Prevention of the complications of sickle cell disease in HbSC patients

Sickle cell disease (SCD) is a very common inherited condition with debilitating consequences. It results from the inheritance of an abnormal haemoglobin, the oxygen-carrying pigment of red blood cells. SCD patients have HbS, rather than the normal HbA, in their red cells. Patients may have only HbS (HbSS genotype) but other combinations are possible. The second most common is co-inheritance of HbS with a second abnormal Hb, HbC (HbSC genotype). In this case, patients? red cells contain equal amounts of HbS and HbC. HbSC disease represents about 1/3rd of the cases of SCD, with about 80,000 born annually worldwide. In all cases of SCD, red cell HbS aggregates into rigid rods when oxygen levels in the circulation are low, distorting red cell shape, making them sticky and fragile, thus reducing red cell longevity. It also encourages blockage of small blood vessels leading to organ damage and ultimately untimely death. A range of complications are seen: chronic anaemia plus symptoms of vascular occlusion (including stroke, damage to bone, retina, kidneys and lungs). This is true for HbSC individuals as well as HbSS ones. However, the disease in HbSC patients is significantly different with a different range of complications and different blood cell picture. This means that they should be considered as a discrete subset of SCD patients. Notwithstanding there is very little research pertaining specifically to HbSC patients. In fact, in most studies analysing the abnormal behaviour of red cells containing HbS and also clinical trials of potential new treatments, HbSC patients are specifically excluded. It is likely that the course of HbSC disease differs and that this results from a different abnormalities in the behaviour of their red cells. Central to this difference is the fact that the red cells contain both HbS and HbC. This work will study specifically HbSC patients. The behaviour of their red cells (containing both HbS and HbC) will be correlated with disease severity. Specific ways of stopping HbS polymerisation in HbSC red cells will be sought. Results will enable better management of HbSC patients and amelioration of the complications of SCD in this significant group of patients.

Sickle cell disease (SCD) is one of the most common severe inherited disorders but specific treatments are lacking and the pathophysiology remains unclear. Approximately 250,000 SCD babies are born annually. Incidence in the UK amounts to around 12-15,000 individuals. Affected individuals have a mutated a globin gene resulting in the presence of an abnormal haemoglobin Hb, HbS, in their red blood cells. Whilst about two-thirds of SCD patients are homozygous HbSS individuals, patients heterozygous for HbS and a second Hb mutation HbC (ie HbSC heterozygotes) constitute about one-third of SCD cases, making HbSC disease the second most common form of SCD in UK and worldwide. In HbSC patients, red cells contain equal amounts of HbS and HbC. The complications of SCD are extensive, many resulting from the tendency of HbS to polymerise into long rigid rods on deoxygenation. Importantly, red cells from all SCD patients have an abnormal permeability, lose solutes and shrink, raising their total [Hb]. This markedly encourages HbS polymerisation. Patients? red cells have a reduced lifespan and are less able to traverse small blood vessels, causing chronic anaemia, microvascular occlusion and ischaemia affecting many organs. Although many symptoms are common to both, the condition is not identical in SCD patients of HbSS and HbSC genotypes. Disease complications and haematological findings differ. As such, HbSC disease should be treated as a discrete subset of SCD patients. Currently there is very little specific information on the pathophysiology and management of HbSC disease, with most knowledge being inferred from studies of HbSS. Differences in pathogenesis between HbSC and HbSS disease are expected. Understanding them will be important directly to the management of HbSC patients, and may also contribute to a better appreciation of HbSS disease. We hypothesise that the transport properties of red cells from HbSC patients differ significantly from those of HbSS individuals, accounting for the different symptoms observed of this group of patients, and enabling the design of unique therapeutic regimes to ameliorate HbSC disease. Preventing solute loss and deoxygenation-induced HbS polymerisation is more feasible in red cells from HbSC patients because their reduced content of HbS means that only a modest increase in cell hydration is required. We aim to understand solute loss in HbSC red cells in order to reduce ion permeability and thus achieve this greater degree of hydration.