Anti-inflammatory effects of long-lasting locally-delivered human recombinant tissue factor pathway inhibitor after balloon angioplasty

Abstract

Background Tissue factor pathway inhibitor (TFPI) has anti-proliferative and anti-migratory effects on cultured smooth muscle cells (SMC) in addition to its anti-thrombotic activity. Here, we assess how long locally delivered recombinant TFPI (rTFPI) remains detectable at the delivery sites and clarify the main mechanism by which rTFPI blocks neointimal growth in vivo. Methods The iliac arteries of 85 Japanese white rabbits were injured using a Cutting Balloon™. First, to establish the efficacy of local delivery of rTFPI, 5 groups of 3 rabbits each were examined immediately or 1, 2, 4 or 7 days after delivery. They were treated locally with a total amount of 200 μg of rTFPI given at 40 μg per pulse per minute by means of a Pulse Spray™ catheter. Thereafter, 34 rabbits which had received 200 μg of rTFPI after cutting angioplasty were compared to the same number of controls regarding thrombosis, inhibition of neointimal proliferation and inflammation. Results A total of 2.6 ± 1.6 ng rTFPI persisted on the injured vessel 4 days after delivery. rTFPI was still present on 48 % of the cut sites 7 days after delivery, despite its short half-life in plasma. Thrombosis in the rTFPI-treated group was significantly reduced compared to the controls. The number of macrophages present within the media and intima was significantly decreased at day 7 after delivery of rTFPI. Furthermore, the number of Ki-67-positive cells 14 days after rTFPI delivery was significantly lower than in controls although there were no significant differences between them after 2 days. Conclusions Local delivery of rTFPI decreased the degree of neointimal formation 4 weeks after TFPI delivery because of anti-inflammatory and anti-proliferative effects in addition to, or rather than, via anti-thrombosis.