The Endothelium

• Endothelial cells synthesize prostacyclin and nitric oxide and release them into the blood, which inhibit platelet activation and subsequent aggregation by stimulating adenylate cyclase and increasing intracellular levels of cyclic adenosine monophospahte (cAMP). In addition, endothelial cells express CD39 on their surfaces, a membrane-associated ectoadenosine diphosphatase (ADPase). By degrading adenosine diphosphate (ADP), which is a platelet agonist, CD39 attenuates platelet activation.
• Endothelial cells produce heparan sulfate proteoglycans, which bind circulating antithrombin and accelerate the rate at which it inhibits thrombin and other coagulation enzymes. Tissue factor pathway inhibitor (TFPI), a naturally occurring inhibitor of coagulation, binds heparan sulfate on the endothelial cell surface. Administration of heparin or low-molecular-weight heparin (LMWH) displaces glycosaminoglycan-bound TFPI from the vascular endothelium, and released TFPI may contribute to the antithrombotic activity of these drugs.
• Thrombomodulin binds thrombin and alters this enzyme's substrate specificity such that it no longer acts as a procoagulant but becomes a potent activator of protein C. Activated protein C serves as an anticoagulant by degrading and inactivating activated factor V and factor VIII (factor Va and VIIIa, respectively), key cofactors involved in thrombin generation. Protein S acts as a cofactor in this reaction, and EPCR enhances this pathway by binding protein C and presenting it to the thrombin–thrombomodulin complex for activation.
• Endothelial cells in most vascular beds synthesize t-PA constitutively and release it in response to stimuli such as thrombin or bradykinin. In contrast, perturbed endothelial cells produce u-PA in the settings of inflammation and wound repair.

Platelets

Adhesion

Von Willebrand factor (VWF)

• VWF is involved in shear‐dependent platelet adhesion to the vessel wall and to other platelets (aggregation). It also carries factor VIII. It is a large glycoprotein, with multimers made up on average of 2–50 dimeric subunits (550 to over 10,000 kDa).
• VWF is synthesized both in endothelial cells and megakaryocytes, and stored in Weibel–Palade bodies and platelet α granules, respectively.