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Sickle cell anemia

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Aetiopathogenesis of Sickle Cell Anemia

1. Genetic Basis (Aetiology)
  • Autosomal recessive disorder caused by a point mutation in the β-globin gene on chromosome 11.
  • Glutamic acid (normally at position 6 of the β-chain) is replaced by valine, producing abnormal Hemoglobin S (HbS).
  • Disease occurs in homozygotes (HbSS); heterozygotes (HbAS = sickle cell trait) are largely asymptomatic.
  • The βS allele is common in malaria-endemic regions (West Africa) because heterozygotes have relative protection against malaria.
2. Molecular Mechanism of Sickling
  • Under low oxygen tension, deoxygenated HbS is only one-fifth as soluble as normal HbA.
  • Deoxygenated HbS molecules polymerize into rod-shaped fibers, distorting RBCs into a characteristic sickle (crescent) shape.
  • Sickling is reversible initially with reoxygenation, but repeated episodes cause irreversible membrane damage.
3. Consequences of Sickling
  • Vaso-occlusion: Rigid sickle cells cannot pass through narrow capillaries, causing microvascular obstruction → tissue ischemia and infarction.
  • Hemolysis: Membrane disruption of sickle cells → chronic hemolytic anemia (shortened RBC survival from 120 days to ~20 days).
  • Nitric oxide depletion: Free hemoglobin released during hemolysis scavenges nitric oxide → impaired vasodilation → worsening ischemia.
  • High HbF levels (fetal hemoglobin, α₂γ₂) inhibit HbS polymerization and reduce clinical severity - the basis for hydroxyurea therapy.
Thompson & Thompson Genetics and Genomics in Medicine, 9th ed., p. 256 | Goldman-Cecil Medicine, Sickle Cell section

Only etiology

Etiology of Sickle Cell Anemia

  1. Genetic mutation: Autosomal recessive disorder caused by a single point mutation in the β-globin gene on chromosome 11 - glutamic acid is replaced by valine at position 6 of the β-globin chain.
  2. Abnormal hemoglobin: This mutation produces Hemoglobin S (HbS) instead of normal HbA.
  3. Inheritance pattern:
    • Homozygous (HbSS) → Sickle cell disease (full manifestation)
    • Heterozygous (HbAS) → Sickle cell trait (carrier, largely asymptomatic)
  4. Geographic/evolutionary factor: The βS allele has attained high frequency in malaria-endemic regions (West Africa, Mediterranean, Middle East, India) because heterozygotes have a survival advantage - relative protection against Plasmodium falciparum malaria.
  5. Compound heterozygous states can also cause disease:
    • HbS + HbC → Sickle cell-HbC disease
    • HbS + β-thalassemia → Sickle cell-β-thalassemia
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