Oxidative damage to red blood cells (RBCs) may contribute to pathogenesis of sickle cell anemia. Reducing the deleterious effects of oxidants by exposing RBCs to a number of antioxidants has been shown to have protective effects against lipid and protein peroxidation. We hypothesize that antioxidants may also have beneficial effects on the abnormal membrane permeability of sickle cells. Increased cation permeability of these cells encourages HbS polymerization by causing RBC dehydration and also leads to externalization of the prothrombotic aminophospholipid phosphatidylserine (PS). Three antioxidants with different mechanisms of action were investigated – dithiothreitol, N -acetylcysteine, and quercetin. All three were found to inhibit the main cation pathways responsible for dehydration – the deoxygenation-induced cation conductance (or P sickle ), the Ca 2+ -activated K + channel (or Gardos channel), and the K + -Cl − cotransporter. They also reduced Ca 2+ -induced PS exposure and hemolysis. Findings provide evidence for additional beneficial actions of antioxidants in maintenance of rheology and reducing vascular adhesion and further inform the rationale for their clinical use.

The early stages of sickle cell nephropathy (SCN) manifest in children with sickle cell anemia (SCA) as hyperfiltration and proteinuria. The physiological conditions of the renovascular system are among the most conducive to hemoglobin S polymerization in the body and will magnify small changes in red cell volume thus crucially modulating intracellular concentrations of hemoglobin S. This large cross-sectional study of children with sickle cell anemia measured glomerular filtration rates and microalbuminuria to report prevalence, clinical correlates and uniquely, association with key red cell cation transport mechanisms. One hundred and twelve patients (mean age 10.7 ± 4.1) were recruited. The prevalence of hyperfiltration and microalbuminuria was 98% and 15.1%, respectively. Glomerular filtration rates did not vary with age, but proteinuria became more prevalent with increasing age. Both features associated with markers of hemolysis, while elevated hemoglobin F was protective, but no association was seen with systolic or diastolic blood pressure. In multivariate analysis, both Gardos channel (β = 0.476, P < 0.001) and KCl co-transporter (KCC; β = −0.216, P = 0.009) activity, alongside age (β = 0.237, P = 0.004), remained independently predictive for microalbuminuria. Increased activity of Gardos channel and Psickle positively associated with microalbuminuria, while increased KCC activity associated with a reduction in microalbuminuria. This study demonstrates a direct link between the abnormally active red cell cation transport systems in sickle cell disease and sickle organopathy. Small variations in the activity of these transport mechanisms predict for SCN and measurement of them may help identify those at risk, while pharmaceutical manipulation of these excessively active systems may ameliorate their risk.

This case represents a successful example of managing hemolytic disease of the fetus due to a rare antibody using maternal blood. It also supports previous data on safety of maternal donations during pregnancy and the use of combination of rHu-EPO and IV-Fe as a supportive measure.

Sickle cell anemia ( SCA ) is one of the commonest severe inherited disorders. Nevertheless, effective treatments remain inadequate and novel ones are avidly sought. A promising advance has been the design of novel compounds which react with hemoglobin S (HbS) to increase oxygen (O 2 ) affinity and reduce sickling. One of these, voxelotor ( GBT 440), is currently in advanced clinical trials. A structural analogue, GBT 1118, was investigated in the current work. As RBC dehydration is important in pathogenesis of SCA , the effect of GBT 1118 on RBC cation permeability was also studied. Activities of P sickle , the Gardos channel and the KC l cotransporter ( KCC ) were all reduced. Gardos channel and KCC activities were also inhibited in RBC s treated with Ca 2+ ionophore or the thiol reagent N ‐ethylmaleimide, indicative of direct effects on these two transport systems. Consistent with its action on RBC membrane transporters, GBT 1118 significantly increased RBC hydration. RBC hemolysis was reduced in a nonelectrolyte lysis assay. Further to its direct effects on O 2 affinity, GBT 1118 was therefore found to reduce RBC shrinkage and fragility. Findings reveal important effects of GBT 1118 on protecting sickle cells and suggest that this is approach may represent a useful therapy for amelioration of the clinical complications of SCA .