Stages in platelet plug formation. A classical model. (A) Prior to vascular injury, platelet activation is suppressed by endothelial cell-derived inhibitory factors. These include prostaglandin PGI₂ (prostacyclin), nitric oxide (NO), and CD39, an ADPase on the surface of endothelial cells that can hydrolyze trace amounts of ADP that might otherwise cause inappropriate platelet activation. (B) Initiation. The development of the platelet plug is initiated by thrombin and by the collagen-VWF complex, which captures and activates moving platelets. Platelets adhere and spread, forming a monolayer. (C) Extension. The platelet plug is extended as additional platelets are activated via the release or secretion of TxA₂, ADP, and other platelet agonists, most of which are ligands for G protein-coupled receptors on the platelet surface. Activated platelets stick to each other via bridges formed by the binding of fibrinogen, fibrin, or VWF to activated α_IIbβ₃. (D) Stabilization. Finally, close contacts between platelets in the growing hemostatic plug, along with a fibrin meshwork (shown in red), help to perpetuate and stabilize the platelet plug. This model is being revised as new observations (described in the text) of the behavior of individual platelets within the hemostatic plug add additional refinements.