Biochemically, SCD occurs due to a non- conservative substitution of a polar glutamate (Glu) by non-polar valine (Val) in an invariant region, the sixth position of Hb-β chain-subunit (GAG/GTG; Glu (E) Val (V); rs334). Replacement of this single non-polar amino acid ‘valine’ results in a biochemical difference that leads to formation of a sticky patch on the surface of the β-chains. The sticky patch is observed on both the oxygenated (“R” Form) and deoxygenated (“T” Form) of HbS. This distort folding and binding pattern of the Hb molecule, due to altered properties. Other known mechanism of polymerization of Hb in SCD involves nucleation, which is due to the aggregation of HbS molecules. At low oxygen level (hypoxia), deoxyhemoglobin S polymerizes inside the red blood cells (RBC). This forms a network of polymers that stiffen and distort cells with rigid, misshape erythrocytes.
Due to oxygen deprivation in the RBC, a critical aggregate of Hb polymer is formed that damages the cellular membrane, promoting aggregation of cellular proteins, stopping the flow of blood in the narrow capillaries and leading to localized oxygen deprivation (anoxia). This polymerization is enhanced by the heterogeneous nature of the nucleus, where new polymers are continually formed on preexisting polymer to form a fourteen inter-wined helical strands of HbS.