Local treatment with recombinant tissue factor pathway inhibitor reduces the development of intimal hyperplasia in experimental vein grafts

Tam T.T. Huynh, Mark G. Davies, Michael A. Thompson, Michael D. Ezekowitz, Per Otto Hagen, Brian H. Annex

Research output: Contribution to journalArticle

Abstract

Background: Tissue factor (TF)-initiated thrombin generation has been implicated in the development of intimal hyperplasia after arterial injury. An increase in intimal TF expression has been shown to precede the development of intimal hyperplasia in vein grafts. This study examines the effects of local treatment with recombinant human tissue factor pathway inhibitor (rTFPI) in experimental vein grafts. Methods: Thirty-six male New Zealand white rabbits underwent bypass grafting of the carotid artery by use of the reversed ipsilateral jugular vein and were divided into four groups. Twenty animals had ex vivo incubation with rTFPI treatment (50 μg · mL -1; n = 10) or placebo vehicle (control; n = 10). Sixteen animals received both ex vivo incubation and in vivo gel treatment with rTFPI (50 μg · mL -1; n = 8) or without rTFPI (gel-control; n = 8). After operation, vein grafts were harvested at 3 days for immunohistochemical and Western analyses and at 28 days for histomorphologic study. Results: Western analysis demonstrated a 6.2-fold reduction in the expression of TF protein with rTFPI treatment in comparison to without rTFPI treatment. CD-18 leukocyte staining was diminished, whereas Tie-2 endothelial staining was increased in all rTFPI-treated vein grafts, compared with control and gel-control vein grafts. Intimal thickness was reduced by 21% with ex vivo rTFPI treatment compared with placebo (69 ± 4 versus 87 ± 5 μm; P < .05) and by 30% with the addition of rTFPI in vivo compared with gel-control (60 ± 4 versus 86 ± 5 μm; P < .01). Conclusion: Local administration of rTFPI exerts early beneficial effects and limits the development of intimal hyperplasia in vein grafts. Therefore blocking TF-mediated pathway may offer new therapeutic options to reduce vein graft failure.

Original languageEnglish (US)
Pages (from-to)400-407
Number of pages8
JournalJournal of Vascular Surgery
Volume33
Issue number2
DOIs
StatePublished - Mar 24 2001
Externally publishedYes

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Tunica Intima
Hyperplasia
Veins
Transplants
Thromboplastin
Gels
Therapeutics
Placebos
lipoprotein-associated coagulation inhibitor
Staining and Labeling
Jugular Veins
Carotid Arteries
Recombinant Proteins
Thrombin
Leukocytes

ASJC Scopus subject areas

  • Surgery
  • Cardiology and Cardiovascular Medicine

Cite this

Local treatment with recombinant tissue factor pathway inhibitor reduces the development of intimal hyperplasia in experimental vein grafts. / Huynh, Tam T.T.; Davies, Mark G.; Thompson, Michael A.; Ezekowitz, Michael D.; Hagen, Per Otto; Annex, Brian H.

In: Journal of Vascular Surgery, Vol. 33, No. 2, 24.03.2001, p. 400-407.

Research output: Contribution to journalArticle

Huynh, Tam T.T. ; Davies, Mark G. ; Thompson, Michael A. ; Ezekowitz, Michael D. ; Hagen, Per Otto ; Annex, Brian H. / Local treatment with recombinant tissue factor pathway inhibitor reduces the development of intimal hyperplasia in experimental vein grafts. In: Journal of Vascular Surgery. 2001 ; Vol. 33, No. 2. pp. 400-407.
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abstract = "Background: Tissue factor (TF)-initiated thrombin generation has been implicated in the development of intimal hyperplasia after arterial injury. An increase in intimal TF expression has been shown to precede the development of intimal hyperplasia in vein grafts. This study examines the effects of local treatment with recombinant human tissue factor pathway inhibitor (rTFPI) in experimental vein grafts. Methods: Thirty-six male New Zealand white rabbits underwent bypass grafting of the carotid artery by use of the reversed ipsilateral jugular vein and were divided into four groups. Twenty animals had ex vivo incubation with rTFPI treatment (50 μg · mL -1; n = 10) or placebo vehicle (control; n = 10). Sixteen animals received both ex vivo incubation and in vivo gel treatment with rTFPI (50 μg · mL -1; n = 8) or without rTFPI (gel-control; n = 8). After operation, vein grafts were harvested at 3 days for immunohistochemical and Western analyses and at 28 days for histomorphologic study. Results: Western analysis demonstrated a 6.2-fold reduction in the expression of TF protein with rTFPI treatment in comparison to without rTFPI treatment. CD-18 leukocyte staining was diminished, whereas Tie-2 endothelial staining was increased in all rTFPI-treated vein grafts, compared with control and gel-control vein grafts. Intimal thickness was reduced by 21{\%} with ex vivo rTFPI treatment compared with placebo (69 ± 4 versus 87 ± 5 μm; P < .05) and by 30{\%} with the addition of rTFPI in vivo compared with gel-control (60 ± 4 versus 86 ± 5 μm; P < .01). Conclusion: Local administration of rTFPI exerts early beneficial effects and limits the development of intimal hyperplasia in vein grafts. Therefore blocking TF-mediated pathway may offer new therapeutic options to reduce vein graft failure.",
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AU - Hagen, Per Otto

AU - Annex, Brian H.

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AB - Background: Tissue factor (TF)-initiated thrombin generation has been implicated in the development of intimal hyperplasia after arterial injury. An increase in intimal TF expression has been shown to precede the development of intimal hyperplasia in vein grafts. This study examines the effects of local treatment with recombinant human tissue factor pathway inhibitor (rTFPI) in experimental vein grafts. Methods: Thirty-six male New Zealand white rabbits underwent bypass grafting of the carotid artery by use of the reversed ipsilateral jugular vein and were divided into four groups. Twenty animals had ex vivo incubation with rTFPI treatment (50 μg · mL -1; n = 10) or placebo vehicle (control; n = 10). Sixteen animals received both ex vivo incubation and in vivo gel treatment with rTFPI (50 μg · mL -1; n = 8) or without rTFPI (gel-control; n = 8). After operation, vein grafts were harvested at 3 days for immunohistochemical and Western analyses and at 28 days for histomorphologic study. Results: Western analysis demonstrated a 6.2-fold reduction in the expression of TF protein with rTFPI treatment in comparison to without rTFPI treatment. CD-18 leukocyte staining was diminished, whereas Tie-2 endothelial staining was increased in all rTFPI-treated vein grafts, compared with control and gel-control vein grafts. Intimal thickness was reduced by 21% with ex vivo rTFPI treatment compared with placebo (69 ± 4 versus 87 ± 5 μm; P < .05) and by 30% with the addition of rTFPI in vivo compared with gel-control (60 ± 4 versus 86 ± 5 μm; P < .01). Conclusion: Local administration of rTFPI exerts early beneficial effects and limits the development of intimal hyperplasia in vein grafts. Therefore blocking TF-mediated pathway may offer new therapeutic options to reduce vein graft failure.

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