We propose to test the hypothesis that thrombosis, thromboembolism, and intimal lesion formation associated with small caliber vascular grafts are influenced directly by graft surface-chemical properties, and that graft performance may be improved by: (1) cellular and chemical modification of the graft surface, (2) mechanical reinforcement of graft-vessel anastomoses, and (3) novel anticoagulant and antiplatelet pharmacologic regimens. Currently, there is a high degree of interest in developing improved materials and therapeutic regimens for use in patients undergoing vascular reconstructive procedures. Despite the widespread use of synthetic grafts in larger arteries, smaller caliber grafts have received only limited application in man due to problems of early thrombotic occlusion or later failure resulting from the stenotic ingrowth of tissue (intimal hyperplasia). Since the mechanisms of both early and late graft failure have not been fully defined, we propose to measure in baboons the effectiveness of promising antithrombotic and antiarteriosclerotic strategies. Specifically, we will use gamma scintillation camera imaging of 111In-labeled platelets to assess graft thrombus formation and thromboembolization to distal microcirculatory beds in animals with: (1) grafts modified chemically by plasma (gas) polymerization or biologically by endothelial cell coverage. (2) endovascular stents to inhibit vessel narrowing at graft-vessel anastomoses, and (3) antithrombotic therapeutic regimens which modify platelet function (monoclonal antibodies against von Willebrand factor, ticlopidine) or inhibit thrombin activity (activated protein C and PPACK, an antithrombin tripeptide). The effects of these strategies on vascular healing and lesion formation will subsequently be assessed. These studies will be relevant to the mechanisms and prevention of thrombosis and restenosis in patients undergoing invasive vascular procedures for arterial repair.
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