Molecular basis of sickle cell-endothelial cell interactions

Adherence of sickle erythrocytes to microvascular endothelium is posited to initiate or contribute to sickle cell vaso-occlusive pain episodes. Adherence and occlusion in vivo may depend on hemodynamics interacting with plasma, erythrocyte, and endothelial cell factors. Four receptor-mediated adherence pathways have been described to date: adherence mediated by high molecular weight von Willebrand factor multimers bridging glycoprotein lb-like and integrin receptors on sickle cells and similar receptors on endothelial cells; thrombospondin bridging CD36 on sickle reticulocytes and the alpha v beta 3 integrin on large-vessel endothelial cells or alpha v beta 3 and CD36 on microvascular endothelium; binding of sickle reticulocyte alpha 4 beta 1 receptors to vascular cell adhesion molecule 1 expressed on endothelial cells stimulated by cytokine or double-stranded RNA viruses; and binding of sickle cells to endothelial cell-associated fibronectin via sickle reticulocyte alpha 4 beta 1 activated by phorbol ester or interleukin-8. The significance of these adherence pathways in sickle cell vaso-occlusion is discussed.