title: Tissue Factor Activity in Dialysis Access Grafts.
abstract: BACKGROUND
  Intimal hyperplasia at the venous anastomosis of dialysis grafts causes early failure. We developed a sheep model of arteriovenous prosthetic grafts that fail rapidly due to intimal hyperplasia with histologic features nearly identical to human access grafts. A prominent feature of lesion development in this model is formation of luminal thrombus that becomes organized into stenosing lesions by macrophage and myofibroblast infiltration. To better understand this process, we examined the presence and activity of tissue factor (TF) in this system. This protein is the physiological initiator of coagulation in vivo and is known to contribute to development of intimal hyperplasia after vascular injury.
  
  
  METHODS
  Expanded polytetrafluorethylene (ePTFE) grafts were placed between the carotid artery and external jugular vein in sheep. Grafts were examined for luminal TF activity using a novel ex vivo assay. In a separate series of grafts, immunohistochemistry was used to localize smooth muscle cells, monocytes, and TF protein.
  
  
  RESULTS
  At 2 days, luminal TF activity already was higher in the venous and arterial end of the graft than in the adventitia. This high level of activity persisted at 8 weeks. TF activity was higher in the venous end of the grafts than in the arterial end at 2 and 8 weeks (40% and 47% increase, n = 5, n = 3, respectively, P < 0.05). Immunohistochemistry revealed TF protein localized in regions with or adjacent to fibrin accumulation and often in regions close to the lumen.
  
  
  CONCLUSIONS
  This study further examines the development of intimal hyperplasia in ePTFE dialysis access grafts. In this model, TF levels on the luminal surface were increased throughout the arteriovenous grafts and the adjacent vessels as early as 2 days after engraftment and for as long as 8 weeks thereafter. The highest levels of activity were found in the venous end of the graft, where hyperplasia is most robust. Increased activity of TF is associated with luminal thrombus, which provides a scaffolding for development of intimal hyperplasia. These findings present an opportunity to develop strategies to limit TF activity within the graft. Further studies using agents delivered locally or incorporated into the graft matrix to block the luminal activity of TF are warranted.
authors.affiliation: Department of Surgery, University of Washington, Seattle, WA.
authors.forename: David
authors.initials: D
authors.lastname: Hasenstab
authors.affiliation: BioDevelopment Associates LLC, Mountlake Terrace, WA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Kirkman
authors.affiliation: Department of Surgery, University of Washington, Seattle, WA.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Clowes
authors.affiliation: Department of Surgery, University of Washington, Seattle, WA; Department of Surgery, Seattle VA Puget Sound Health Care System, Seattle, WA. Electronic address: kohler@uw.edu.
authors.forename: Ted R
authors.initials: TR
authors.lastname: Kohler
mesh_terms: D000818:Animals; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects / Q000295:instrumentation*; D001807:Blood Vessel Prosthesis; D019917:Blood Vessel Prosthesis Implantation / Q000009:adverse effects / Q000295:instrumentation*; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D005260:Female; D006083:Graft Occlusion, Vascular / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D006965:Hyperplasia; D007150:Immunohistochemistry; D007601:Jugular Veins / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D008297:Male; D023421:Models, Animal; D058426:Neointima; D011474:Prosthesis Design; D006435:Renal Dialysis; D012756:Sheep; D013925:Thromboplastin / Q000378:metabolism*; D013997:Time Factors
chemical_list: D013925:Thromboplastin