Proposed mechanism of NET-dependent thrombosis in vivo. (1) Neutrophils adhere to the endothelium by interaction between E-selectin and neutrophil P-selectin glycoprotein ligand (PSGL) and CXCR2. Platelets (PLTs) adhere by binding to von Willebrand factor (VWF) attached to the endothelium. (2) PSGL-1 and CXCR2 signaling in neutrophils (PMNs), as well as interactions between adherent neutrophils and platelets mediated by platelet HMGB1 or P-selectin, promote NET release. (3) NETs adhere and damage the vascular wall, impair flow, trap circulating procoagulant actors, impair physiologic anticoagulants, (4) ultimately leading to enhanced coagulation and thrombosis. aPTL, activated platelet; E-SEL, endothelial selectin; NE, neutrophil elastase; PMV, procoagulant microvesicle; TFPI, TF pathway inhibitor.