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The coagulation and fibrinolytic systems are central to the hemostatic mechanism, which works promptly on vascular injury and tissue damage. The rapid response is generated by specific molecular interactions between components in these systems. Thus, the regulation mechanism of the systems is programmed in each component, as exemplified by the elegant processes in zymogen activation. This review describes recently identified small molecules that modulate the activation of zymogens in the fibrinolytic and coagulation systems.