Sickle cell disease endothelial activation and dysfunction

Sickle cell anemia is characterized by hemolytic anemia, acute painful episodes that are believed to be caused by vaso-occlusion, and various organ-specific complications (1). Although the fundamental molecular basis for this disease is the inherited presence of the mutant sickle hemoglobin, the pathogenesis of clinical sickle disease is exceedingly complex. The studies described here, both bedside-to-bench and bench-to-bedside, have suggested that the endothelium contributes substantially to the vascular pathobiology of sickle disease and helps govern clinical phenotype (2). Indeed, we regard sickle cell anemia as an “endothelial disease” in which the endothelium is abnormally activated and dysfunctional. It is likely that the vascular pathobiology of this disease is affected by the endothelial cell (EC)'s functions as a space-defining physical barrier, an adhesive surface, a regulator of vascular tone, a balancer of the anticoagulant and procoagulant properties of blood and vessel wall, a participant in the inflammatory response, and a responsive surface that is dynamically alterable. THE BEGINNING: FROM BEDSIDE TO BENCH After the first medical literature report of a patient with sickle disease in 1910 (3), early studies identified the relationship between deoxygenation and cytoplasmic changes and red cell sickling (4), and ultimately the molecular character of the disease as being caused by an abnormal hemoglobin molecule (5). Thereafter, the traditional view of sickle disease explained pathophysiology simply via the sickling phenomenon, a view we now recognize as being highly oversimplified (6). The bedside observation of marked heterogeneity in clinical phenotype, both from person-to-person and from time-to-time for any given patient, stimulated our original interest in the endothelial biology of this disease.