Thromb Haemost 2001; 86(04): 959-972
DOI: 10.1055/s-0037-1616518
Review Article
Schattauer GmbH

Structure and Biology of Tissue Factor Pathway Inhibitor

Madhu S. Bajaj
1   Department of Internal Medicine, Saint Louis University School of Medicine, New York, NY
,
Jens J. Birktoft
2   X-tal Designs, New York, NY
,
Sarah A. Steer
1   Department of Internal Medicine, Saint Louis University School of Medicine, New York, NY
,
S. Paul Bajaj
1   Department of Internal Medicine, Saint Louis University School of Medicine, New York, NY
3   Departments of Pathology and Pharmacological and Physiological Sciences, Saint Louis University School of Medicine, Saint Louis, MO, USA
› Author Affiliations
Further Information

Publication History

Received 29 December 2001

Accepted after revision 19 June 2001

Publication Date:
09 December 2017 (online)

Summary

Human tissue factor pathway inhibitor (TFPI) is a modular protein comprised of three Kunitz type domains flanked by peptide segments that are less structured. The sequential order of the elements are: an N-terminal acidic region followed by the first Kunitz domain (K1), a linker region, a second Kunitz domain (K2), a second linker region, the third Kunitz domain (K3), and the C-terminal basic region. The K1 domain inhibits factor VIIa complexed to tissue factor (TF) while the K2 domain inhibits factor Xa. No direct protease inhibiting functions have been demonstrated for the K3 domain. Importantly, the Xa-TFPI complex is a much more potent inhibitor of the VIIa-TF than TFPI by itself. Furthermore, the C-terminal basic region of TFPI is required for rapid physiologic inhibition of coagulation and is needed for the inhibition of smooth muscle cell proliferation. Although a number of additional targets for attachment have been reported, the C-terminal basic region 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 TFPI contributes to the antithrombotic potential of the vascular endothelium. Further, increased levels of plasma TFPI under septic conditions may represent 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 synthesis in these cells is augmented by serum, so is the case with the TFPI gene expression. TFPI gene knock out mice reveal embryonic lethality suggesting a possible role of this protein in early development. Since TF-induced coagulation is thought to play a significant role in many disease states, including disseminated intravascular clotting, sepsis, acute lung injury and cancer, recombinant TFPI may be a beneficial therapeutic agent in these disease states to attenuate pathologic clotting. The purpose of this review is to outline recent developments in the field related to the structural specificity and biology of TFPI.

 
  • References

  • 1 Broze Jr GJ. Tissue factor pathway inhibitor and the current concept of blood coagulation. Blood Coagul Fibrinolysis 1995; (Suppl 1): S7-S13.
  • 2 Rapaport SI, Rao LVM. The tissue factor pathway: How it has become a “prima ballerina”. Thromb Haemost 1995; 74: 7-17.
  • 3 Bajaj SP, Joist JH. New insights into how blood clots: implications for the use of APTT and PT as coagulation screening tests and in monitoring of anticoagulant therapy. Semin Thromb Hemost 1999; 25: 407-18.
  • 4 Wildgoose P, Nemerson Y, Hansen LL, Nielsen FE, Glazer S, Hedner U. Measurement of basal levels of factor VIIa in hemophilia A and B patients. Blood 1992; 80: 25-8.
  • 5 Morrissey JH, Macik BG, Neuenschwander PF, Comp PC. Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation. Blood 1993; 81: 734-44.
  • 6 van’t Veer C, Mann KG. The regulation of the factor VII-dependent coagulation pathway: rationale for the effectiveness of recombinant factor VIIa in refractory bleeding disorders. Semin Thromb Hemost 2000; 26: 367-72.
  • 7 Masys DR, Bajaj SP, Rapaport SI. Activation of human factor VII by activated factors IX and X. Blood 1982; 60: 1143-50.
  • 8 Nemerson Y. Tissue factor and haemostasis. Blood 1988; 71: 1-8.
  • 9 Bajaj SP, Rapaport SI, Brown SF. Isolation and characterization of human factor VII. Activation of factor VII by factor Xa. J Biol Chem 1981; 256: 253-9.
  • 10 Butenas S, Mann KG. Kinetics of human factor VII activation. Biochemistry 1996; 35: 1904-10.
  • 11 Nakagaki T, Foster DC, Berkner KL, Kisiel W. Initiation of the extrinsic pathway of blood coagulation: evidence for the tissue factor dependent autoactivation of human coagulation factor VII. Biochemistry 1991; 30: 10819-24.
