The landmark report of the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group demonstrated that the use of a left ventricular assist device (VAD) in patients with advanced heart failure resulted in a significantly meaningful survival benefit and an improved quality of life compared with medically-treated subjects with similarly advanced heart failure. Yet, despite the increased survival benefit, subject with VADs displayed increased frequency of serious adverse events, including bleeding, infection and device malfunction. Unlike subjects with medically-managed CHF, subjects with VADs require cardiopulmonary bypass (CPB) for device insertion. Cardiopulmonary bypass (CPB) initiates activation of the intrinsic and extrinsic pathways of the prothrombotic response. The intrinsic pathway of coagulation is rapidly recruited secondary to blood flow across the artificial bypass circuit. In parallel, the extrinsic pathway of coagulation is activated by the tremendous amounts of tissue factor released from the surgical wound, such as sternotomy and pericardiotomy. These two pathways synergize in CPB to amplify thrombin generation. In addition, activation of platelets and complement cascades sustains the host response. In settings such as coronary artery bypass grafting or valve replacement, upon reversal of heparin and restoration of blood flow across natural endothelial surfaces, gradual resolution of the prothrombotic stimulus ensues. However, in subjects undergoing CPB for ventricular assist devices (VAD) placement, we postulate that CPB-triggered activation of coagulation fails to resolve, as VAD-host interaction sustains activation of prothrombotic mechanisms. We propose that unless effective equilibrium is achieved between prothrombotic and antithrombotic forces in the VAD milieu, imbalance leads to untoward bleeding and/or procoagulant diatheses. Subjects with VADs display an increased incidence of bleeding complications, both at the time of VAD placement, and, at later times after implantation.
Aim 1 : To fully characterize the time course of activation of prothrombotic pathways in animals undergoing CPB and VAD implantation.
Aim 2 : To test novel antagonists of the Intrinsic Pathway of coagulation in CPB and VAD placement in canine and porcine models, and to monitor the response to CPB/VAD placement in human subjects.
Aim 3 : To perform Phase II trials in human subjects with advanced heart failure undergoing CPB and VAD placement with Intrinsic Pathway antagonists.
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