title: The effect of a polyurethane coating incorporating both a thrombin inhibitor and nitric oxide on hemocompatibility in extracorporeal circulation.
abstract: Nitric oxide (NO) releasing (NORel) materials have been extensively investigated to create localized increases in NO concentration by the proton driven diazeniumdiolate-containing polymer coatings and demonstrated to improve extracorporeal circulation (ECC) hemocompatibility. In this work, the NORel polymeric coating composed of a diazeniumdiolated dibutylhexanediamine (DBHD-N2O2)-containing hydrophobic Elast-eon™ (E2As) polyurethane was combined with a direct thrombin inhibitor, argatroban (AG), and evaluated in a 4 h rabbit thrombogenicity model without systemic anticoagulation. In addition, the immobilizing of argatroban to E2As polymer was achieved by either a polyethylene glycol-containing (PEGDI) or hexane methylene (HMDI) diisocyanate linker. The combined polymer film was coated on the inner walls of ECC circuits to yield significantly reduced ECC thrombus formation compared to argatroban alone ECC control after 4 h blood exposure (0.6 ± 0.1 AG/HMDI/NORel vs 1.7 ± 0.2 cm(2) AG/HMDI control). Platelet count (2.8 ± 0.3 AG/HMDI/NORel vs 1.9 ± 0.1 × 10(8)/ml AG/HMDI control) and plasma fibrinogen levels were preserved after 4 h blood exposure with both the NORel/argatroban combination and the AG/HMDI control group compared to baseline. Platelet function as measured by aggregometry remained near normal in both the AG/HMDI/NORel (63 ± 5%) and AG/HMDI control (58 ± 7%) groups after 3 h compared to baseline (77 ± 1%). Platelet P-selectin mean fluorescence intensity (MFI) as measured by flow cytometry also remained near baseline levels after 4 h on ECC to ex vivo collagen stimulation (16 ± 3 AG/HMDI/NORel vs 11 ± 2 MFI baseline). These results suggest that the combined AG/HMDI/NORel polymer coating preserves platelets in blood exposure to ECCs to a better degree than AG/PEGDI/NORel, NORel alone or AG alone. These combined antithrombin, NO-mediated antiplatelet effects were shown to improve thromboresistance of the AG/HMDI/NORel polymer-coated ECCs and move potential nonthrombogenic polymers closer to mimicking vascular endothelium.
authors.affiliation: Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, USA. Electronic address: tcmajor@umich.edu.
authors.forename: Terry C
authors.initials: TC
authors.lastname: Major
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Brisbois
authors.affiliation: Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Jones
authors.affiliation: Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, USA.
authors.forename: Margaux E
authors.initials: ME
authors.lastname: Zanetti
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical Center, Ann Arbor, MI, USA.
authors.forename: Gail M
authors.initials: GM
authors.lastname: Annich
authors.affiliation: Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bartlett
authors.affiliation: Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, USA. Electronic address: hhanda@umich.edu.
authors.forename: Hitesh
authors.initials: H
authors.lastname: Handa
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000008:administration & dosage*; D001120:Arginine / Q000031:analogs & derivatives; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D020099:Coated Materials, Biocompatible / Q000737:chemistry*; D005112:Extracorporeal Circulation / Q000295:instrumentation*; D017953:Isocyanates / Q000737:chemistry; D009569:Nitric Oxide / Q000008:administration & dosage*; D010875:Pipecolic Acids / Q000008:administration & dosage*; D015539:Platelet Activation / Q000187:drug effects; D010979:Platelet Function Tests; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011140:Polyurethanes / Q000737:chemistry*; D011817:Rabbits; D013449:Sulfonamides; D013917:Thrombin / Q000037:antagonists & inhibitors; D013927:Thrombosis / Q000517:prevention & control
chemical_list: D000991:Antithrombins; D020099:Coated Materials, Biocompatible; D017953:Isocyanates; D010875:Pipecolic Acids; D011108:Polymers; D011140:Polyurethanes; D013449:Sulfonamides; C015262:1,6-hexamethylene diisocyanate; D009569:Nitric Oxide; D011092:Polyethylene Glycols; D001120:Arginine; D013917:Thrombin; C031942:argatroban
keywords: Argatroban; Direct thrombin inhibition; Hexane methylene diisocyanate (HMDI); Nitric oxide releasing polymer; Polyethylene glycol (PEG); Thrombogenicity