There is a distinct difference in the clinical expression of an individual who is heterozygous for the bS mutation versus one who is homozygous for the mutation. Sherman described this important distinction in 1940. In the classic case of SCA, and the more general case of SCD, the RBC becomes dense, dehydrated, rigid and deformed (sickled), as a result of intracellular Hb S polymerization. Individuals with SCD suffer from sickling-induced chronic hemolytic anemia and acute painful 'crisis' events (vaso-occlusion and/or sequestration) [27-29], which can lead to end-organ damage. In stark contrast, the sickle trait phenotype exhibited by a heterozygote HbAS carrier is associated with negligible morbidity, with the exception of some exercise limitations under extreme hypoxic conditions.
As evidence, and disease severity generally correlates with the level of mutant Hb S protein in RBCs. The adult carrier state is asymptomatic since only ~40% Hb S is produced in HbAS RBCs as compared to ~50 % Hb S in compound heterozygote Hb SC RBCs and ~90-95% Hb S in Hb SS RBCs from homozygotes[33,34]. The Hb SC individuals are typically symptomatic but display a milder clinical course than Hb SS individuals. However, the disease’s severity can be ameliorated by a reduction in total intracellular Hb S, as is observed in the concurrent Hb SS/a-thalassemic and compound Hb S/b-thalassemic states[35-37].