Expression of exogenous tissue factor pathway inhibitor in vivo suppressesthrombus formation in injured rabbit carotid arteries

OBJECTIVES The aim of the present study was to test the hypothesis that ret rovirus-mediated in vivo tissue factor pathway inhibitor {TFPI) gene transf er to the arterial wall would efficiently inhibit thrombosis without causin g significant changes in systemic hemostatic variables. BACKGROUND Acute coronary syndromes (unstable angina and acute myocardial i nfarction) are usually caused by atherosclerotic plaque rupture, with conse quent activation of the coagulation cascade and circulating platelets. Tiss ue Factor (TF) exposure represents an early event in this pathophysiologic sequence, leading to activation of the extrinsic coagulation pathway and th rombin 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 tr ansfect rabbit carotid arteries with either TFPI or a reporter gene-green f luorescent protein (GFP). RESULTS Retroviral-mediated arterial gene transfer of TFPI resulted in pote nt inhibition of intravascular thrombus formation in stenotic and injured r abbit carotid arteries, whereas transfection of the contralateral carotid a rtery with GFP had no effect on thrombosis. No significant changes in syste mic 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 tre atment of thrombotic disorders. (J Am Coll Cardiol 2001;38:569-76) (C) 2001 by the American College of Cardiology.