  • 12 Neuenschwander PF, Fiore MM, Morrissey JH. Factor VII autoactivation proceeds via interaction of distinct protease-cofactor and zymogen-cofactor complexes. Implications of a two-dimensional enzyme kinetic mechanism. J Biol Chem 1993; 268: 21489-92.
  • 13 Naito K, Fujikawa K. Activation of human blood coagulation factor XI independent of factor XII. Factor XI is activated by thrombin and factor XIa in the presence of negatively charged surfaces. J Biol Chem 1991; 266: 7353-8.
  • 14 Gailani D, Broze GJ. Factor XI activation in a revised model of blood coagulation. Science 1991; 253: 909-12.
  • 15 Minnema MC, Ten Cate H, Hack CE. The role of factor XI in coagulation: a matter of revision. Semin Thromb Hemost 1999; 25: 419-28.
  • 16 Oliver JA, Monroe DM, Roberts HR, Hoffman M. Thrombin activates factor XI on activated platelets in the absence of factor XII. Arterioscler Thromb Vasc Biol 1999; 19: 170-7.
  • 17 Baglia FA, Walsh PN. Thrombin-mediated feedback activation of factor XI on the activated platelet surface is preferred over contact activation by factor XIIa or factor XIa. J Biol Chem 2000; 275: 20514-9.
  • 18 Hoffman M, Monroe DM, Oliver JA, Robert HR. Factors IXa and Xa play distinct roles in tissue factor-dependent initiation of coagulation. Blood 1995; 1794-801.
  • 19 Colman RW. Biological activities of the contact factors in vivo – potentiation of hypertension, inflammation and fibrinolysis, and inhibition of cell adhesion. Thromb Haemost 1999; 82: 1568-77.
  • 20 Rapaport SI. Inhibition of factor VIIa/tissue factor-induced coagulation: with particular emphasis upon a factor Xa-dependent mechanism. Blood 1989; 73: 359-65.
  • 21 Lawson JH, Butenas S, Ribarik N, Mann KG. Complex dependent inhibition of factor VIIa by antithrombin and heparin. J Biol Chem 1993; 81: 704-19.
  • 22 Rao LVM, Rapaport SI, Hoang AD. Binding of factor VIIa to tissue factor permits rapid antithrombin III/heparin inhibition of factor VIIa. Blood 1993; 81: 2600-7.
  • 23 Sandset PM, Warn-Cramer BJ, Rao LVM, Maki SL, Rapaport SI. Depletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminated intravascular coagulation induced with tissue factor: Evidence supporting a physiologic role for EPI as a natural anticoagulant. Proc Natl Acad Sci USA 1991; 88: 708-12.
  • 24 Sandset PM, Warn-Cramer BJ, Maki SL, Rapaport SI. Immunodepletion of extrinsic pathway inhibitor sensitizes rabbits to endotoxin-induced intravascular coagulation and the generalized Schwartzman reaction. Blood 1990; 78: 1496-502.
  • 25 Sanders NL, Bajaj SP, Rapaport SI. A plasma protein that inhibits tissue factor-factor VII activation of factor IX in the presence of factor X. Circulation 1983; 68 Suppl 1266a (abstr).
  • 26 Sanders NL, Bajaj SP, Zivelin A, Rapaport SI. Inhibition of tissue factor/factor VIIa activity in plasma requires factor X and an additional plasma component. Blood 1985; 66: 204-12.
  • 27 Broze Jr GJ, Girard TJ, Novotny WF. Regulation of coagulation by a multivalent Kunitz-type inhibitor. Biochemistry 1990; 29: 7539-46.
  • 28 Rapaport SI. The extrinsic pathway inhibitor. A regulator of tissue factor dependent blood coagulation. Thromb Haemost 1991; 66: 6-15.
  • 29 Wun T-C, Kretzmer KK, Girard TJ, Miletich JP, Broze Jr GJ. Cloning and characterization of a cDNA coding for the lipoprotein-associated coagulation inhibitor shows that it consists of three tandem Kunitz-type inhibitory domains. J Biol Chem 1988; 263: 6001-4.
  • 30 Baugh RJ, Broze GJ, Krishnaswamy S. Regulation of extrinsic pathway factor Xa formation by tissue factor pathway inhibitor. J Biol Chem 1998; 273: 4378-86.
  • 31 Girard TJ, Warren LA, Novotny WF, Likert KM, Brown SG, Miletich JP, Broze GJ. Functional significance of the Kunitz-type inhibitor domains of lipoprotein-associated coagulation inhibitor. Nature (London) 1989; 338: 518-20.
