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EXPERIMENTAL STUDY

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

Paolo Golino, MD, PhD^*, Plinio Cirillo, MD^*, Paolo Calabro’, MD^*, Massimo Ragni, MD^*, Davide D’Andrea, MD, Enrico V. Avvedimento, MD, Francesco Vigorito, MD^*, Nicola Corcione, MD^*, Francesco Loffredo, BS^* and Massimo Chiariello, MD^*

^* Department of Internal Medicine, Division of Cardiology, University of Naples "Federico II," Naples, Italy
Department of Experimental Medicine, School of Medicine at Catanzaro, University of Reggio Calabria, Italy

Manuscript received July 28, 2000; revised manuscript received April 2, 2001, accepted April 11, 2001.

Reprint requests and correspondence: Dr. Paolo Golino, Division of Cardiology, University of Naples "Federico II," via Sergio Pansini 5, 80131 Naples, Italy
golino{at}unina.it

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.

Abbreviations and Acronyms   CFV = cyclic flow variation   DMEM = Dulbecco’s modified Eagles medium   GFP = green fluorescent protein   PBS = phosphate-buffered saline   PCR = polymerase chain reaction   PT = prothrombin time   PTT = partial thromboplastin time   SMC = smooth muscle cell   rtTA = reverse tetracycline-controlled transactivator   (TF)PI = (tissue factor) pathway inhibitor

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