Pathophysiology
Clinical meaning
Sickle cell disease (SCD) is an autosomal recessive hemoglobinopathy caused by a point mutation in the beta-globin gene (chromosome 11), substituting valine for glutamic acid at position 6 (HbS: beta-6 Glu->Val). Under deoxygenated conditions, HbS molecules polymerize into rigid, insoluble fibers that deform the erythrocyte into a sickled (crescent) shape. The rate of HbS polymerization depends on intracellular HbS concentration, degree of deoxygenation, pH, and 2,3-DPG levels. Sickled cells are rigid and adhesive, causing vaso-occlusion in the microvasculature through four mechanisms: (1) sickled RBC adhesion to vascular endothelium via VCAM-1, thrombospondin, and von Willebrand factor, (2) neutrophil-RBC interactions amplifying adhesion, (3) activation of the coagulation cascade with thrombin generation, and (4) endothelial dysfunction from chronic hemolysis releasing free hemoglobin that scavenges nitric oxide, producing a vasculopathy with pulmonary hypertension, stroke, and priapism. Chronic hemolysis (RBC lifespan 10-20 days vs normal 120 days) causes anemia (Hb 6-9 g/dL baseline), jaundice, pigment gallstones, and iron overload from transfusion therapy. Splenic autoinfarction by age 5 in HbSS produces functional asplenia with lifelong susceptibility to encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis).