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OBJECTIVES The aim of the present study was to test the hypothesis that retrovirus-mediated in vivo tissue factor pathway inhibitor {TFPI) gene transfer to the arterial wall would efficiently inhibit thrombosis without causing significant changes in systemic hemostatic variables. BACKGROUND Acute coronary syndromes (unstable angina and acute myocardial infarction) are usually caused by atherosclerotic plaque rupture, with consequent activation of the coagulation cascade and circulating platelets. Tissue Factor (TF) exposure represents an early event in this pathophysiologic sequence, leading to activation of the extrinsic coagulation pathway and thrombin formation. Tissue factor pathway inhibitor is a naturally occurring inhibitor of the extrinsic pathway. METHODS In the present study, the gene coding for rabbit TFPI was inserted in a retroviral vector under control of a tetracycline-inducible promoter. Replication-defective, infectious, recombinant retroviruses were used to transfect rabbit carotid arteries with either TFPI or a reporter gene-green fluorescent protein (GFP). RESULTS Retroviral-mediated arterial gene transfer of TFPI resulted in potent inhibition of intravascular thrombus formation in stenotic and injured rabbit carotid arteries, whereas transfection of the contralateral carotid artery with GFP had no effect on thrombosis. No significant changes in systemic hemostatic variables {prothrombin time and partial thromboplastin time) were observed when thrombosis was inhibited. CONCLUSIONS These data suggest that retroviral-mediated transfection of the arterial wall with TFPI might represent an attractive approach for the treatment of thrombotic disorders. (J Am Coll Cardiol 2001;38:569-76) (C) 2001 by the American College of Cardiology.