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Gene Review

TFPI  -  tissue factor pathway inhibitor...

Homo sapiens

Synonyms: EPI, Extrinsic pathway inhibitor, LACI, Lipoprotein-associated coagulation inhibitor, TFI, ...
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Disease relevance of TFPI


Psychiatry related information on TFPI


High impact information on TFPI


Chemical compound and disease context of TFPI


Biological context of TFPI

  • Tissue factor pathway inhibitor (TFPI) is a Kunitz-type serine proteinase inhibitor that down-regulates tissue factor-initiated blood coagulation [17].
  • Proposed cellular binding sites for TFPI include nonspecific association with cell surface glycosaminoglycans and binding to glycosyl phosphatidylinositol-anchored proteins [17].
  • We investigated the localisation, gene expression, and activity of tissue factor pathway inhibitor (TFPI) in endothelial cells (EC) grown in static conditions or under shear stress, in the presence of unfractionated heparin (UFH) and two low-molecular-weight heparins (LMWHs). dalteparin and bemiparin (a second generation of LMWHs) [18].
  • In parallel we could document EC expression of TF, downregulation of TM and depletion of tissue factor pathway inhibitor (TFPI) in inflamed areas [19].
  • In 171 controls and 49 cases in whom blood was taken at least three months after the thrombotic event, the CC genotype was associated with significantly higher total TFPI levels than the TT genotype [20].

Anatomical context of TFPI

  • The most biologically active pool of TFPI is associated with the vascular endothelium, however, the biochemical mechanisms responsible for its cellular binding are not entirely defined [17].
  • Co-localization of MMPs, TF, and TFPI in atherosclerotic tissues suggests that release of MMPs from inflammatory cell leukocytes may effect TF-mediated coagulation [21].
  • We recently reported that recombinant tissue factor pathway inhibitor (r-TFPI), an important inhibitor of the extrinsic pathway of the coagulation system, inhibits TNF-alpha production by monocytes [12].
  • TF and TFPI mRNA expression, protein levels and activity were determined and compared to human umbilical vein endothelial cells (HUVEC) [22].
  • To evaluate the effects of LMWH, tinzaparin, and TFPI in a model of angiogenesis-mediated processes, we compared the effects of tinzaparin, and recombinant TFPI in inhibiting either basic fibroblast growth factor-2 (FGF2)- or TF/fVIIa-induced endothelial cell tube formation in human umbilical vein endothelial cells (HUVEC) [23].

Associations of TFPI with chemical compounds

  • Binding experiments done in the presence of heparin and with altered forms of TFPI suggest that the basic C-terminal region of TFPI is required for TSP-1 binding [17].
  • The patients had lower preheparin free TFPI and lower HDL cholesterol (HDL-C) levels than the healthy subjects with equivalent Lp-bound forms (free TFPI, 15. 9+/-6.5 versus 19.2+/-8.1 ng/mL) [24].
  • Tissue Factor Pathway Inhibitor (TFPI) is a 36 kDa glycoprotein that helps maintain haemostasis by inhibiting Factor Xa and the Factor VIIa/Tissue Factor (TF) complex [3].
  • It is possible that negatively charged n-butyric acid is sequestered by the positively charged peptide or the basic region of recombinant full length TFPI [25].
  • When rTFPI was incubated with purified oxononanoyl PC (9CHO-PC) and its carboxylic form (9COOH-PC), the catalytic activity was specifically impaired, though neither oxovaleroyl PC (5CHO-PC) nor lyso-phospholipids reduced the TFPI activity [26].

Physical interactions of TFPI

  • Here, we report that TFPI binds specifically and saturably to thrombospondin-1 (TSP-1) purified from platelet alpha-granules with an apparent K(D) of approximately 7.5 nm [17].
  • (125)I-factor Xa ligand blots of TFPI fragments generated following MMP-8 degradation were used for probing binding interactions between factor Xa and regions of TFPI, other than the second Kunitz domain [27].
  • The activation of factor X by VIIa/TF and the Xa-dependent inhibition of the enzyme complex by tissue factor pathway inhibitor (TFPI) are considered primary steps in the initiation of coagulation [28].
  • The masking of the mutational effect by the presence of phospholipid shows a critical importance of Xa Gla-domain interactions in stabilizing the quaternary TF-VIIa-Xa-TFPI complex [29].
  • Here, we studied whether the three GATA motifs flanking the transcription initiation sites regulate TFPI gene expression in HepG2 and ECV304 cells by binding to the GATA-2 transcription factor [30].

