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Sickle cell disease is characterized by the presence of sickle hemoglobin (HbS), chronic hemolysis, recurrent pain episodes (called sickle cell–related pain crises or vaso-occlusive crises), multiorgan dysfunction, and early death. Sickle cell–related pain crises are the primary cause of health care encounters in patients with sickle cell disease.1 These crises result in a decrease in quality of life2 and an increase in the risk of death.3 Crises are thought to be caused by vascular occlusion in the microcirculation, increased inflammation, and alterations in nociception.4 The prevention of crises could minimize or prevent tissue and organ damage and decrease the subsequent risk of death among patients with sickle cell disease.
Although polymerization of deoxygenated HbS is the primary event in the pathophysiology of sickle cell disease,5 the pathogenesis of vaso-occlusion is complex. Vaso-occlusion is caused by the adhesion of sickle erythrocytes and leukocytes to the endothelium, which results in vascular obstruction and tissue ischemia.6 The degree of sickle erythrocyte adhesion correlates with vaso-occlusion and increased severity of disease.7 Activated and adherent leukocytes are the likely drivers of vaso-occlusion in collecting venules, whereas sickle erythrocytes may contribute to the occlusion of smaller vessels.8 In addition, platelets can bind to erythrocytes, monocytes, and neutrophils to form aggregates,9,10 which contribute to abnormalities of blood flow in patients with sickle cell disease.11
Although the adhesion of leukocytes to the endothelium during inflammation can involve multiple molecules, the process is initiated by P-selectin.12 P-selectin is found in storage granules of resting endothelial cells and platelets and is rapidly transferred to the cell membrane on activation of the cell during processes such as inflammation. P-selectin that is expressed on the surface of the endothelium mediates abnormal rolling and static adhesion of sickle erythrocytes to the vessel surface in vitro.13,14 Translocation of endothelial P-selectin to the cell surface results in the prompt adhesion of sickle erythrocytes to vessels and the development of vascular occlusion in transgenic mice with sickle cell disease.15 Furthermore, activated platelets bind to neutrophils to form aggregates in a P-selectin–dependent manner in mice and humans with sickle cell disease.16
Transgenic mice with sickle cell disease that are deficient in P-selectin and E-selectin...