First Things First

• Mutant, dysfunctional hemoglobinopathy in which valine substitutes for glutamic acid in the sixth position of the beta-globulin chain from earlier substitution of thymine for adenine in glutamic acid codon
• This abnormal hemoglobin (Hb-S) polymerizes when O2 tensions are low and becomes insoluble.
• In pts with full trait (Hb-SS) and subclinical traits (Hb-SC, D, SO-Arab, SA), an equilibrium exists between a physiologic dynamic fluid state and a pathologic static-gel state based on concentrations of abnormal Hb subtypes.
• Increases in concentration of Hb-S (≥21 g/dL) cause formation of tactoid polymers, which are insoluble and hyperviscous in circulatory system.
• This insolubility causes structural changes that distort and stiffen RBC membranes, causing them to aggregate and further amalgamate with fibrin, resulting in a gelatinous agglomeration.
• The biological alloy also renders the RBC susceptible to adhesiveness, hemolysis, dehydration, and cellular electrolyte changes over time (influx of Na+, efflux of K+, Cl-).
• Subclinical sickling and unsickling can also cause irreversible membrane changes that are not amenable to high O2 tensions.
• These irreversibly deformed cells increase viscosity and change rheology; this blocks small vessels (especially capillaries and venules), leading to further crisis.
• Immature reticulocytes from earlier hemolysis are especially vulnerable to these changes, and this can catalyze a further crisis.
• Recurrence of any syndrome below, especially if multiple and frequent, portends a poor prognosis and shortens life span.