Red cell volume-related ion transport systems in hemoglobinopathies.

This review has examined the expression of ion transporters involved in cell volume regulation in erythrocytes of patients homozygous for hemoglobin S (Hb S) with SS cells, of patients homozygous for Hb C (CC cells), or from patients with SC disease whose red cells contain both Hb S and Hb C (SC cells). Transport proteins that control intracellular cation content and, hence, red cell volume, may have pathophysiologic implications for these hemoglobinopathies. Ion transporters involved in volume regulation are highly expressed in the young circulating cells of these hemoglobinopathies, which display large interindividual differences. In SS disease, there are a large number of circulating young cells that exhibit a very high activity of ion transporters involved in cell volume reduction such as K:Cl cotransport. The activation of this transport system leads to significant reduction in cell volume when cells encounter an acid or deoxygenated environment. This process is particularly harmful because it favors Hb S polymerization and cell sickling. Another transport process that can contribute to the deoxy-stimulated K+ efflux exhibited by SS red cells is the opening of Ca(++)-activated K+ channels. The use of charybdotoxin (a very specific inhibitor of these channels) can yield information about the number of channels and the contribution of this pathway to the generation of dense and irreversibly sickled cells. Lastly, studies of ion transporters leading to cell volume increases indicate that Na+/H+ exchange activity (which is very high in young AA, SS, and SC red cells and persists after reticulocyte maturation) may counteract the volume reduction effects of K:Cl cotransport. The physiologic role of this antiporter in human red cells has not yet been studied.