpha chains due to gene deletion
  2. Presentation
    1. Hydrops fetalis if all genes deleted
    2. Hemoglobin H if three genes deleted
    3. Mild hypochromic microcytic anemia if two genes deleted
    4. Asymptomatic if one gene is affected.
  3. Treatment
    1. Hydrops fetalis: None available
    2. Hemoglobin H: No specific therapy required; avoid iron therapy. If folic acid is given
The four classic alpha-thalassemias, most common in Asians, are: (Ref. Robbins, 7th ed., Pg - 634)
  Type of alpha thalassemias: Characterized by:
1. Alpha-thalassemia-2 trait One of the four alpha-globin loci is deleted;
2. Alpha-thalassemia-1 trait Two loci deleted;
3. HbH disease Three loci deleted;
4. Hydrops fetalis with Hb Bart's All four loci deleted.

The α Thalassemias (Ref. Hari. 18th ed., Pg - 859, table 104.4)
Condition Hemoglobin A, % Hemoglobin H (β4), % Hemoglobin Level, g/L (g/dL) MCV, fL
Normal 97 0 150 (15) 90
Silent thalassemia: –α/αα 98–100 0 150 (15) 90
Thalassemia trait: –α/–αhomozygous αor – –/αα heterozygous α- 85–95 Rare red blood cell inclusions 120–130 (12–13) 70–80
HbH disease: – –/–α 70–95 5–30 60–100 (6–10) 60–70
Hydrops fetalis: – –/– – 0 5–10b
Fatal in utero or at birth  


Extra Edge (Ref. Hari. 18th ed., Pg- 859)
Thalassemia Syndromes: The four classic  thalassemias, most common in Asians, are -thalassemia-2 trait, in which one of the four -globin loci is deleted; -thalassemia-1 trait, with two deleted loci; HbH disease, with three loci deleted; (AIPG 2011) and hydrops fetalis with Hb Barts, with all four loci deleted.

Diagnostic Features

  1. Thalassanemia major
    1. Profound hypochromic anemia, severe red cell dysplasia
    2. Absence or severe reduction of HbA
    3. NESTROFT test (AIIMS Nov 2011) – It is screening test for the detection of thalassanemia & common hemoglobinopathies-
    4. Raised HbF (Most characteristic feature) in Hb electrophoresis (most important Test)
    5. Family history showing both parents having thalassanemia minor.
Erythrocyte protoporphyrin levels are characteristically normal in Thalassemia 
  1. Free Erythrocyte Protoporphyrin is a useful screening test for microcytic hypochromic anemias. 
  2. Free Erythrocyte protoporphyrin levels are increased in iron deficiency anemias, lead poisoning many cases of sideroblastic anemia and anemias of chronic disease. 
  3. Erythrocyte protoporphyrin levels are normal in Thalassemias.
Parameter Iron deficiency Lead poisoning Thalassemia trait Chronic disease
Fee erythrocyte
Protoporphyrin (FEP)
↑ed ↑ed Normal ↑ed
Iron overload conditions
  1. Sideroblastic anemia
  2. Thalassemia
  3. Chronic hemolytic anemia
  4. Repeated blood transfusion
  5. Hepatitis C
  6. Advance alcoholic liver disease
  7. Non alcoholic steatohepatitis
  8. Porphyria cutanea tarda    
  9. Porto caval shunt
  10. Hemochromatosis
  11. Dietary Fe overload

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