  • 32 Repke D, Gemmell CH, Guha A, Turitto VT, Broze GJ, Nemerson Y. Hemophilia as a defect of the tissue factor pathway of blood coagulation: effect of factors VIII and IX on factor X activation in a continuous-flow reactor. Proc Natl Acad Sci USA 1990; 87: 7623-7.
  • 33 Rapaport SI, Rao LVM. Initiation and regulation of tissue factor dependent blood coagulation. Arterioscler Thrombos 1993; 13: 105-11.
  • 34 Broze Jr GJ. The role of tissue factor pathway inhibitor in a revised coagulation cascade. Sem Hematol 1992; 29: 159-69.
  • 35 Bajaj MS, Ameri A, Bajaj SP. Tissue factor pathway inhibitor – A regulator of tissue factor-induced coagulation. In: Anticoagulants: Physiologic, Pathologic and Pharmacologic. Green D. ed. Florida: CRC Press; 1994: 41-65.
  • 36 Sandset PM, Bendz B. Tissue factor pathway inhibitor: Clinical deficiency states. Thromb Haemost 1997; 78: 467-70.
  • 37 Bajaj MS, Bajaj SP. Tissue factor pathway inhibitor: potential therapeutic applications. Thromb Haemost 1997; 78: 471-7.
  • 38 Girard TJ. Tissue Factor Pathway Inhibitor. In: Novel Therapeutic Agents in Thrombosis and Thrombolysis. Sasahara A, Lascalzo J. eds. New York: Marcel Dekker; 1997: 225-60.
  • 39 Zhang E, St. Charles R, Tulinsky A. Structure of extracellular tissue factor complexed with factor VIIa inhibited with a BPTI mutant. J Mol Biol 1999; 285: 2089-104.
  • 40 Burgering MJM, Orbons LPM, van der Doelen A, Mulders J, Theunissen HJM, Grootenhuis PDJ, Bode W, Huber R, Stubbs MT. The second Kunitz domain of tissue factor pathway inhibitor: cloning, structure determination and interaction with factor Xa. J Mol Biol 1997; 269: 395-407.
  • 41 Banner DW, D’Arcy A, Chene C, Winkler FK, Guha A, Konigsberg WH, Nemerson Y, Kirchhofter D. The crystal structure of the complex of blood coagulation factor VIIa with soluble tissue factor. Nature 1996; 380: 41-6.
  • 42 Padmanabhan K, Padmanabhan KP, Tulinsky A, Park CH, Bode W, Huber R, Blankenship DT, Cardin AD, Kisiel W. Structure of human des (1-45) factor Xa at 2.2 Å resolution. J Mol Biol 1993; 232: 947-66.
  • 43 Brandstetter H, Kühne A, Bode W, Huber R, von der Sall W, Wirthensohn K, Engh RA. X-ray structure of active site-inhibited clotting factor Xa: Implications for drug design and substrate recognition. J Biol Chem 1996; 271: 29988-92.
  • 44 Birktoft JJ, Norris K, Norris F. The three dimensional structure of the second Kunitz-like domain of the tissue factor pathway inhibitor. Thromb Haemost 1993; 69: 679 (Abstr).
  • 45 Huber R, Kukla D, Bode W, Schwager P, Bartels K, Deisenhofer J, Steigemann W. Structure of the complex formed by bovine trypsin and bovine pancreatic trypsin inhibitor: Crystallographic refinement at 1.9 Å resolution. J Mol Biol 1974; 89: 73-101.
  • 46 Bajaj SP, Birktoft JJ. Human factor IX and factor IXa. Methods Enzymol 1993; 222: 96-128.
  • 47 Ripka W, Brunck T, Stanssens P, LaRoche Y, Lauwereys M, Lambeir A-M, Lasters I, De Maeyer M, Vlasuk G, Levy O, Miller T, Webb T, Tamura S, Pearson D. Strategies in the design of inhibitors of serine proteases of the coagulation cascade: factor Xa. Eur J Med Chem 1995; 30: 87-100.
  • 48 Neuenschwander PF, Morrissey JH. Alteration of the substrate and inhibitor specificities of blood coagulation factor VIIa: importance of amino acid residue K192. Biochemistry 1995; 34: 8701-7.
  • 49 Rao LVM, Ruf W. Tissue factor residues Lys165 and Lys166 are essential for rapid formation of the quaternary complex of tissue factor-VIIa with Xa-tissue factor pathway inhibitor. Biochemistry 1995; 34: 10867-71.
  • 50 Rudolph AE, Mathur A, Bajaj SP, Miletich JP. Unpublished data.
  • 51 Cook BC, Rudolph AE, Kurumbail RG, Porche-Sorbet R, Miletich JP. Directed glycosylation of human coagulation factor X at residue 333. Insight into factor Va-dependent prothrombin catalysis. J Biol Chem 2000; 275: 38774-9.
