title: The hemocompatibility of a nitric oxide generating polymer that catalyzes S-nitrosothiol decomposition in an extracorporeal circulation model.
abstract: Nitric oxide (NO) generating (NOGen) materials have been shown previously to create localized increases in NO concentration by the catalytic decomposition of blood S-nitrosothiols (RSNO) via copper (Cu)-containing polymer coatings and may improve extracorporeal circulation (ECC) hemocompatibility. In this work, a NOGen polymeric coating composed of a Cu⁰-nanoparticle (80 nm)-containing hydrophilic polyurethane (SP-60D-60) combined with the intravenous infusion of an RSNO, S- nitroso-N-acetylpenicillamine (SNAP), is evaluated in a 4 h rabbit thrombogenicity model and the anti-thrombotic mechanism is investigated. Polymer films containing 10 wt.% Cu⁰-nanoparticles coated on the inner walls of ECC circuits are employed concomitantly with systemic SNAP administration (0.1182 μmol/kg/min) to yield significantly reduced ECC thrombus formation compared to polymer control + systemic SNAP or 10 wt.% Cu NOGen + systemic saline after 4 h blood exposure (0.4 ± 0.2 NOGen/SNAP vs 4.9 ± 0.5 control/SNAP or 3.2 ± 0.2 pixels/cm² NOGen/saline). Platelet count (3.9 ± 0.7 NOGen/SNAP vs 1.8 ± 0.1 control/SNAP or 3.0 ± 0.2 × 10⁸/ml NOGen/saline) and plasma fibrinogen levels were preserved after 4 h blood exposure with the NOGen/SNAP combination vs either the control/SNAP or the NOGen/saline groups. Platelet function as measured by aggregometry (51 ± 9 NOGen/SNAP vs 49 ± 3% NOGen/saline) significantly decreased in both the NOGen/SNAP and NOGen/saline groups while platelet P-selectin mean fluorescence intensity (MFI) as measured by flow cytometry was not decreased after 4 h on ECC to ex vivo collagen stimulation (26 ± 2 NOGen/SNAP vs 29 ± 1 MFI baseline). Western blotting showed that fibrinogen activation as assessed by Aγ dimer expression was reduced after 4 h on ECC with NOGen/SNAP (68 ± 7 vs 83 ± 3% control/SNAP). These results suggest that the NOGen polymer coating combined with SNAP infusion preserves platelets in blood exposure to ECCs by attenuating activated fibrinogen and preventing platelet aggregation. These NO-mediated platelet changes were shown to improve thromboresistance of the NOGen polymer-coated ECCs when adequate levels of RSNOs are present.
authors.affiliation: Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109, USA. tcmajor@umich.edu
authors.forename: Terry C
authors.initials: TC
authors.lastname: Major
authors.forename: David O
authors.initials: DO
authors.lastname: Brant
authors.forename: Charles P
authors.initials: CP
authors.lastname: Burney
authors.forename: Kagya A
authors.initials: KA
authors.lastname: Amoako
authors.forename: Gail M
authors.initials: GM
authors.lastname: Annich
authors.forename: Mark E
authors.initials: ME
authors.lastname: Meyerhoff
authors.forename: Hitesh
authors.initials: H
authors.lastname: Handa
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bartlett
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005112:Extracorporeal Circulation; D005340:Fibrinogen / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D009569:Nitric Oxide / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D011817:Rabbits; D026403:S-Nitrosothiols / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D011108:Polymers; D026403:S-Nitrosothiols; D009569:Nitric Oxide; D005340:Fibrinogen