Inhibition of tissue factor-mediated coagulation markedly attenuates stenosis after balloon-induced arterial injury in minipigs.

Abstract

Exposure and upregulation of tissue factor in the wall of balloon-injured arteries may result in prolonged activation of coagulation contributing to restenosis. This study was designed to determine whether brief or more prolonged inhibition of tissue factor-mediated coagulation with tissue factor pathway inhibitor (TFPI) attenuates neointimal formation and luminal stenosis after balloon-induced arterial injury. The carotid artery of minipigs fed an atherogenic diet was injured by repetitive balloon hyperinflations, a procedure that rapidly yields complex, plaque-like neointimal lesions and high-grade luminal stenosis. Recombinant TFPI (rTFPI) was administered intravenously beginning 15 minutes before balloon injury as either a high dose (0.5 mg/kg bolus and 100 microg x kg(-1) x min(-1)) for 3 hours (n=7) or 24 hours (n=6) or as a low dose (0.5 mg/kg and 25 microg x kg(-1) x min(-1)) for 24 hours (n=6). Control animals received intravenous heparin (100 U x kg(-1) x h(-1)) for 3 hours (n=6) or 24 hours (n=7) or aspirin (5 mg/kg P.O.) followed by heparin for 24 hours (n=7). Luminal stenosis, assessed histologically 4 weeks after injury, was 73+/-17% and 76+/-18% (mean+/-SEM) in animals that received rTFPI or heparin for 3 hours, respectively. In contrast, luminal stenosis was only 11+/-12% and 6+/-3% in pigs given high and low doses, respectively, of rTFPI for 24 hours compared with 46+/-22% in pigs given heparin for 24 hours and 40+/-19% in those given both heparin and aspirin (P<.0002). Inhibition of tissue factor-mediated coagulation during the first 24 hours after deep arterial injury appears to be particularly effective for attenuating subsequent neointimal formation and stenosis.