Combined Nitric Oxide Release and Argatroban for Thromboresistant Coatings

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DESCRIPTION (provided by applicant): Extracorporeal circulation (ECC) on blood through artificial organs is practiced thousands of times each day (CPB, hemodialysis, hemofiltration, plasma phoresis, ECMO). Systemic anticoagulation is required to prevent clotting in the devices resulting in the major complication: bleeding. Despite decades of research development of a nonthrombogenic surface to eliminate the need for systemic anticoagulation remains an elusive goal. Clotting as on prosthetic surfaces has two components: platelet adhesion/activation and conversion of fibrinogen to fibrin. Bonding the anticoagulant heparin to the surface prevents local fibrin formation but does not prevent platelet adhesion. We have developed nitric oxide (NO) secreting surfaces which prevent platelet adhesion. We are currently developing combined heparin and NO polymer surfaces with the goal of eliminating the need for systemic anticoagulation in ECC. Although heparin/NO combination promises to be an ideal nonthrombogenic surface, there are drawbacks to heparin. Heparin is derived from animal tissue, acts at several points in the coagulation cascade, is not a direct thrombin inhibitor, and s dependent on plasma antithrombin (AT). Heparin can result in the allergic syndrome called heparin induced thrombocytopenia (HIT). Argatroban is a direct thrombin inhibitor that prevents fibrin formation. Argatroban is synthetic, easily available and FDA approved for intravenous administration, and is nonallergenic. This research will evaluate the combination of NO secretion with surface bound argatroban as a nonthrombogenic surface for ECC. The objective of this research is to develop and evaluate the combined effect of argatroban and NO on thrombus formation and platelet activity in ECC. Our central hypothesis is that a NO release coating combined with immobilized thrombin inhibitor, argatroban, will allow ECC without systemic anticoagulation.