Regulation of functions of vascular wall cells by tissue factor pathway inhibitor: basic and clinical aspects

Tissue factor pathway inhibitor (TFPI) is a Kunitz-type protease inhibitor that inhibits the initial reactions of blood coagulation. A major pool of TFPI is the form associated with the surface of endothelial cells, which is speculated to play an important role in regulating the functions of vascular wall cells. TFPI consists of 3 tandem Kunitz inhibitor domains, the first and second of which inhibit the tissue factor-factor VIIa complex and factor Xa, respectively. Recent findings indicate that TFPI has another function, ie, the modulation of cell proliferation. This function is based on the interaction of the C-terminal region of TFPI with these cells. In addition to endothelial cells, it has been shown that many other vascular wall cells can synthesize TFPI, eg, mesangial cells, smooth muscle cells, monocytes, fibroblasts, and cardiomyocytes. TFPI is associated with these cells mainly through heparan sulfate proteoglycans on their surface. However, recent findings suggest that there are several other candidates for TFPI-binding proteins on these cells. On the other hand, studies on plasma levels of TFPI in patients with various diseases suggest that TFPI may be a marker of endothelial cell dysfunction. An increasing number of reports suggest that recombinant TFPI may attenuate thrombosis and prevent restenosis. Clinical trials are needed to explore these possibilities. Recent reports also indicate that the application of recombinant TFPI or TFPI gene transfer prevents restenosis in addition to thrombosis after arterial injury in the animal model; corroboration of these reports awaits clinical investigation.