  • 52 Morrison JF, Walsh CT. The behavior and significance of slow-binding enzyme inhibitors. Adv Enzymol Relat Areas Mol Biol 1988; 61: 201-301.
  • 53 Huang Z-F, Wun T-C, Broze Jr GJ. Kinetics of factor Xa inhibition by tissue factor pathway inhibitor. J Biol Chem 1993; 268: 26950-5.
  • 54 Underwood MC, Zhong D, Mathur A, Heyduk T, Bajaj SP. Thermodynamic linkage between the S1 site, the Na+ site and the Ca2+ site in the pro-tease domain of human coagulation factor Xa. J Biol Chem 2000; 275: 36876-84.
  • 55 Petersen LC, Bjorn SE, Olsen OH, Nordfang O, Norris F, Norris K. Inhibitory properties of separate recombinant Kunitz type protease inhibitor domains from tissue factor pathway inhibitor. Eur J Biochem 1996; 235: 310-6.
  • 56 Wun T-C.. Lipoprotein associated coagulation inhibitor (LACI) is a cofactor for heparin: Synergetic anticoagulant action between LACI and sulfated polysaccharides. Blood 1992; 79: 430-8.
  • 57 Enjyoji K, Miyata T, Kamikubo Y, Kato H. Effect of heparin on the inhibition of factor Xa by tissue factor pathway inhibitor: a segment, Gly212-Phe243 is a heparin binding site. Biochemistry 1995; 34: 5725-35.
  • 58 Nordfang O, Bjørn SE, Valentin S, Nielsen LS, Wildgoose P, Beck TC, Hedner U. The C-terminus of tissue factor pathway inhibitor is essential to its anticoagulant activity. Biochemistry 1991; 30: 10371-6.
  • 59 Wesselschmidt R, Likert K, Girard T, Wun T-C, Broze Jr GJ. Tissue factor pathway inhibitor: The carboxy-terminus is required for optimal inhibition of factor Xa. Blood 1992; 79: 2004-10.
  • 60 Lindhout T, Willems G, Blezer R, Hemker HC. Kinetics of inhibition of human factor Xa by full-length and truncated recombinant tissue factor pathway inhibitor. Biochem J 1994; 297: 131-6.
  • 61 Higuchi DA, Wun T-C, Likert K, Broze Jr GJ. The effect of leukocyte elastase on tissue factor pathway inhibitor. Blood 1992; 79: 1712-9.
  • 62 Petersen LC, Bjørn SE, Nordfang O. Effect of leukocyte proteinase on tissue factor pathway inhibitor. Thromb Haemost 1992; 67: 537-41.
  • 63 Bajaj MS, Kuppuswamy MN, Saito H, Spitzer SG, Bajaj SP. Cultured normal human hepatocytes do not synthesize lipoprotein-associated coagulation inhibitor: Evidence that endothelium is the principal site of its synthesis. Proc Natl Acad Sci USA 1990; 87: 8869-73.
  • 64 Werling RW, Zacharski LR, Kisiel W, Bajaj SP, Memoli VA, Rousseau SM. Distribution of tissue factor pathway inhibitor in normal and malignant human tissues. Thromb Haemost 1993; 69: 366-9.
  • 65 Bajaj MS, Kuppuswamy MN, Manepalli AN, Bajaj SP. Transcriptional expression of tissue factor pathway inhibitor, thrombomodulin and von Willebrand factor in normal human tissues. Thromb Haemost 1999; 82: 1047-52.
  • 66 Shimokawa T, Yamamoto K, Kojima T, Saito H. Down-regulation of urine tissue factor pathway inhibitor mRNA by endotoxin and tumor necrosis factor-alpha in vitro and in vivo. Thromb Res 2000; 100: 211-21.
  • 67 Wojtukiewicz MZ, Zacharski LR, Rucinska M, Zimnoch L, Jaromin J, Rozanska-Kudelska M, Kisiel W, Kudryk BJ. Expression of tissue factor and tissue factor pathway inhibitor in situ in laryngeal carcinoma. Thromb Haemost 1999; 82: 1659-62.
  • 68 Bajaj MS, Pendurthi U, Koenig K, Pueblitz S, Idell S. Tissue factor pathway inhibitor expression by human pleural mesothelial and mesothelioma cells. Eur Respir J 2000; 15: 1069-78.
  • 69 Yamabe H, Osawa H, Inuma H, Kaizuka M, Tamura N, Tsunoda S, Fujita Y, Shirato K, Onodera K. Tissue factor pathway inhibitor production by human mesangial cells in culture. Thromb Haemost 1996; 76: 215-9.
