INHIBITION OF THROMBIN ATTENUATES STENOSIS AFTER ARTERIAL INJURY IN MINIPIGS

Objectives. We sought to determine whether brief, profound inhibition of thrombin or prothrombin activation by factor Xa limits neointimal f ormation and stenosis after arterial injury. Background. Thrombin has been implicated as a mediator of neointimal formation, but adjunctive administration of anticoagulant agents has not proven effective to dec rease restenosis in patients undergoing coronary angioplasty. Methods. We infused recombinant desulfatohirudin (r-hirudin, bolus of 2 mg/kg body weight followed by 2 mg/kg per h, n = 9), heparin (100 U/kg per h , n = 6) or recombinant tick anticoagulant peptide (rTAP, 1-mg/kg bolu s followed by 3 mg/kg per h, n = 5), a specific inhibitor of factor Xa , intravenously, beginning 15 min before and for up to 3 h after repet itive balloon hyperinflations sufficient to disrupt the internal elast ic lamina in a carotid artery of minipigs with hypercholesterolemia in duced by feeding them an atherogenic diet. Results. Partial thrombopla stin time was increased six- to sevenfold over baseline levels at the end of the infusions of the anticoagulant agents. Lumen stenosis measu red histologically 4 weeks after balloon-induced carotid injury was 29 +/- 16% (mean +/- SEM) in r-hirudin-treated, 52 +/- 19% in rTAP-treat ed and 76 +/- 18% in heparin-treated pigs (p < 0.02 for r-hirudin vs. heparin treatment). Conclusions. The marked reduction of stenosis in r -hirudin-treated animals indicates that thrombin plays a major role in neointimal formation after balloon-induced arterial injury. A relativ ely brief interval of profound, direct inhibition of thrombin map be p articularly effective to attenuate restenosis after balloon angioplast y. (C) 1996 by the American College of Cardiology