Enzymatic interactions of TFPI

  • MMP-7 (matrilysin) rapidly cleaved TFPI to a major 35-kDa product [21].
  • NH(2)-terminal amino acid sequencing revealed that MMP-12 cleaved TFPI at Lys(20)-Leu(21)(close to Kunitz I domain and producing a 35-kDa band), Arg(83)-Ile(84) (between Kunitz I and II domains), and Ser(174)-Thr(175) (between Kunitz II and III domains) [21].
  • MMP-7 and MMP-9 cleaved TFPI at Lys(20)-Leu(21) with additional COOH-terminal processing [21].
  • MMP-8 cleaves TFPI following Ser(174) within the connecting region between the second and third Kunitz domains ( k (cat)/ K (m) approximately 75 M(-1).s(-1)) as well as following Lys(20) within the NH(2)-terminal region [27].
  • Neutrophil elastase rapidly cleaved TFPI at the Thr87-Thr88 bond situated at the link between Kunitz domains I and II [31].

Co-localisations of TFPI

  • In atherosclerotic vessels, TFPI protein and mRNA frequently colocalized with TF in ECs overlying the plaque and in microvessels, as well as in the medial and neointimal SMCs, and in macrophages and T cells in areas surrounding the necrotic core [32].
  • TFPI also colocalized with antibodies to the human transferrin receptor, a marker for early endocytic, recycling compartment [33].

Regulatory relationships of TFPI

  • Binding is inhibited by polyclonal antibodies against TFPI and partially inhibited by the B-7 monoclonal anti-TSP-1 antibody [17].
  • HLE treatment not only affects the ability of TFPI to inhibit factor VIIa/TF, but also dramatically reduces its inhibition of factor Xa [34].
  • Our results show that tinzaparin and recombinant TFPI both blocked endothelial tube formation induced by either FGF2 or TF/fVIIa, in a concentration-dependent manner [23].
  • LPL-induced hydrolysis of VLDL in vitro was not influenced by TFPI neither in suspension nor at the endothelial surface [35].
  • Conversely, formation of a factor Xa/TFPI complex may reduce or modulate the proteolytic potential of stimulated leukocytes by temporary inhibition of cathepsin G [31].

Other interactions of TFPI

  • Recombinant full-length tissue factor pathway inhibitor (RTFPI) was included in the system because of a previously observed synergistic inhibitory effect of TFPI and the protein C pathway on TF-initiated thrombin generation [36].
  • ICAM1, TM and TFPI were elevated in cerebral SVD subjects compared with controls (P <or= 0.006) [2].
  • We conclude that the imbalances of PAI-I/tPA and TF/TFPI are significantly associated with MI at a young age, perhaps mediated via impaired fibrinolytic activity [37].
  • We have investigated the effect of MMP-8 degradation on the anticoagulant function of tissue factor pathway inhibitor (TFPI) as a potential pathological mechanism contributing to coagulation disorders [27].
  • However, we speculate that the anticoagulant efficacy of rhAPC is impaired in neonates and in clinical situations associated with consumption and/or inhibition of PS, AT, and TFPI, such as severe sepsis [38].