  • 70 Osterud B, Bajaj MS, Bajaj SP. Sites of tissue factor pathway inhibitor (TFPI) and tissue factor expression under physiologic and pathologic conditions. On behalf of the Subcommittee on Tissue Factor Pathway Inhibitor (TFPI) of the Scientific and Standardization Committee of the ISTH. Thromb Haemost 1995; 73: 873-5.
  • 71 Edstrom CS, Calhoun DA, Christensen RD. Expression of tissue factor pathway inhibitor in human fetal and placental tissues. Early Hum Dev 2000; 59: 77-84.
  • 72 Ameri A, Kuppuswamy MN, Basu S, Bajaj SP. Expression of tissue factor pathway inhibitor by cultured endothelial cells in response to inflammatory mediators. Blood 1992; 79: 3219-26.
  • 73 Grabowski EF, Reininger AJ, Petteruti PG, Tsukurov O, Orkin RW. Shear stress decreases endothelial cell tissue factor activity by augmenting secretion of tissue factor pathway inhibitor. Arterioscler Thromb Vasc Biol 2001; 21: 157-62.
  • 74 Lupu C, Lupu F, Dennehy U, Kakkar VV, Scully MF. Thrombin induces the redistribution and acute release of tissue factor pathway inhibitor from specific granules within human endothelial cells in culture. Arterioscler Thromb Vasc Biol 1995; 15: 2055-62.
  • 75 Kopp CW, Robson SC, Siegel JB, Anrather J, Winkler H, Grey S, Kaczmarek E, Bach FH, Geezy CL. Regulation of monocyte tissue factor activity by allogenic and xenogenic endothelial cells. Thromb Haemost 1998; 79: 529-38.
  • 76 McGee MP, Foster S, Wang X. Simultaneous expression of tissue factor and tissue factor pathway inhibitor by human monocytes. A potential mechanism for localized control of blood coagulation. J Exp Med 1994; 179: 1847-54.
  • 77 Rana SV, Reimers HJ, Pathikonda MS, Bajaj SP. Expression of tissue factor and factor VIIa/tissue factor inhibitor activity in endotoxin or phorbol ester stimulated U937 monocyte-like cells. Blood 1988; 71: 259-62.
  • 78 Caplice NM, Mueske CS, Kleppe LS, Peterson TE, Broze GJ, Simari RD. Expression of tissue factor pathway inhibitor in vascular smooth muscle cells and its regulation by growth factors. Cir Res 1998; 83: 1264-70.
  • 79 Pendurthi UR, Rao LV, Williams JT, Idell S. Regulation of tissue factor pathway inhibitor expression in smooth muscle cells. Blood 1999; 94: 579-86.
  • 80 Bajaj MS, Steer S, Kuppuswamy MN, Kisiel W, Bajaj SP. Synthesis and expression of tissue factor pathway inhibitor by serum-stimulated fibro-blasts, smooth muscle cells and cardiac myocytes. Thromb Haemost 1999; 82: 1663-72.
  • 81 Machman N. Regulation of tissue factor gene. Thromb Haemost 1997; 78: 747-54.
  • 82 Broze Jr GJ, Lange GW, Duffin KL, MacPhail L. Heterogeneity of plasma tissue factor pathway inhibitor. Blood Coagul Fibrinolysis 1994; 5: 551-9.
  • 83 Sandset PM, Abildgaard U, Larsen ML. Heparin induces release of extrinsic coagulation pathway inhibitor (EPI). Thromb Res 1988; 50: 803-13.
  • 84 Novotny WF, Brown SG, Miletich JP, Rader DJ, Broze GJ JR. Plasma antigen levels of the lipoprotein-associated coagulation inhibitor in patient samples. Blood 1991; 78: 387-93.
  • 85 Sandset PM, Hellgren M, Uvebrandt M, Bergstrom H. Extrinsic coagulation pathway inhibitor and heparin cofactor II during normal and hyper-tensive pregnancy. Thromb Res 1989; 55: 665-70.
  • 86 Warr TA, Warn CB, Cramer BJ, Rao LV, Rapaport SI. Human plasma extrinsic pathway inhibitor activity: I. Standardization of assay and evaluation of physiologic variables. Blood 1989; 74: 201-6.
  • 87 Harris GM, Stendt CL, Vollenhoven BJ, Gan TE, Tipping PG. Decreased plasma tissue factor pathway inhibitor in women taking combined oral contraceptives. Am J Hematol 1999; 60: 175-80.
