Current therapy of sickle cell disease.

H omozygous sickle cell disease (SCD) is an auto-somal recessive genetic disease that results from the substitution of valine for glutamic acid at position 6 of the β-globin gene, leading to production of a defective form of hemoglobin, hemoglo-bin S (HbS). The prevalence of SCD is about 1-2% among African descendants in Europe and the United States and 4% or higher in West Africa. SCD shows broad phenotypic expression that varies greatly between regions, among patients and longitudinally in the same patient. 1,2 The protean clinical features of SCD result from chronic variable intravascular hemol-ysis, microvascular ischemia and organ damage. Vaso-occlusion is the outcome of a dynamic combination of abnormalities in hemoglobin structure and function, red blood cell membrane integrity, erythrocyte density , endothelial activation, microvascular tone, inflam-matory mediators, and coagulation. These pathophys-iologic events translate into clinical manifestations that fall into four general categories: anemia and its sequelae; vaso-occlusive crises and bone marrow fat embolization syndrome; infection (from functional asplenia) and organ dysfunction. Organ damage results from a combination of hemolysis and infarc-tion and may be manifested as stroke, retinopathy, nephropathy, liver disease or pulmonary arterial hypertension. Intravascular hemolysis in SCD causes the release of hemoglobin into the plasma. When the capacity of protective hemoglobin-scavenging mechanisms (haptoglobin and hemopexin) has been saturated , levels of cell-free hemoglobin increase in the plasma resulting in the consumption of nitric oxide (NO) by hemoglobin-mediated NO scavenging. 3 In addition , arginase released by hemolyzed red cells can deplete blood plasma of arginine, the substrate for NO production by NO synthase. 4 NO plays a major role in vascular homeostasis and is a critical regulator of smooth muscle relaxation and vasomotor tone, expression of endothelial adhesion molecules and platelet activation and aggregation. 5 A deficiency in NO, due to its inactivation by cell-free plasma hemo-globin levels during intravascular hemolysis in SCD, may underlie complications associated with SCD. 6 In this editorial, we briefly review the currently available treatments for SCD. For more detail on specific topics, the reader is directed to more extensive recent review articles as cited in the references. Three prophylactic measures have become widely accepted in the management of SCD; penicillin pro-phylaxis, immunization against pneumococcal infection and folate administration. The mortality rate due to Streptococcus pneumoniae pneumonia, sepsis, and meningitis was historically very high prior to the age of 6 years in children with SCD. This rate has been lowered tremendously …