Platelets initiate arrest of bleeding at sites of vascular injury but also trigger inopportune arterial thrombosis, which causes heart attacks and strokes. After formation of a single platelet monolayer at the site of injury, additional platelets are recruited into the growing hemostatic plug. Without further stabilization, the platelet plug disaggregates. Its stabilization is insured by perpetuation of platelet activation. Drugs designed to prevent thrombus stabilization rather than inhibition of its formation are currently not available. Targeting perpetuation of platelet activation reveals that it is possible to block thrombosis without eliciting bleeding.