Analytical, diagnostic and therapeutic context of TFPI


  1. Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor. Hackeng, T.M., Seré, K.M., Tans, G., Rosing, J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  2. Markers of endothelial dysfunction in lacunar infarction and ischaemic leukoaraiosis. Hassan, A., Hunt, B.J., O'Sullivan, M., Parmar, K., Bamford, J.M., Briley, D., Brown, M.M., Thomas, D.J., Markus, H.S. Brain (2003) [Pubmed]
  3. The second Kunitz domain of human tissue factor pathway inhibitor: cloning, structure determination and interaction with factor Xa. Burgering, M.J., Orbons, L.P., van der Doelen, A., Mulders, J., Theunissen, H.J., Grootenhuis, P.D., Bode, W., Huber, R., Stubbs, M.T. J. Mol. Biol. (1997) [Pubmed]
  4. Tissue factor pathway inhibitor and the risk of recurrent venous thromboembolism. Hoke, M., Kyrle, P.A., Minar, E., Bialonzcyk, C., Hirschl, M., Schneider, B., Kollars, M., Weltermann, A., Eichinger, S. Thromb. Haemost. (2005) [Pubmed]
  5. Decreased plasma tissue factor pathway inhibitor levels in patients with thrombotic thrombocytopenic purpura. Kobayashi, M., Wada, H., Wakita, Y., Shimura, M., Nakase, T., Hiyoyama, K., Nagaya, S., Minami, N., Nakano, T., Shiku, H. Thromb. Haemost. (1995) [Pubmed]
  6. Sepsis-induced coagulation in the baboon lung is associated with decreased tissue factor pathway inhibitor. Tang, H., Ivanciu, L., Popescu, N., Peer, G., Hack, E., Lupu, C., Taylor, F.B., Lupu, F. Am. J. Pathol. (2007) [Pubmed]
  7. The anticoagulant effect in heparinized blood and plasma resulting from interactions with extrinsic pathway inhibitor. Lindahl, A.K., Abildgaard, U., Staalesen, R. Thromb. Res. (1991) [Pubmed]
  8. Immunohistochemical localization of tissue factor pathway inhibitor-1 (TFPI-1), a Kunitz proteinase inhibitor, in Alzheimer's disease. Hollister, R.D., Kisiel, W., Hyman, B.T. Brain Res. (1996) [Pubmed]
  9. Functional significance of the Kunitz-type inhibitory domains of lipoprotein-associated coagulation inhibitor. Girard, T.J., Warren, L.A., Novotny, W.F., Likert, K.M., Brown, S.G., Miletich, J.P., Broze, G.J. Nature (1989) [Pubmed]
  10. Simultaneous expression of tissue factor and tissue factor pathway inhibitor by human monocytes. A potential mechanism for localized control of blood coagulation. McGee, M.P., Foster, S., Wang, X. J. Exp. Med. (1994) [Pubmed]
  11. Tumor cell adhesion and migration supported by interaction of a receptor-protease complex with its inhibitor. Fischer, E.G., Riewald, M., Huang, H.Y., Miyagi, Y., Kubota, Y., Mueller, B.M., Ruf, W. J. Clin. Invest. (1999) [Pubmed]
  12. Recombinant tissue factor pathway inhibitor prevents lipopolysaccharide-induced systemic hypotension in rats by inhibiting excessive production of nitric oxide. Enkhbaatar, P., Okajima, K., Uchiba, M., Isobe, H., Okabe, H. Thromb. Haemost. (2001) [Pubmed]
  13. Antithrombotics in thrombosis and cancer. Mousa, S.A. Hamostaseologie (2005) [Pubmed]
  14. Inhibition of tissue factor reduces thrombus formation and intimal hyperplasia after porcine coronary angioplasty. Roqué, M., Reis, E.D., Fuster, V., Padurean, A., Fallon, J.T., Taubman, M.B., Chesebro, J.H., Badimon, J.J. J. Am. Coll. Cardiol. (2000) [Pubmed]
  15. Tissue factor production not balanced by tissue factor pathway inhibitor in sepsis promotes poor prognosis. Gando, S., Kameue, T., Morimoto, Y., Matsuda, N., Hayakawa, M., Kemmotsu, O. Crit. Care Med. (2002) [Pubmed]
  16. Treatment of symptomatic patients with essential thrombocythemia: effectiveness of anagrelide. Cacciola, R.R., Cipolla, A., Di Francesco, E., Giustolisi, R., Cacciola, E. Am. J. Hematol. (2005) [Pubmed]
  17. Tissue factor pathway inhibitor binds to platelet thrombospondin-1. Mast, A.E., Stadanlick, J.E., Lockett, J.M., Dietzen, D.J., Hasty, K.A., Hall, C.L. J. Biol. Chem. (2000) [Pubmed]
  18. Bemiparin and fluid flow modulate the expression, activity and release of tissue factor pathway inhibitor in human endothelial cells in vitro. Westmuckett, A.D., Kakkar, V.V., Hamuro, T., Lupu, F., Lupu, C. Thromb. Haemost. (2001) [Pubmed]
  19. Effect of intradermal tumor necrosis factor-alpha-induced inflammation on coagulation factors in dermal vessel endothelium. An in vivo study of human skin biopsies. Speiser, W., Kapiotis, S., Kopp, C.W., Simonitsch, I., Jilma, B., Jansen, B., Exner, M., Chott, A. Thromb. Haemost. (2001) [Pubmed]
  20. The -33T-->C polymorphism in intron 7 of the TFPI gene influences the risk of venous thromboembolism, independently of the factor V Leiden and prothrombin mutations. Ameziane, N., Seguin, C., Borgel, D., Fumeron, F., Moatti, D., Alhenc-Gelas, M., Grandchamp, B., Aiach, M., Emmerich, J., de Prost, D. Thromb. Haemost. (2002) [Pubmed]
