Combination of a brief irrigation with tissue factor pathway inhibitor (TFPI) and adenovirus-mediated local TFPI gene transfer additively reduces neointima formation in balloon-injured rabbit carotid arteries

Background-Tissue factor pathway inhibitor (TFPI) is a physiological antago nist of TF. We tested whether a brief irrigation with TFPI protein (rTFPI) or TFPI gene transfer into injured arteries would suppress TF activity and reduce fibroproliferative changes and investigated whether a combination of these methods would show an additive effect. Methods and Results-We prepared adenoviruses expressing either TFPI (AdTFPI ) or bacterial beta -galactosidase (AdLacZ). Rabbit carotid arteries were b alloon-injured and either infected with AdTFPI (or AdLacZ) or irrigated bri efly with rTFPI (or saline). After injury, TF activity in arteries increase d and was sustained; however, it was suppressed during the initial 24 hours by rTFPI irrigation (but not by gene transfer) and for a substantial perio d of time by TFPI gene transfer (but not by rTFPI irrigation). Four weeks l ater, the ratio of the intimal to medial areas was 34.3+/-8.7% (mean+/-SD, n = 14) in saline-treated arteries and 33.3+/-4.2% in AdLacZ-infected arter ies (P = NS versus saline). However, it was reduced to 25.5+/-8.5% in rTFPI -irrigated arteries (P<0.01 versus saline) and to 20.7+/-5.3% in AdTFPI-inf ected arteries (P<0.01 versus AdLacZ). With a combination of irrigation and gene transfer, the ratio was further reduced to 12.6+/-4.7% (P<0.01 versus rTFPI, P<0.05 versus AdTFPI). Systemic coagulation status was not affected in these animals. Conclusions-A combination of rTFPI irrigation and TFPI gene transfer overco mes the shortcomings shown by each method when used alone and achieves a fu ll coverage of TF activity suppression, thereby enhancing their therapeutic effects without systemic side effects. This combination may be an effectiv e strategy for the prevention of thrombosis and proliferative changes after angioplasty in humans.