Cargando…

Assessment of Novel Anti-thrombotic Fusion Proteins for Inhibition of Stenosis in a Porcine Model of Arteriovenous Graft

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,...

Descripción completa

Detalles Bibliográficos
Autores principales: Terry, Christi M., Zhuplatov, Ilya, He, Yuxia, Wun, Tze-Chein, Kim, Seong-Eun, Cheung, Alfred K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567316/
https://www.ncbi.nlm.nih.gov/pubmed/26360605
http://dx.doi.org/10.1371/journal.pone.0137381
_version_ 1782389806577221632
author Terry, Christi M.
Zhuplatov, Ilya
He, Yuxia
Wun, Tze-Chein
Kim, Seong-Eun
Cheung, Alfred K.
author_facet Terry, Christi M.
Zhuplatov, Ilya
He, Yuxia
Wun, Tze-Chein
Kim, Seong-Eun
Cheung, Alfred K.
author_sort Terry, Christi M.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4567316
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-45673162015-09-18 Assessment of Novel Anti-thrombotic Fusion Proteins for Inhibition of Stenosis in a Porcine Model of Arteriovenous Graft Terry, Christi M. Zhuplatov, Ilya He, Yuxia Wun, Tze-Chein Kim, Seong-Eun Cheung, Alfred K. PLoS One Research Article 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. Public Library of Science 2015-09-11 /pmc/articles/PMC4567316/ /pubmed/26360605 http://dx.doi.org/10.1371/journal.pone.0137381 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
spellingShingle Research Article
Terry, Christi M.
Zhuplatov, Ilya
He, Yuxia
Wun, Tze-Chein
Kim, Seong-Eun
Cheung, Alfred K.
Assessment of Novel Anti-thrombotic Fusion Proteins for Inhibition of Stenosis in a Porcine Model of Arteriovenous Graft
title Assessment of Novel Anti-thrombotic Fusion Proteins for Inhibition of Stenosis in a Porcine Model of Arteriovenous Graft
title_full Assessment of Novel Anti-thrombotic Fusion Proteins for Inhibition of Stenosis in a Porcine Model of Arteriovenous Graft
title_fullStr Assessment of Novel Anti-thrombotic Fusion Proteins for Inhibition of Stenosis in a Porcine Model of Arteriovenous Graft
title_full_unstemmed Assessment of Novel Anti-thrombotic Fusion Proteins for Inhibition of Stenosis in a Porcine Model of Arteriovenous Graft
title_short Assessment of Novel Anti-thrombotic Fusion Proteins for Inhibition of Stenosis in a Porcine Model of Arteriovenous Graft
title_sort assessment of novel anti-thrombotic fusion proteins for inhibition of stenosis in a porcine model of arteriovenous graft
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567316/
https://www.ncbi.nlm.nih.gov/pubmed/26360605
http://dx.doi.org/10.1371/journal.pone.0137381
work_keys_str_mv AT terrychristim assessmentofnovelantithromboticfusionproteinsforinhibitionofstenosisinaporcinemodelofarteriovenousgraft
AT zhuplatovilya assessmentofnovelantithromboticfusionproteinsforinhibitionofstenosisinaporcinemodelofarteriovenousgraft
AT heyuxia assessmentofnovelantithromboticfusionproteinsforinhibitionofstenosisinaporcinemodelofarteriovenousgraft
AT wuntzechein assessmentofnovelantithromboticfusionproteinsforinhibitionofstenosisinaporcinemodelofarteriovenousgraft
AT kimseongeun assessmentofnovelantithromboticfusionproteinsforinhibitionofstenosisinaporcinemodelofarteriovenousgraft
AT cheungalfredk assessmentofnovelantithromboticfusionproteinsforinhibitionofstenosisinaporcinemodelofarteriovenousgraft