Sickle cell disease is a hemoglobinopathy which affects approximately 100,000 individuals in the United States and almost 20,000–25,000 subjects in Europe, mainly immigrants from endemic areas such as Sub-Saharan Africa to European countries. Estimates of the number of affected newborn in 2010 are of approximately 312,302 subjects with 75.5% being born in Africa. The invalidating impact of SCD on patient survival, quality of life and cost for health systems, requires the development of new therapeutic options to treat sickle cell related acute and chronic complications.
SCD is caused by a point mutation in the β-globin gene resulting in the synthesis of pathological hemoglobin S. HbS displays peculiar biochemical characteristics, polymerizing when deoxygenated with associated reduction in cell ion and water content, increased red cell density and further acceleration of HbS polymerization. Pathophysiological studies have shown that dense, dehydrated red cells play a central role in acute and chronic clinical manifestations of SCD, in which intravascular sickling in capillaries and small vessels leads to vaso-occlusion and impaired blood flow with ischemic/reperfusion injury. In microcirculation, vaso-occlusive events result from a complex and still partially known scenario, involving the interactions between different cell types, including dense red cells, reticulocytes, abnormally activated endothelial cells, leukocytes, platelets and plasma factors. Acute VOCs have been associated with increased expression of pro-adhesion molecules such as vascular adhesion molecule-1, intracellular adhesion molecule-1 or selectins. These molecules are important in recruitment and adhesion of both neutrophils and sickle red cells to the abnormally activated vascular endothelial surface. In addition, the presence of free Hb and free heme contribute to the local reduction of nitric oxide bioavailability, establishing an endovascular high pro-oxidant and pro-inflammatory environment. This is associated with modulation of innate immunity and increased iNKT lymphocytes, increase levels of vascular active cytokines such as endothelin 1, combined with the final contribution of platelets.
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