A MONOCLONAL-ANTIBODY AGAINST RABBIT-TISSUE FACTOR INHIBITS THROMBUS FORMATION IN STENOTIC INJURED RABBIT CAROTID ARTERIES

Tissue factor (TF) is a transmembrane protein that binds factor VII/VI Ia, thus activating the extrinsic blood coagulation pathway. Since thi s pathway appears to be involved in the formation of intravascular thr ombi, the anti-rabbit TF monoclonal antibody, AP-1, was produced and t ested as an antithrombotic agent in a rabbit model of recurrent intrav ascular thrombosis. In this model, a plastic constrictor is positioned around the injured rabbit carotid arteries, and flow is monitored wit h a Doppler flow probe. This produces cyclic flow variation (CFV) in t he carotid artery, which is caused by recurrent formation and dislodgm ent of thrombi at the site of the stenosis. After monitoring CFV patte rn for 30 minutes, AP-1 was infused intravenously into nine rabbits at doses of 0.05 to 1.5 mg/kg body weight, and a control monoclonal anti body that does not react with rabbit TF was infused into four addition al rabbits. In all rabbits receiving AP-1, CFV was abolished, and a st eady normal blood flow was restored, indicating that thrombus formatio n had been blocked by AP-1. By contrast, in all rabbits that received the control monoclonal antibody, CFV continued unaltered, There was no change in the partial thromboplastin time and ex vivo platelet aggreg ation to several different agonists after infusion of AP-1, indicating an absence of systemic effects on the coagulation process. We conclud e that activation of the extrinsic coagulation pathway has a key role in triggering intravascular thrombosis and that an anti-TF monoclonal antibody is an effective antithrombotic agent that could have therapeu tic potential for humans.