Hereditary spherocytosis (HS) is the most common inherited hemolytic anemia in people of Northern European descent (prevalence ~1:2,000), caused by mutations in genes encoding red blood cell membrane skeleton proteins: ankyrin (most common, ~40%), band 3 protein (~25%), alpha-spectrin, beta-spectrin, or protein 4.2. These proteins form a lattice beneath the lipid bilayer that provides structural support, maintaining the red blood cell's characteristic biconcave disc shape and deformability. When these skeletal proteins are deficient or dysfunctional, the lipid bilayer loses its attachment to the underlying skeleton and undergoes progressive vesiculation (budding off of lipid microvesicles), reducing the membrane surface area while maintaining cell volume. This transforms the normal biconcave disc (high surface-area-to-volume ratio enabling deformability through capillaries) into a sphere (low surface-area-to-volume ratio with reduced deformability). Spherocytes are rigid cells that become trapped in the splenic red pulp, where they must squeeze through narrow (1-3 μm) inter-endothelial slits between the splenic cords and sinusoids. Unable to deform sufficiently, spherocytes are retained, further conditioned (additional membrane loss), and ultimately phagocytosed by splenic macrophages — this is extravascular hemolysis. Laboratory findings include anemia...