Genetic anemias: abnormal hemoglobins (HbS); anemias in erythrocyte membrane defects (hereditary spherocytosis); anemias in enzyme defects (pyruvate kinase deficiency, G6PD deficiency). I. Abnormal Hemoglobins – Sickle Cell Disease (HbS)
Sickle cell disease is the prototype of abnormal hemoglobin disorders. It is caused by a missense mutation in the β-globin gene where glutamic acid is replaced by valine at position 6. This single amino acid substitution produces HbS.
In normal oxygenated conditions, HbS behaves like HbA. However, when oxygen tension falls, HbS molecules tend to polymerize into long rigid fibers, distorting the RBC into a sickle shape. Sickling is initially reversible, but repeated cycles cause permanent membrane damage.
Pathogenesis
- Polymerization of HbS → sickle-shaped RBCs.
- Sickled cells are fragile → undergo hemolysis (shortened lifespan).
- They also obstruct small vessels → vaso-occlusion and ischemic damage.
Clinical features
- Chronic hemolytic anemia: jaundice, gallstones.
- Vaso-occlusive crises: sudden painful episodes affecting bones, chest (acute chest syndrome), brain (stroke).
- Splenic infarction → functional asplenia → ↑ infections with encapsulated bacteria.
- Chronic complications: leg ulcers, avascular necrosis of femoral head, renal papillary necrosis.
Inheritance
- Autosomal recessive.
- Homozygotes (HbSS) → disease.
- Heterozygotes (HbAS, sickle trait) → usually asymptomatic, but protected against malaria.
Diagnosis
- Blood smear: sickled cells, target cells.
- Hb electrophoresis: HbS predominates.
Management
- Hydroxyurea ↑ HbF (which inhibits sickling).
- Supportive: transfusions, folate, infection prevention.
- Curative: bone marrow transplantation.