Antithrombotic function of endothelial cells. (A) The endothelium presents an antiadhesive phenotype maintained through 3 intrinsic pathways: the CD39/ecto-adenosine diphosphatase (ecto-ADPase) pathway, which depletes the platelet agonist, ADP, and the PGI₂ and NO pathways, which inhibit platelet activation. With respect to depletion of ADP, spatial limitations dictate that this primarily occurs for ADP release from platelets adherent to activated endothelium or matrix proteins. (B-E) The endothelium uses several mechanisms to neutralize α-thrombin. (B) First, antithrombin (AT) binds to GAGs on the endothelial cell surface and inactivates α-thrombin (IIa), FXa, and several other coagulation proteases. (C-D) Second, thrombin can be efficiently converted from a procoagulant to anticoagulant protease in the microcirculation by binding the endothelial integral membrane protein TM and the endothelial protein C receptor (EPCR). Once bound to these receptors, thrombin cleaves and activates protein C (PC) to generate APC. (C) APC functions as an anticoagulant by proteolytically inactivating FVa and FVIIIa. (D) If APC remains bound to the EPCR, it induces signaling through PAR1 to elicit cytoprotection and increased endothelial barrier function. (E) Healthy endothelium also expresses high levels of TFPI that inhibit formation of the tissue factor (TF)/FVIIa complex, thereby preventing the initiation of coagulation and subsequent thrombin generation. AMP, ecto-adenosine monophosphate; P_i, inorganic phosphate, PAR1, protease-activated receptor 1; RBC, red blood cell.