Novel agents targeting adhesion and coagulation in SCD. Numerous adhesive interactions among sRBCs, neutrophils, and endothelial cells contribute to sickle cell vasoocclusion. Activation of endothelial cells leads to the recruitment of neutrophils, which is initiated by rolling of neutrophils on endothelial selectins, followed by adhesion. Adherent neutrophils receive a secondary wave of signals transduced through E-selectin, leading to the activation of αMβ2 (Mac-1) integrin on the leading edge. Activated Mac-1 on adherent neutrophils mediates the capture of circulating sRBCs. In addition, sRBCs express multiple adhesion molecules that interact with ligands on endothelial cells or the subendothelial matrix either directly or via bridging molecules in the plasma. Rivipansel targets E-selectin predominantly, whereas crizanlizumab and sevuparin inhibit P-selectin–mediated adhesive interactions. IV immunoglobulin (IVIG) interferes with neutrophil-mediated sRBC capture. Propranol blocks various sRBC-endothelial interactions that are stimulated by β-adrenergic signaling, such as LW (ICAM4)-αVβ3 and BCAM/lu-laminin (LM). Unfractionated heparin (UFH) and tinzaparin, in addition to their anticoagulant effects, target P-selectin. ESL, E-selectin ligand; PSGL-1, P-selectin ligand 1. Adapted from Morrone et al48 with permission.