title: Assessment of Novel Anti-thrombotic Fusion Proteins for Inhibition of Stenosis in a Porcine Model of Arteriovenous Graft.
abstract: BACKGROUND
  Hemodialysis arteriovenous synthetic grafts (AVG) provide high volumetric blood flow rates shortly after surgical placement. However, stenosis often develops at the vein-graft anastomosis contributing to thrombosis and early graft failure. Two novel fusion proteins, ANV-6L15 and TAP-ANV, inhibit the tissue factor/factor VIIa coagulation complex and the factor Xa/factor Va complex, respectively. Each inhibitor domain is fused to an annexin V domain that targets the inhibitor activity to sites of vascular injury to locally inhibit thrombosis. This study's objective was to determine if these antithrombotic proteins are safe and effective in inhibiting AVG stenosis.
  
  
  METHODS
  A bolus of either TAP-ANV or ANV-6L15 fusion protein was administered intravenously immediately prior to surgical placement of a synthetic graft between the external jugular vein and common carotid artery in a porcine model. At surgery, the vein and artery were irrigated with the anti-thrombotic fusion protein. Control animals received intravenous heparin. At 4 weeks, MRI was performed to evaluate graft patency, the pigs were then euthanized and grafts and attached vessels were explanted for histomorphometric assessment of neointimal hyperplasia at the vein-graft anastomosis. Blood was collected at surgery, immediately after surgery and at euthanasia for serum metabolic panels and coagulation chemistries.
  
  
  RESULTS
  No acute thrombosis occurred in the control group or in either experimental group. No abnormal serum chemistries, activated clotting times or PT, PTT values were observed after treatment in experimental or control animals. However, at the vein-graft anastomosis, there was no difference between the control and experimental groups in cross-sectional lumen areas, as measured on MRI, and no difference in hyperplasia areas as determined by histomorphometry. These results suggest that local irrigation of TAP-ANV or ANV-6L15 intra-operatively was as effective in inhibiting acute graft thrombosis as intravenous administration of heparin, but failed to inhibit hyperplasia development and stenosis in AVG.
authors.affiliation: Division of Nephrology & Hypertension, University of Utah, Salt Lake City, UT, United States of America.
authors.forename: Christi M
authors.initials: CM
authors.lastname: Terry
authors.affiliation: Division of Nephrology & Hypertension, University of Utah, Salt Lake City, UT, United States of America.
authors.forename: Ilya
authors.initials: I
authors.lastname: Zhuplatov
authors.affiliation: Division of Nephrology & Hypertension, University of Utah, Salt Lake City, UT, United States of America.
authors.forename: Yuxia
authors.initials: Y
authors.lastname: He
authors.affiliation: EVAS Therapeutics, LLC, Ballwin, MO, United States of America.
authors.forename: Tze-Chein
authors.initials: TC
authors.lastname: Wun
authors.affiliation: Department of Radiology, Utah Center for Advanced Imaging Research, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Seong-Eun
authors.initials: SE
authors.lastname: Kim
authors.affiliation: Division of Nephrology & Hypertension, University of Utah, Salt Lake City, UT, United States of America; Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, UT, United States of America.
authors.forename: Alfred K
authors.initials: AK
authors.lastname: Cheung
mesh_terms: D000818:Animals; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D001780:Blood Coagulation Tests; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D006083:Graft Occlusion, Vascular / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology*; D008279:Magnetic Resonance Imaging; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D013552:Swine
chemical_list: D005343:Fibrinolytic Agents; D011993:Recombinant Fusion Proteins