A revised model of platelet aggregation

In this study we have examined the mechanism of platelet aggregation under physiological flow conditions using an in vitro flow-based platelet aggrega tion assay and an in vivo rat thrombosis model. Our studies demonstrate an unexpected complexity to the platelet aggregation process in which platelet s in flowing blood continuously tether, translocate, and/or detach from the luminal surface of a growing platelet thrombus at both arterial and venous shear rates. Studies of platelets congenitally deficient in von Willebrand factor (vWf) or integrin alpha(IIb)beta(3) demonstrated a key role for pla telet vWfin mediating platelet tethering and translocation, whereas integri n alpha(IIb)beta(3) mediated cell arrest. Platelet aggregation under flow a ppears to be a multistep process involving: (a) exposure of vWfon the surfa ce of immobilized platelets; (b) a reversible phase of platelet aggregation mediated by the binding of GPIb alpha on the surface of free-flowing plate lets to vWf on the surface of immobilized platelets; and (c) an irreversibl e phase of aggregation dependent on integrin alpha(IIb)beta(3). studies of platelet thrombus formation in vivo demonstrate that this multistep adhesio n mechanism is indispensable for platelet aggregation in arterioles and als o appears to promote platelet aggregate formation in venules. Together, our studies demonstrate an important role for platelet vWfin initiating the pl atelet aggregation process under flow and challenge the currently accepted view that the vWf-GPIb alpha interaction is exclusively involved in initiat ing platelet aggregation at elevated shear rates.