  • 88 Sakkinen PA, Cushman M, Psaty BM, Kuller LH, Bajaj SP, Sabharwal AK, Boineau R, Macy E, Tracy RP. Correlates of antithrombin, protein C, protein S, and TFPI in a healthy elderly cohort. Thromb Haemost 1998; 80: 134-9.
  • 89 Palmier MO, Hall LJ, Reisch CM, Baldwin MK, Wilson AG, Wun TC. Clearance of recombinant tissue factor pathway inhibitor (TFPI) in rabbits. Thromb Haemost 1992; 68: 33-6.
  • 90 Mast AE, Higuchi DA, Huang ZF, Warshawsky I, Schwartz AL, Broze Jr GJ. Glypican-3 is a binding protein on the HepG2 cell surface for tissue factor pathway inhibitor. Biochem J 1997; 327: 577-83.
  • 91 Kojima T, Katsumi A, Yamazaki T, Muramatsu T, Nagasaka T, Ohsumi K, Saito H. Human Ryudocan from endothelium-like cells binds basic fibroblast growth factor, midkine, and tissue factor pathway inhibitor. J Biol Chem 1996; 271: 5914-20.
  • 92 Warshawsky I, Herz J, Broze Jr GJ, Schwartz AL. The low density lipo-protein receptor-related protein can function independently from heparan sulfate proteoglycans in tissue factor pathway inhibitor endocytosis. J Biol Chem 1996; 271: 25873-9.
  • 93 Ho G, Narita M, Broze Jr GJ, Schwartz AL. Recombinant full-length tissue factor pathway inhibitor fails to bind to the cell surface: implications for catabolism in vitro and in vivo. Blood 2000; 95: 1973-8.
  • 94 Ho G, Toomey JR, Broze Jr GJ, Schwartz AL. Receptor-mediated endocytosis of coagulation factor Xa requires cell surface-bound tissue factor pathway inhibitor. J Biol Chem 1996; 271: 9497-502.
  • 95 Hamik A, Setiadi H, Bu G, McEver RP, Morrissey JH. Down-regulation of monocyte tissue factor mediated by tissue factor pathway inhibitor and the low density lipoprotein receptor-related protein. J Biol Chem 1999; 274: 4962-9.
  • 96 Ott I, Miyagi Y, Miyazaki K, Heeb MJ, Mueller BM, Rao LVM, Ruf W. Reversible regulation of tissue factor-induced coagulation by glycosyl phosphatidylinositol-anchored tissue factor pathway inhibitor. Arterioscler Thromb Vasc Biol 2000; 20: 874-82.
  • 97 Girard TJ, Warren LA, Novotny WF, Bejcek BE, Miletich JP, Broze GJ. Identification of the 1.4 kb and 4.0 kb messages from the lipoprotein-associated coagulation inhibitor and expression of the encoded protein. Thromb Res 1989; 55: 37-50.
  • 98 Girard TJ, Eddy R, Wesselschmidt RL, MacPhail LA, Likert KM, Byers MG, Shows TB, Broze Jr GJ. Structure of the human lipoprotein-associated coagulation inhibitor gene. Intron/exon gene organization and localization of the gene to chromosome 2. J Biol Chem 1991; 206: 5036-41.
  • 99 van der Logt CP, Reitsma PH, Bertina RM. Intron-exon organization of the human gene coding for the lipoprotein-associated coagulation inhibitor: the factor Xa dependent inhibitor of the extrinsic pathway of coagulation. Biochemistry 1991; 30: 1571-7.
  • 100 Tyson DR, Kuppuswamy MN, Broze Jr GJ, Bajaj SP. Revised DNA sequence of exon 1 and 5N flanking region of the human tissue factor pathway inhibitor gene. Thromb Res 1993; 70: 269-73.
  • 101 Petit L, Lesnik P, Dachet C, Hugou I, Moreau M, Chapman J, Rouis M. The promoter of the human tissue factor pathway inhibitor gene: identification of potential regulatory elements. Thromb Res 1999; 95: 255-62.
  • 102 Orkin SH. GATA-binding transcription factors in hematopoietic cells. Blood 1992; 80: 575-81.
  • 103 Lee ME, Temizer DH, Clifford JA, Quertermous T. Cloning of the GATA-binding protein that regulates endothelin-1 gene expression in endothelial cells. J Biol Chem 1992; 266: 16188-92.
  • 104 Bajaj MS, Tyson DR, Steer SA, Kuppuswamy MN. Role of GATA motifs in tissue factor pathway inhibitor gene expression in malignant cells. Thromb Res 2001; 101: 203-11.
  • 105 Broze Jr GJ. Tissue factor pathway inhibitor gene disruption. Blood Coagul Fibrinolysis 1998; 9 (Suppl. 01) S89-92.
