Thalassemia

Epidemiology

• Beta thalassemia: most commonly seen in people of Mediterranean descent
• Alpha thalassemia: most commonly seen in people of Asian and African descent

Mnemonic

Alpha thalassemia is common in Asia and Africa.

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Etiology

• Beta thalassemia: usually due to point mutations in promoter sequences or splicing sites
  • β-globin locus - short arm of chromosome 11
• Alpha thalassemia: usually due to deletion of at least one out of the four existing alleles
  • The α-globin gene cluster is located on chromosome 16

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Pathophysiology

• Inefficient erythropoiesis → anemia
  • Beta-thalassemia minor and major: faulty β-globin chain synthesis → ↓ β-chains→ ↑ γ-,δ-chains → ↑ HbF and ↑ HbA2.
  • Alpha-thalassemia intermedia (HbH disease) and alpha-thalassemia major (Bart’s disease): faulty α-globin chain synthesis → ↓ α-chains → impaired pairing of α-chains with β-chains and γ-chains→ ↑ free β-, γ-chains → ↑ HbH, ↑ Hb Barts
  • Sickle cell anemia: Point mutation in the β-globin gene (chromosome 11) → glutamic acid replaced with valine (single amino acid substitution) → 2 α-globin and 2 mutated β-globin subunits create pathological hemoglobin S (HbS).
• Increased hemolysis: One of the chains (either α or β) is reduced → compensatory overproduction of other chains → excess globin chains precipitate and form inclusions within RBCs → erythrocyte instability with hemolysis
• Anemia → ↑ erythropoietin → bone marrow hyperplasia and skeletal deformities

Tip

Hemoglobin A2 is elevated in beta-thalassemia to compensate for beta-globin–chain underproduction, but results in microcytic red cells that are prone to hemolysis. Increased erythrocyte turnover results in a misleadingly low hemoglobin A1c level. In such cases, measurement of glycated serum proteins (ie, fructosamine) is sometimes used to estimate glycemic control. See Diabetes mellitus > Hyperglycemia tests

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Clinical features

• Alpha (α)-Thalassemia
  • 1 gene deletion (Silent Carrier): Asymptomatic, no treatment needed.
  • 2 gene deletions (α-Thalassemia Trait): Usually asymptomatic with mild microcytic anemia.
  • 3 gene deletions (HbH Disease): Excess β-chains form HbH (β₄) tetramers. This leads to moderate-to-severe chronic hemolytic anemia and splenomegaly.
  • 4 gene deletions (Hb Barts): Incompatible with life, resulting in hydrops fetalis. Excess γ-chains (from fetal Hb) form Hb Barts (γ₄).
    • Mechanism: Hb Barts has an extremely high affinity for oxygen. It binds O₂ in the placenta but fails to release it to fetal tissues.
    • Result: This leads to profound tissue hypoxia, causing a cascade of:
      1. High-Output Heart Failure: The heart overworks to compensate for the lack of oxygen delivery.
      2. Massive Edema (Anasarca): The combination of heart failure and liver dysfunction (from extramedullary hematopoiesis) causes fluid to leak out of the vessels.
• Beta (β)-Thalassemia
  • β-Thalassemia Minor (Trait): Heterozygous (one defective gene). Typically asymptomatic with mild microcytic anemia. A classic finding is a normal or increased RBC count despite low Hb and MCV.
  • β-Thalassemia Major (Cooley Anemia): Homozygous (two defective genes). Severe anemia becomes symptomatic around 6 months of age as fetal hemoglobin (HbF) levels decline.
    • Clinical Features: Massive hepatosplenomegaly from extramedullary hematopoiesis, “crewcut” appearance on skull x-ray, and “chipmunk” facies due to bone marrow expansion.
    • Requires lifelong blood transfusions.

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Diagnostics

• Initial / Screening:
  • CBC with Differential:
    • Marked microcytosis (MCV < 75 fL) disproportionate to the degree of anemia.
    • RBC count is normal or mildly elevated.
    • Mentzer Index: $\text{MCV}/\text{RBC count}<13$ strongly suggests Thalassemia trait (vs $>13$ in IDA).
    • RDW is characteristically NORMAL in uncomplicated thalassemia trait.
  • Peripheral Blood Smear:
    • Target cells (codocytes), microcytosis, hypochromia, anisopoikilocytosis, basophilic stippling, nucleated RBCs (in severe forms).
• Hb-electrophoresis

Tip

α-thalassemia minima vs β-thalassemia minor:

• Both asymptomatic
• α-thalassemia minima is normal on electrophoresis, while β-thalassemia shows narrowed HbA band and widened HbA2 band

• Peripheral blood smear findings include:
  • Target cells
    • ↑ surface area-to-volume ratio
  • Teardrop cells
• Skull x-ray: Hair-on-end (also known as “crew cut”) sign, caused by excessive expansion of the bone marrow to compensate for the destruction of red blood cells

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Treatment

• Thalassemia Minor / Trait ($\alpha$ or $\beta$):
  1. Reassurance: No active treatment required.
  2. Avoid empiric iron therapy: Prevents secondary iron overload.
  3. Genetic Counseling: Offer prenatal carrier screening to partner.
• Hb H Disease / $\beta$-Thalassemia Intermedia:
  1. Folic acid supplementation (due to chronic high RBC turnover).
  2. Transfusions: Avoid routine transfusions; administer during hemolytic/aplastic crises, infection, or pregnancy.
  3. Avoid oxidant drugs (in Hb H disease).
• $\beta$-Thalassemia Major:
  1. First-line Maintenance:
     • Chronic hypertransfusion protocol: Regular PRBC transfusions (every 2–4 weeks) titrated to maintain pre-transfusion Hb > 9.5–10.0 g/dL (suppresses endogenous ineffective erythropoiesis and skeletal deformities).
     • Daily oral folic acid supplementation.
  2. Iron Chelation Therapy (Mandatory with chronic transfusions): c
     • Initiate when serum ferritin > 1,000 ng/mL or after ~10–20 transfusions.
     • Deferasirox (oral, 1st-line) or Deferoxamine (IV/SC) or Deferiprone (oral).
  3. Second-line / Adjunctive:
     • Splenectomy: Indicated if hypersplenism increases transfusion requirements by > 50%. Requires pre-splenectomy immunization (S. pneumoniae, N. meningitidis, H. influenzae) and prophylactic penicillin post-op.
     • Luspatercept: Erythroid maturation agent that reduces transfusion burden.
  4. Definitive / Curative:
     • Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): Best outcomes when performed in early childhood before transfusional organ toxicity occurs.