In sickle cell disease (HbSS), polymerisation of deoxy-HbS is driven by the beta-Glu6Val substitution. The critical factor that determines clinical severity during a vaso-occlusive crisis is:

• A Extracellular HbS concentration in plasma
• B Heme iron oxidation state (Fe3+/Fe2+ ratio)
• C Rate of intracellular HbS polymerisation (delay time), which is an inverse 30th-power function of HbS concentration ✓
• D Absolute plasma bilirubin level indicating haemolysis rate

Explanation

HbS polymerisation follows a nucleation-propagation kinetic model with a characteristic 'delay time' before polymer formation. Critically, this delay time is an extremely steep inverse function of HbS concentration — approximately inversely proportional to [HbS]^30 or higher. This means even small reductions in intracellular HbS concentration (e.g., from fetal hemoglobin HbF co-expression, or hydroxyurea increasing HbF) dramatically extend the delay time, preventing polymer formation before the RBC traverses the microcirculation. This is the scientific basis for hydroxyurea therapy.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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