  21. Matrix metalloproteinases cleave tissue factor pathway inhibitor. Effects on coagulation. Belaaouaj, A.A., Li, A., Wun, T.C., Welgus, H.G., Shapiro, S.D. J. Biol. Chem. (2000) [Pubmed]
  22. Tissue factor and tissue factor pathway inhibitor levels in trophoblast cells: implications for placental hemostasis. Aharon, A., Brenner, B., Katz, T., Miyagi, Y., Lanir, N. Thromb. Haemost. (2004) [Pubmed]
  23. Inhibition of endothelial cell tube formation by the low molecular weight heparin, tinzaparin, is mediated by tissue factor pathway inhibitor. Mousa, S.A., Mohamed, S. Thromb. Haemost. (2004) [Pubmed]
  24. Intravascular free tissue factor pathway inhibitor is inversely correlated with HDL cholesterol and postheparin lipoprotein lipase but proportional to apolipoprotein A-II. Kawaguchi, A., Miyao, Y., Noguchi, T., Nonogi, H., Yamagishi, M., Miyatake, K., Kamikubo, Y., Kumeda, K., Tsushima, M., Yamamoto, A., Kato, H. Arterioscler. Thromb. Vasc. Biol. (2000) [Pubmed]
  25. Enhancement of lipoprotein lipase activity by tissue factor pathway inhibitor. Mukherjee, M., Kakkar, V.V. Thromb. Haemost. (1999) [Pubmed]
  26. Oxidation products of phospholipid-containing delta-9 fatty acids specifically impair the activity of tissue factor pathway inhibitor. Hiraishi, S., Horie, S., Seyama, Y. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  27. Structural and functional characterization of tissue factor pathway inhibitor following degradation by matrix metalloproteinase-8. Cunningham, A.C., Hasty, K.A., Enghild, J.J., Mast, A.E. Biochem. J. (2002) [Pubmed]
  28. Formation of factors IXa and Xa by the extrinsic pathway: differential regulation by tissue factor pathway inhibitor and antithrombin III. Lu, G., Broze, G.J., Krishnaswamy, S. J. Biol. Chem. (2004) [Pubmed]
  29. The role of catalytic cleft and exosite residues of factor VIIa for complex formation with tissue factor pathway inhibitor. Iakhiaev, A., Ruf, W., Rao, L.V. Thromb. Haemost. (2001) [Pubmed]
  30. Role of GATA motifs in tissue factor pathway inhibitor gene expression in malignant cells. Bajaj, M.S., Tyson, D.R., Steer, S.A., Kuppuswamy, M.N. Thromb. Res. (2001) [Pubmed]
  31. Effect of leukocyte proteinases on tissue factor pathway inhibitor. Petersen, L.C., Bjørn, S.E., Nordfang, O. Thromb. Haemost. (1992) [Pubmed]
  32. Expression, localization, and activity of tissue factor pathway inhibitor in normal and atherosclerotic human vessels. Crawley, J., Lupu, F., Westmuckett, A.D., Severs, N.J., Kakkar, V.V., Lupu, C. Arterioscler. Thromb. Vasc. Biol. (2000) [Pubmed]
  33. Association of tissue factor pathway inhibitor with human umbilical vein endothelial cells. Hansen, J.B., Olsen, R., Webster, P. Blood (1997) [Pubmed]
  34. The effect of leukocyte elastase on tissue factor pathway inhibitor. Higuchi, D.A., Wun, T.C., Likert, K.M., Broze, G.J. Blood (1992) [Pubmed]
  35. Impact of native VLDL on tissue factor pathway inhibitor in endothelial cells and interactions between TFPI and lipoprotein lipase. Brodin, E., Iversen, N., Hansen, J.B. J. Lab. Clin. Med. (2006) [Pubmed]
  36. Increased tissue factor-initiated prothrombin activation as a result of the Arg506 --> Gln mutation in factor VLEIDEN. van 't Veer, C., Kalafatis, M., Bertina, R.M., Simioni, P., Mann, K.G. J. Biol. Chem. (1997) [Pubmed]
  37. Imbalance of plasminogen activator inhibitor-I/ tissue plasminogen activator and tissue factor/tissue factor pathway inhibitor in young Japanese men with myocardial infarction. Saigo, M., Abe, S., Ogawa, M., Yamashita, T., Biro, S., Minagoe, S., Maruyama, I., Tei, C. Thromb. Haemost. (2001) [Pubmed]
  38. Protein S modulates the anticoagulant action of recombinant human activated protein C: a comparison between neonates and adults. Cvirn, G., Koestenberger, M., Leschnik, B., Male, C., Kutschera, J., Ferstl, U., Muntean, W., Juergens, G., Gallistl, S. Br. J. Pharmacol. (2005) [Pubmed]
  39. Does human semen contain a functional haemostatic system? A possible role for Tissue Factor Pathway Inhibitor in fertility through semen liquefaction. Lwaleed, B.A., Greenfield, R.S., Birch, B.R., Cooper, A.J. Thromb. Haemost. (2005) [Pubmed]
  40. Oxidized low-density lipoprotein associates strongly with carboxy-terminal domain of tissue factor pathway inhibitor and reduces the catalytic activity of the protein. Horie, S., Hiraishi, S., Hamuro, T., Kamikubo, Y., Matsuda, J. Thromb. Haemost. (2002) [Pubmed]
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