  • 106 Moatti D, Seknadji P, Galand C, Poirier O, Fumeron F, Desprez S, Garbarz M, Dhermy D, Arveiler D, Evans A, Luc G, Ruidavets JB, Ollivier V, Hakim J, Aumont MC, de Prost D. Polymorphisms of the tissue factor pathway inhibitor (TFPI) gene in patients with acute coronary syndromes and in healthy subjects: impact of the V264M substitution on plasma levels of TFPI. Arterioscler Thromb Vasc Biol 1999; 19: 862-9.
  • 107 Arnaud E, Moatti D, Emmerich J, Aiach M, de Prost D. No link between the TFPI V264M mutation and venous thromboembolic disease. Thromb Haemost 1999; 82: 159-60.
  • 108 Miyata T, Sakata T, Kumeda K, Uchida K, Tsushima M, Fujimura H, Kawasaki T, Kato H. C-399T polymorphism in the promoter region of human tissue factor pathway inhibitor (TFPI) gene does not change the plasma TFPI antigen level and does not cause venous thrombosis. Thromb Haemost 1998; 80: 345-6.
  • 109 Moatti D, Haidar B, Fumeron F, Gauci L, Boudvillain O, Seknadji P, Olliver V, Aumont MC, de Prost D. A new T287C polymorphism in the 5′ regulatory region of the tissue factor pathway inhibitor gene. Association study of the T287C and C399T polymorphisms with coronary artery disease and plasma TFPI levels. Thromb Haemost 2000; 84: 244-9.
  • 110 Kleesiek K, Schmidt M, Gotting C, Schwenz B, Lange S, Muller-Berghaus G, Brinkmann T, Prohaska W. The 536C T transition in the human tissue factor pathway inhibitor (TFPI) gene is statistically associated with a higher risk for venous thrombosis. Thromb Haemost 1999; 82: 1-5.
  • 111 Gonzalez-Conejero R, Lozano ML, Corral J, Martinez C, Vicente V. The TFPI 536C T mutation is not associated with increased risk for venous or arterial thrombosis. Thromb Haemost 2000; 83: 787-8.
  • 112 Hessner MJ, Luhm RA. The C536T transition in the tissue factor pathway inhibitor gene does not contribute to risk of venous thrombosis among carriers of factor V Leiden. Thromb Haemost 2000; 84: 724-5.
  • 113 Fuster V. Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation 1994; 90: 2126-46.
  • 114 Wilcox JN, Smith KM, Schwartz SM, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA 1989; 86: 2839-43.
  • 115 Tipping PG, Malliaros J, Holdsworth SR. Procoagulant activity expression by macrophages from atheromatous vascular plaques. Atherosclerosis 1989; 79: 237-43.
  • 116 Drew AF, Davenport P, Apostolopoulos J, Tipping PG. Tissue factor pathway inhibitor expression in atherosclerosis. Lab Invest 1997; 77: 291-8.
  • 117 Caplice NM, Mueske CS, Kleppe LS, Simari RD. Presence of tissue factor pathway inhibitor in human atherosclerotic plaques is associated with reduced tissue factor activity. Circulation 1998; 98: 1051-7.
  • 118 Kaikita K, Takeya M, Ogawa H, Suefuji H, Yasue H, Takahashi K. Co-localization of tissue factor and tissue factor pathway inhibitor in coronary atherosclerosis. J Pathol 1999; 188: 180-8.
  • 119 Crawley J, Lupu F, Westmuckett AD, Severs NJ, Kakkar VV, Lupu C. Expression, localization, and activity of tissue factor pathway inhibitor in normal and atherosclerotic human vessels. Arterioscler Thromb Vasc Biol 2000; 20: 1362-73.
  • 120 Petit L, Lesnik P, Dachet C, Moreau M, Chapman MJ. Tissue factor pathway inhibitor is expressed by human monocyte-derived macrophages: relationship to tissue factor induction by cholesterol and oxidized LDL. Arterioscler Thromb Vasc Biol 1999; 19: 309-15.
  • 121 Chesebro JH, Toschi V, Lettino M, Gallo R, Badimon JJ, Fallon JT, Fuster V. Evolving concepts in the pathogenesis and treatment of arterial thrombosis (Grand rounds). Mt Sinai J Med 1995; 62: 275-86.
  • 122 Haskel EJ, Torr SR, Day KC, Palmier MO, Wun TC, Sobel BE, Abendschein DR. Prevention of arterial reocclusion after thrombolysis with recombinant lipoprotein-associated coagulation inhibitor. Circulation 1991; 84: 821-7.
