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

Background: Tissue factor (TF)-initiated thrombin generation has been impli cated in the development of intimal hyperplasia after arterial injury. An i ncrease in intimal TF expression has been shown to precede the development of intimal hyperplasia in vein grafts. This study examines the effects of l ocal treatment with recombinant human tissue factor pathway inhibitor (rTFP I) in experimental vein grafts. Methods: Thirty-six male New Zealand white rabbits underwent bypass graftin g 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 mug . mL(-1); n = 10) or placebo vehicle (control; n = 10). Sixteen animals received both ex vivo incubation and in vivo gel treat ment with rTFPI (50 mug . mL(-1); n = 8) or without rTFPI (gel-control; n = 8). After operation, vein grafts were harvested at 3 days for immunohistoc hemical and Western analyses and at 28 days for histomorphologic study. Results: Western analysis demonstrated a 6.2-fold reduction in the expressi on of TF protein with rTFPI treatment in comparison to without rTFPI treatm ent. CD-18 leukocyte staining was diminished, whereas Tie-2 endothelial sta ining 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 mum; P < .05) and by 30% with the addition of rTFPI in vivo compared with gel-con trol (60 +/- 4 versus 86 +/- 5 <mu>m; P < .01). Conclusion: Local administration of rTFPI exerts early beneficial effects a nd limits the development of intimal hyperplasia in vein grafts. Therefore blocking TF-mediated pathway may offer new therapeutic options to reduce ve in graft failure.