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.

Public Health Relevance

The ideal nonthrombogenic surface would combine nitric oxide secretion to prevent platelet adhesion with a surface bound anticoagulant to prevent fibrin formation. This research will develop and evaluate the combination of NO secretion with surface immobilized thrombin inhibitor argatroban.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Exploratory/Developmental Grants (R21)
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Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
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Hunziker, Rosemarie
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Yu, Jane; Brisbois, Elizabeth; Handa, Hitesh et al. (2016) The immobilization of a direct thrombin inhibitor to a polyurethane as a nonthrombogenic surface coating for extracorporeal circulation. J Mater Chem B Mater Biol Med 4:2264-2272
Major, Terry C; Brisbois, Elizabeth J; Jones, Anna M et al. (2014) The effect of a polyurethane coating incorporating both a thrombin inhibitor and nitric oxide on hemocompatibility in extracorporeal circulation. Biomaterials 35:7271-85
Handa, Hitesh; Major, Terry C; Brisbois, Elizabeth J et al. (2014) Hemocompatibility Comparison of Biomedical Grade Polymers Using Rabbit Thrombogenicity Model for Preparing Nonthrombogenic Nitric Oxide Releasing Surfaces. J Mater Chem B Mater Biol Med 2:1059-1067
Brisbois, Elizabeth J; Handa, Hitesh; Major, Terry C et al. (2013) Long-term nitric oxide release and elevated temperature stability with S-nitroso-N-acetylpenicillamine (SNAP)-doped Elast-eon E2As polymer. Biomaterials 34:6957-66