In hereditary spherocytosis caused by spectrin deficiency, why is the osmotic fragility increased?

• A Spectrin deficiency allows complement binding, making cells fragile to osmotic stress
• B Reduced spectrin increases membrane cholesterol, stiffening the bilayer
• C Spectrin-deficient cells have reduced surface area-to-volume ratio and lyse in mildly hypotonic saline ✓
• D Spectrin loss activates caspase-3, pre-sensitising cells to apoptotic swelling

Explanation

Spectrin (and associated proteins ankyrin, Band 4.2, Band 3) normally tethers the lipid bilayer to the underlying cytoskeleton. Spectrin deficiency causes membrane lipid loss (vesiculation), decreasing the surface area while volume remains fixed, converting biconcave discs into spherocytes. Spherocytes have a reduced surface-to-volume ratio with no reserve deformability; therefore they lyse at mildly hypotonic saline concentrations that normal biconcave cells can withstand. The mechanism is purely mechanical, not complement-mediated.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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