Deconstructing sickle cell disease: Reappraisal of the role of hemolysis in the development of clinical subphenotypes

Hemotysis, long discounted as a critical measure of sickle cell disease severity when compared with sickle vaso-occlusion, may be the proximate cause of some disease complications. New mechanistic information about hemotysis and its effects on nitric oxide (NO) biology and further examination of the subpheno-types of disease requires a reappraisal and deconstruction of the clinical features of sickle cell disease. The biology underlying clinical phenotypes linked to hemotysis may increase our understanding of the pathogenesis of other chronic hemolytic diseases while providing new insights into treating sickle cell disease. The pathophysiological roles of dysregulated NO homeostasis and sickle reticulocyte adherence have linked hemolysis and hemolytic rate to sickle vasculopathy. Nitric oxide binds soluble guanylate cyclase which converts GTP to cGMP, relaxing vascular smooth muscle and causing vasoditatation. When plasma hemoglobin liberated from intravascutarly hemolyzed sickle erythrocytes consumes NO, the normal balance of vasoconstriction:vasodflation is skewed toward vasoconstriction. Pulmonary hypertension, priapism, leg ulceration and stroke, all subphenotypes of sickle cell disease, can be Linked to the intensity of hemotysis. Hemotysis plays less of a role in the vaso-occlusive-viscosity complications of disease like the acute painful episode, osteonecrosis of bone and the acute chest syndrome. Agents that decrease hemolysis or restore NO bioavailability or responsiveness may have potential to reduce the incidence and severity of the hemotytic subphenotypes of sickle cell disease. Some of these drugs are now being studied in clinical trials. (c) 2006 Elsevier Ltd. All rights reserved.