A revised model of platelet aggregation. (a and b) The mechanisms by which platelets in suspension aggregate following exposure to a soluble agonist or high shear stress are depicted. (c) The multistep mechanism by which circulating platelets form stationary adhesion contacts with the luminal surface of a growing thrombus under physiological flow conditions is demonstrated. (a) The addition of a soluble agonist to a stirred platelet suspension leads to the activation of integrin α_IIbβ₃ (GPIIb-IIIa) and its subsequent binding to soluble fibrinogen. Fibrinogen’s dimeric structure enables it to cross-link adjacent activated platelets and mediate stable platelet aggregation (5, 38). (b) Under high shear conditions, vWf becomes the relevant ligand responsible for platelet activation. Shear-induced binding of soluble vWf to GPIb-V-IX induces platelet activation. At elevated levels of shear, stable platelet aggregation is thought to be dependent primarily on vWf binding to GPIIb-IIIa (7, 39). (c) Upon vascular injury, platelets are recruited to the subendothelium where they become activated, releasing their granule contents. vWf expressed on the surface of immobilized platelets tethers circulating platelets by binding GPIbα. The majority of platelets that tether subsequently translocate or detach from the surface of immobilized platelets. The formation of stationary adhesion contacts is dependent on the cross-linking of integrin α_IIbβ₃ on the surface of free-flowing and immobilized platelets by plasma vWf or fibrinogen. This multistep adhesion process operates at both arterial and venous levels of shear and appears to be the predominant mechanism by which platelets aggregate in vivo. However, note that at venous levels of shear, platelets can also form immediate stationary adhesion contacts with immobilized platelets independent of the vWf-GPIbα interaction.