Pathophysiology Sickle Cell Anemia; Genetic Mutation, Hemoglobin Polymerization

The pathophysiology of sickle cell anemia is driven by a mutation in the β‑globin gene that produces hemoglobin S (HbS). Under low oxygen, HbS polymerizes, causing red blood cells to become rigid and sickle‑shaped. This leads to chronic hemolysis, vaso‑occlusion, ischemia, and multi‑organ damage. 🧬 Pathophysiology of Sickle Cell Anemia 1. Genetic Basis Caused by a point mutation in the HBB gene on chromosome 11. Substitution of valine for glutamic acid at position 6 of the β‑globin chain. Produces hemoglobin S (HbS). 2. Molecular Mechanism In low oxygen tension, HbS molecules polymerize into long fibers. This distorts red blood cells into the classic sickle shape. Sickled cells are rigid, fragile, and prone to hemolysis. 3. Cellular Consequences Hemolysis: Sickled RBCs have a lifespan of ~10–20 days (normal ~120 days). Leads to chronic anemia and hyperbilirubinemia (jaundice, gallstones). Vaso‑occlusion: Sickled cells block small vessels. Causes ischemia, infarction, and pain crises. Endothelial damage: Hemolysis releases free hemoglobin, which scavenges nitric oxide → vasoconstriction and pulmonary hypertension. 4. Systemic Effects Bone marrow hyperplasia: Compensates for anemia, leading to bone deformities. Splenic infarction: Causes autosplenectomy → increased infection risk. Organ damage: Kidneys (papillary necrosis, CKD), CNS (stroke), lungs (acute chest syndrome), heart (cardiomegaly, failure). Inflammation: Chronic hemolysis and ischemia trigger systemic inflammation, worsening complications #Sickle