Adenovirus-mediated local expression of human tissue factor pathway inhibitor eliminates shear stress-induced recurrent thrombosis in the injured carotid artery of the rabbit

The main cause of acute coronary syndrome may be recurrent thrombosis, whic h is initiated by the activation of the extrinsic coagulation pathway. Tiss ue factor (TF) pathway inhibitor (TFPI) efficiently inhibits an early step in this pathway by the formation of a complex with factor Wa, TF, and facto r Xa. We determined whether local TFPI gene transfer can inhibit thrombosis in an injured artery without inducing systemic side effects. Balloon-injur ed rabbit carotid arteries were infected with an adenoviral vector that exp ressed either human TFPI (AdCATFPI) or bacterial P-galactosidase (AdCALacZ) . Two to 6 days after gene transfer, thrombosis was induced by the producti on of constant stenosis of the artery, and blood flow was measured continuo usly with an electromagnetic flow probe. A cyclic flow variation, which is thought to reflect the recurrent formation and dislodgment of mural thrombi , was observed in all AdCALacZ-infected arteries as well as in saline-infus ed arteries. In contrast, no cyclic flow variation was detectable in AdCATF PI-transfected arteries, even in the presence of epinephrine (1 mu g, kg(-1 ) min(-1) infusion). Prothrombin time, activated partial thromboplastin tim e, and the ex vivo platelet aggregation induced by either adenosine diphosp hate or collagen were unaltered in AdCATFPI,infected rabbits. We found that in vivo TFPI gene transfer into an injured artery completely inhibits the recurrent thrombosis induced by shear stress even in the presence of catech olamine, without affecting systemic coagulation status. Adenovirus-mediated local expression of TFPI may have the potential for the treatment of human thrombosis.