Tissue Factor Mediates Prolonged Procoagulant Activity on the Luminal Surface of Balloon-Injured Aortas in Rabbits

Abstract

Background Activation of coagulation has been implicated in both acute thrombotic occlusion and restenosis after balloon angioplasty. However, concomitant administration of antithrombotic agents has thus far failed to prevent these complications. Importantly, the factors contributing to procoagulant activity of balloon-injured arteries over time have not been defined. This study was designed to determine the duration of procoagulant activity on the luminal surface of balloon-injured arteries and the relative roles of tissue factor and thrombin in this response. Methods and Results Abdominal aortas in rabbits were subjected to repetitive balloon hyperinflations sufficient to disrupt the internal elastic lamina. Aortas were excised at <1, 2, 4, 8, 16, 24, 48, and 72 hours and 1, 2, and 4 weeks after injury; divided into segments; and perfused with recalcified human pooled plasma (n=58) or plasma depleted of vitamin K–dependent coagulation factors (n=27) or first incubated with a monoclonal antibody to rabbit tissue factor (n=33) followed by perfusion with human plasma. Samples of the effluent and plasma perfusate were collected over 10 minutes and assayed for fibrinopeptide A (FPA) as an index of the rate of thrombin-induced fibrin formation. FPA in the effluent from segments perfused with recalcified plasma, expressed as a percentage of FPA in the perfusate, was elevated for 16 hours after balloon-induced injury and exhibited two distinct increases occurring <1 hour (1297±473%, mean±SD, n=5) and 8 hours (1052±330%, n=6) after injury ( P ≤.000001 versus uninjured vessels). Preincubation of segments at these intervals with an antibody to tissue factor markedly attenuated the increases in FPA, as did perfusion of segments with plasma depleted of vitamin K–dependent coagulation factors, indicating that the observed increases in FPA in whole plasma did not result from preformed thrombin bound to the injured vessel wall. Conclusions Tissue factor–mediated coagulation appears to be primarily responsible for prolonged procoagulant activity of balloon-injured arteries.