Cation Homeostasis in Red Cells From Patients With Sickle Cell Disease Heterologous for HbS and HbC (HbSC Genotype)

• Red cells from HbSC sickle cell patients showed significant differences in K+ permeability cf. those from HbSS patients.
• Conductive potassium pathways, Psickle and the Gardos channel were less active in red cells from HbSC patients.
• KCl cotransport (KCC) had higher activity in HbSC red cells, altered regulation, and correlates with disease severity.
• The genetic, molecular and pharmacological regulation of KCC in HbSC patients is thus of particular clinical relevance.Sickle cell disease (SCD) is the commonest severe inherited disorder affecting millions of people. Two-thirds of patients are homozygous (HbSS genotype); one-third are heterologous for HbS and HbC (HbSC genotype). Effective treatment remains elusive. Patients' red cells contain the abnormal haemoglobin HbS. Deoxygenated HbS polymerises, initiating clinical sequelae. Sickle red cells lose solutes more rapidly than normal which greatly encourages HbS polymerisation. Red cell permeability is critical. HbSC red cells have significant permeability differences which correlate with disease severity. Understanding regulation of red cell permeability in these patients is thus of particular clinical relevance and may lead to novel treatments.

Sickle cell disease (SCD) in patients of HbSC genotype is considered similar, albeit milder, to that in homozygous HbSS individuals — but with little justification. In SCD, elevated red cell cation permeability is critical as increased solute loss causes dehydration and encourages sickling. Recently, we showed that the KCl cotransporter (KCC) activity in red cells from HbSC patients correlated significantly with disease severity, but that in HbSS patients did not. Two transporters involved in red cell dehydration, the conductive channels Psickle and the Gardos channel, behaved similarly in red cells from the two genotypes, but were significantly less active in HbSC patients. By contrast, KCC activity was quantitatively greater in HbSC red cells. Results suggest that KCC is likely to have greater involvement in red cell dehydration in HbSC patients, which could explain its association with disease severity in this genotype. This work supports the hypothesis that SCD in HbSC patients is a distinct disease entity to that in HbSS patients. Results suggest the possibility of designing specific treatments of particular benefit to HbSC patients and a rationale for the development of prognostic markers, to inform early treatment of children likely to develop more severe complications of the disease.