A multistep process of occlusive thrombosis. (A) First, platelets aggregate through involvement of their GpIIb/IIIa receptors, resulting in partial occlusion of the blood vessel and a locally increased shear rate (Step 1). At this early stage, the nonocclusive thrombi are responsive to treatment with GpIIb/IIIa inhibitors. Subsequently, when the shear stress becomes elevated, platelet aggregation to the developing thrombus becomes GpIbα-VWF dependent, until closure of the vessel lumen (Step 2). At this later stage, the occlusive thrombi are resistant to GpIIb/IIIa inhibitors or tPA and only responsive to inhibitors of the GpIbα-VWF interaction. Then, the thrombus progressively stabilizes (>1 hour) and finally becomes resistant to inhibitors of the GpIbα-VWF interactions (Step 3). Additionally, all over the thrombotic process, the low shear rates at the base of the thrombus (both upstream and downstream) favor the formation of fibrin networks, which anchor the thrombus to the vessel wall. (B) Each of the 3 regions in occlusive thrombi is responsive to a specific thrombolytic agent. (C) Therefore, the most efficient thrombolytic strategy may depend on the thrombus developmental stage and on the mechanism responsible for its formation.