Mechanical circulatory support with ventricular assist devices (VADs) for end-stage heart failure has been a focus of intense interest for nearly four decades. Despite improvements in VAD design and biomaterial composition, it is common to administer anti-coagulation (e.g., warfarin, anti-platelet agents) to prevent both device thrombosis and thromboembolism. We present a patient with pre-operative thrombophilia (pulmonary embolism, intracardiac thrombus) and hypofibrinolysis, who subsequently developed hypercoagulability with hyperfibrinolysis with normalization of clot lifespan after left VAD placement. Such complex patient-VAD-hemostatic-state interactions serve as the rationale for continuing investigation of the effects of mechanical circulation on the fibrinolytic system and thrombophilia. © 2008 International Society for Heart and Lung Transplantation.