Tissue factor pathway inhibitor attenuates procoagulant activity and upregulation of tissue factor at the site of balloon-induced arterial injury in pigs

Intravenous infusion of recombinant tissue factor pathway inhibitor (rTFPI) for 24 hours decreases neointimal thickening and luminal stenosis 1 month after balloon-induced injury to the carotid arteries in minipigs, This stud y was designed to determine whether the effect of rTFPI is accounted for by early decreases in procoagulant activity and thrombosis on the injured ves sel wall. Vascular injury was induced by balloon hyperinflations in both ca rotid arteries of anesthetized pigs given no anticoagulant as a control (n= 16), an intravenous infusion for 24 hours of rTFPI (0.5 mg/kg bolus and 25 mu g.kg(-1).min(-1), n=14), or an intravenous infusion of unfractionated he parin (100 U.kg(-1).h(-1), n=19). Accumulation of radiolabeled autologous p latelets was markedly decreased over 24 hours on injured arteries from anim als given rTFPI (0.6 X 10(6)/cm(2)) compared with controls (2.5 X 10(6)/cm( 2), P =0.0004), Deposition of radiolabeled fibrin was also decreased in rTF PI-treated animals (269+/-266 mu g/cm(2)) compared with controls (2389+/-16 73 mu g/cm(2), P=0.04), Similar effects were observed with heparin, However , factor Xa activity, assayed after 24 hours by incubation of the injured a rterial segments with the chromogenic substrate S-2222, was decreased more markedly on arteries from rTFPI-treated animals (0.14+/-0.13 OD) than those from heparin-treated animals (0.29+/-0.18 OD) compared with controls (0.47 +/-0.24 OD, P=0.0007), In addition, arteries from rTFPI-treated animals sho wed a I-fold lower induction of tissue factor protein compared with control s (P=0.0002), Attenuation of procoagulant activity and tissue factor-mediat ed thrombin generation in response to injury may account for the promising results with rTFPI in the porcine angioplasty model.