Structure and biology of tissue factor pathway inhibitor

Human tissue factor pathway inhibitor (TFPI) is a modular protein comprised of three Kunitz type domains flanked by peptide segments that are less str uctured. The sequential order of the elements are: an N-terminal acidic reg ion followed by the first Kunitz domain ( K1), a linker region, a second Ku nitz domain (K2), a second linker region, the third Kunitz domain (K3), and the C-terminal basic region. The KI domain inhibits factor VIIa complexed to tissue factor (TF) while the K2 domain inhibits factor Xa. No direct pro tease inhibiting functions have been demonstrated for the K3 domain. Import antly, the Xa-TFPI complex is a much more potent inhibitor of the VIIa-TF t han TFPI by itself. Furthermore, the C-terminal basic region of TFPI is req uired for rapid physiologic inhibition of coagulation and is needed for the inhibition of smooth muscle cell proliferation. Although a number of addit ional targets for attachment have been reported, the C-terminal basic regio n appears to play an important role in binding of TFPI to cell surfaces. A primary site of TFPI synthesis is endothelium and the endothelium-bound TFP I contributes to the antithrombotic potential of the vascular endothelium. Further, increased levels of plasma TFPI under septic conditions may repres ent endothelial dysfunction. We have proposed that the extravascular cells that synthesize TF also synthesize TFPI providing dual components necessary for the regulation of clotting in their microenvironment. Like the TF synt hesis in these cells is augmented by serum, so is the case with the TFPI ge ne expression, TFPI gene knock out mice reveal embryonic lethality suggesti ng a possible role of this protein in early development. Since TF-induced c oagulation is thought to play a significant role in many disease states, in cluding disseminated intravascular clotting, sepsis, acute lung injury and cancer, recombinant TFPI may be a beneficial therapeutic agent in these dis ease states to attenuate pathologic clotting. The purpose of this review is to outline recent developments in the field related to the structural spec ificity and biology of TFPI.