Pathophysiology
Clinical meaning
Sickle cell disease (SCD) results from a single nucleotide mutation in the beta-globin gene (GAG→GTG at codon 6), producing valine instead of glutamic acid at position 6 of the beta-globin chain. This creates hemoglobin S (HbS), which polymerizes when deoxygenated, distorting the RBC into a rigid sickle shape. The pathophysiology involves three interconnected mechanisms: (1) Vaso-occlusion: sickled RBCs are rigid and adhesive, adhering to vascular endothelium (via P-selectin, VCAM-1, and thrombospondin), neutrophils, and other blood cells, creating heterocellular aggregates that obstruct microvasculature → tissue ischemia and infarction (pain crisis, acute chest syndrome, stroke, avascular necrosis, splenic infarction); (2) Chronic hemolytic anemia: sickled RBCs have shortened lifespan (10-20 days vs normal 120 days); chronic hemolysis releases free hemoglobin that scavenges nitric oxide (NO), causing endothelial dysfunction, pulmonary hypertension, and vasculopathy; (3) Chronic inflammation: vaso-occlusion-reperfusion injury generates reactive oxygen species and activates endothelial cells, maintaining a chronic inflammatory state with elevated WBC, CRP, and activated neutrophils (which participate in vaso-occlusion). Hydroxyurea is the cornerstone disease-modifying therapy: it increases fetal hemoglobin (HbF) production by reactivating gamma-globin gene expression; HbF inhibits HbS polymerization (HbF...