Pathophysiology of hereditary spherocytosis. The primary defect in hereditary spherocytosis is a deficiency of membrane surface area. Decreased surface area may produced by two different mechanisms: 1) Defects of spectrin, ankyrin, or protein 4.2 lead to reduced density of the membrane skeleton, destabilizing the overlying lipid bilayer and releasing band 3-containing microvesicles. 2) Defects of band 3 lead to band 3 deficiency and loss of its lipid-stabilizing effect. This results in the loss of band 3-free microvesicles. Both pathways result in membrane loss, decreased surface area, and formation of spherocytes with decreased deformability. These deformed erythrocytes become trapped in the hostile environment of the spleen where splenic conditioning inflicts further membrane damage, amplifying the cycle of membrane injury.

Reprinted with permission from Gallagher PG, Jarolim P: Red cell membrane disorders. In Hematology: Basic Principles and Practice. Hoffman R, Benz EJ Jr, Shattil SJ, et al (eds). 4th ed, WB Saunders, Philadelphia, 2005.