Clinical meaning
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 with elevated reticulocyte count (appropriate marrow response), elevated MCHC (mean corpuscular hemoglobin concentration — the RBC is smaller but contains the same hemoglobin), spherocytes on peripheral smear, positive osmotic fragility test (spherocytes lyse at higher saline concentrations than normal cells because they cannot swell), and elevated indirect bilirubin and LDH with decreased haptoglobin (hemolysis markers). Eosin-5-maleimide (EMA) binding test has replaced osmotic fragility as the preferred diagnostic test — decreased fluorescence indicates reduced membrane band 3 protein. Complications include pigmented (bilirubin) gallstones (chronic hemolysis increases bilirubin production), aplastic crisis (parvovirus B19 infection halts erythropoiesis in the already stressed marrow), and folate deficiency (chronic increased erythropoiesis depletes folate stores). Splenectomy is curative for moderate-severe HS (eliminates the site of red cell destruction), but increases lifelong risk of encapsulated organism infections (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis) — patients must be vaccinated before splenectomy and may require prophylactic penicillin.