THE UNUSUAL PATHOBIOLOGY OF HEMOGLOBIN CONSTANT SPRING RED-BLOOD-CELLS

Hemoglobin Constant Spring (HbCS) is the most common nondeletional alp ha-thalassemic mutation and is an important cause of HbH-like disease in Southeast Asia. HbCS variants have an almost normal mean cell volum e (MCV) and the anemia is more severe when compared with other alpha-t halassemic variants. We explored the pathobiology of HbCS red blood ce lls (RBCs) because the underlying cause(s) of this MCV ''normalizing'' effect of HbCS and the more severe anemia are not fully explained. Hb CS containing RBCs are distinctly overhydrated relative to deletional alpha-thalassemia variants, and the derangement of volume regulation a nd cell hydration occurs early in erythroid maturation and is fully ex pressed at the reticulocyte stage. Furthermore, the membrane rigidity and membrane mechanical stability of HbCS containing RBCs is increased when compared with HbH and alpha-thalassemia-1 trait RBCs. In seeking the cause(s) underlying these cellular alterations we analyzed membra nes from HbCS and deletional alpha-thalassemic variants and found that in addition to oxidized beta-globin chains, oxidized alpha(cs)-globin chains are also associated with the membranes and their skeletons in HbCS containing RBCs. We propose that the membrane pathology of HbCS v ariants is caused by combination of the deleterious effects induced by membrane-bound oxidized alpha(cs)- and beta-globin chains. The membra ne alterations induced by alpha(cs) chains are more akin to those indu ced by beta(A)-globin chains than those induced by the alpha(A)-globin chains that accumulate in the beta-thalassemias. Thus, each globin ch ain, alpha(cs), alpha(A), beta(A), appears to produce its own form of membrane perturbation. (C) 1997 by The American Society of Hematology.