Balloon angioplasty is limited by early thrombotic occlusion and accelerated restenosis. Activation of coagulation has been implicated in these complications, but specific mediators have not ben elucidated. This research is designed to define the time after vessel injury that the luminal surface remains procoagulant, to define determinants of procoagulant activity associated with the site of injury and their changes with time, and to determine whether agents that inhibit the activity of procoagulant moieties can accelerate passivation of the luminal surface (i.e., induce a nonthrombogenic surface) and thereby alter vascular remodeling leading to decreased stenosis. In this extensively revised and focused proposal, all experiments will be conducted in pigs because their response to vascular injury and coagulation system resemble most closely those in humans. To observe the time course of passivation of vascular lesions, the carotid arteries of pigs will be injured by balloon hyperinflations and the procoagulant activity and factors responsible for its induction will be assessed at intervals from <1 h to 48 h or longer after the vascular insult by perfusion of excised vessel segments with recalcified porcine plasma and measurement of the rate of fibrin formation in the eluant as an index of activation of the coagulation system, by direct characterization of the functional activity of coagulation factors on the luminal surface of the injured vessel with use of chromogenic substrates, by analysis of expression of tissue factor mRNA in the vessel wall, and by detection of the cellular distribution of tissue factor with use of immunohistochemistry. The extent of in vivo thrombus formation at the site of injury will be quantified as well by intravenous administration of radiolabeled platelets and fibrinogen and counting the radioactivity bound to the excised. vessel. Antithrombotic agents targeted to the moieties identified will be administered in other pigs and the effects of vessel procoagulant activity assessed. Approaches shown to accelerate vessel passivation will be tested in minipigs with balloon-induced injury of the carotid and coronary arteries to determine their effect on neointimal proliferation and stenosis after 4 wk and in minipigs with angioplasty of plaque-like lesions induced previously to determine the effect on restenosis in a preparation that mimics human pathophysiology. Because procoagulant activity may differ depending on macrophage and cholesterol enrichment of lesions, experiments are planned in the setting of both low and high serum cholesterol levels. Results obtained should clarify the role of specific mediator of coagulation in the response to vessel injury, define the interval of inhibition of specific moieties required to potentiate passivation of injured vessel walls, and ultimately lead to more effective pharmacologic prevention of restenosis in patients.
| Martin, D J; Toce, J A; Anevski, P J et al. (1999) Anticoagulant and antithrombotic activity of maltodapoh, a novel sulfated tetrasaccharide. J Pharmacol Exp Ther 288:516-21 |
| Yang, L Y; St Pierre, J; Scherrer, D E et al. (1999) Comparison of methods for local delivery of tissue factor pathway inhibitor to balloon-injured arteries in rabbits. Coron Artery Dis 10:327-33 |
| St Pierre, J; Yang, L Y; Tamirisa, K et al. (1999) Tissue factor pathway inhibitor attenuates procoagulant activity and upregulation of tissue factor at the site of balloon-induced arterial injury in pigs. Arterioscler Thromb Vasc Biol 19:2263-8 |
