The pathophysiologic hallmark of sickle cell disease is episodic occurrence of vasoocclusive events that precipitate acute painful episodes and lead, ultimately, to organ failure and death. Based upon studies from multiple laboratories over the last two decades, it is widely believed now that a key participant in this process may be the sickle erythrocyte’s predilection for adhesiveness to endothelium. Initial studies of this abnormal cell–cell interaction were stimulated by skepticism regarding the extant dogma that ascribed sickle vasoocclusion solely to deoxygenation-induced polymerization of the mutant hemoglobin and resultant cell sickling. In fact, emerging data were revealing that the time required for the development of cell sickling is, for most red cells, actually longer than the microvascular transit time. Thus, anything serving to delay microvascular passage of red cells might allow sickling to occur, and thereby would be a critical participant in evolution of occlusive manifestations. Hence, consideration was given to the possibility that abnormal adhesion of sickle red cells to endothelium might be such a factor (1, 2). Ensuing studies have provided convincing support for this notion (3), with the caveat that definitive proof of the pathophysiologic importance of this cell–cell interaction in the human model, per se, has not yet been obtained (or sought).

The interaction of sickle red cells with endothelial cells has been studied in a great variety of experimental systems using various suspending media (serum, plasma, culture media, buffers) and a variety of adhesion assays (static, vessel perfusion, flow cell, in vivo). These studies, most using human umbilical vein endothelial cells as the target cell type, clearly establish that oxygenated sickle red cells are abnormally adherent to endothelium. Development of effective adhesive interaction requires some degree of intimate contact, so red cells that are stiffened or actually sickled before contact with endothelium are less able to become attached. Perplexingly, the magnitude of the observed difference in adhesivity between normal and sickle red cells has varied markedly from study to study, reflecting, in part, interpatient differences; in part, the specific mechanism of adhesion being studied; and in large part, the