Inhibition of Tissue Factor–Mediated Coagulation Markedly Attenuates Stenosis After Balloon-Induced Arterial Injury in Minipigs

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Abstract
BackgroundExposure 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.Methods and ResultsThe 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 μg·kg−1·min−1) for 3 hours (n=7) or 24 hours (n=6) or as a low dose (0.5 mg/kg and 25 μg·kg−1·min−1) for 24 hours (n=6). Control animals received intravenous heparin (100 U·kg−1·h−1) for 3 hours (n=6) or 24 hours (n=7) or aspirin (5 mg/kg PO) 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).ConclusionsInhibition 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.

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