  • 123 Abendschein DR, Meng YY, Torr-Brown S, Sobel BE. Maintenance of coronary patency after fibrinolysis with tissue factor pathway inhibitor. Circulation 1995; 92: 944-9.
  • 124 Badimon JJ, Lettino M, Toschi V, Fuster V, Berrozpe M, Chesebro JH, Badimon L. Local inhibition of tissue factor reduces the thrombogenicity of disrupted human atherosclerotic plaques: effects of tissue factor pathway inhibitor on plaque thrombogenicity under flow conditions. Circulation 1999; 99: 1780-7.
  • 125 Roque M, Reis ED, Fuster V, Padurean A, Fallon JT, Taubman MB, Chesebro JH, Badimon JJ. Inhibition of tissue factor reduces thrombus formation and intimal hyperplasia after porcine coronary angioplasty. J Am Coll Cardiol 2000; 36: 2303-10.
  • 126 Eisenberg PR. Current concepts in coronary thrombolysis (Review). Hematol Oncol Clin North Am 1992; 6: 1161-70.
  • 127 Nishida T, Ueno H, Atsuchi N, Kawano R, Asada Y, Nakahara Y, Kamikuto YI, Takeshita A, Yasaui H. Adenovirus-mediated local expression of human tissue factor pathway inhibitor eliminates shear stress-induced recurrent thrombosis in the injured carotid artery of the rabbit. Circ Res 1999; 84: 1446-52.
  • 128 Zoldhelyi P, McNatt J, Shelat HS, Yamamoto Y, Chen ZQ, Willerson JT. Thromboresistance of balloon-injured porcine carotid arteries after local gene transfer of human tissue factor pathway inhibitor. Circulation 2000; 101: 289-95.
  • 129 Jang Y, Guzman LA, Lincoff M, Gottsauner WM, Forudi F, Hart CE, Courtman DW, Ezban M, Ellis SG, Topol EJ. Influence of blockade at specific levels of the coagulation cascade on restenosis in a rabbit athero-sclerotic femoral artery injury model. Circulation 1995; 92: 3041-50.
  • 130 St. Pierre J, Yang LY, Tamirisa K, Scherrer D, De Ciechi P, Eisenberg P, Tolunay E, Abendschein D. Tissue factor pathway inhibitor attenuates procoagulant activity and upregulation of tissue factor at the site of balloon-induced arterial injury in pigs. Arterioscler Thromb Vasc Biol 1999; 19: 2263-8.
  • 131 Atsuchi N, Nishida T, Marutsuka K, Asada Y, Kamikubo Y, Takeshita A, Ueno H. 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. Circulation 2001; 103: 570-5.
  • 132 Han X, Girard TJ, Baum P, Abendschein DR, Broze Jr GJ. Structural requirements for TFPI-mediated inhibition of neointimal thickening after balloon injury in the rat. Arterioscler Thromb Vasc Biol 1999; 19: 2563-7.
  • 133 Del Zoppo GJ, Copeland BR, Harker LA, Waltz TA, Zyroff J, Hanson SR, Battenberg E. Experimental acute thrombotic stroke in baboons. Stroke 1986; 17: 1254-65.
  • 134 Kobayashi Y, Yoshimura N, Nakamura K, Yamagishi H, Oka T. Expression of tissue factor in hepatic ischemia-reperfusion injury of the rat. Transplantation 1998; 66: 708-16.
  • 135 Koudsi B, Chatman DM, Ballinger BA, Ferguson EW, Kraemer BA, Miller GA, Wun TC, Farr G, Money SR. Tissue factor pathway inhibitor protects the ischemic spinal cord. J Surg Res 1996; 63: 174-8.
  • 136 Yoshimura N, Kobayashi Y, Nakamura K, Yamagishi H, Oka T. The effect of tissue factor pathway inhibitor on hepatic ischemia reperfusion injury of the rat. Transplantation 1999; 67: 45-53.
  • 137 Kamikura Y, Wada H, Yamada A, Shimura M, Hiyoyama K, Shiku H, Tanigawa M, Nishikawa H, Yamada N, Isaka N, Nakano T, Kumeda K, Kato H. Increased tissue factor pathway inhibitor in patients with acute myocardial infarction. Am J Hematol 1997; 55: 183-7.
  • 138 Van Dreden P, Grosley M, Cost H. Total and free levels of tissue factor pathway inhibitor: a risk factor in patients with factor V Leiden?. Blood Coagul Fibrinolysis 1999; 10: 115-6.
  • 139 Amengual O, Atsumi T, Khamashta MA, Hughes GR. The role of the tissue factor pathway in the hypercoagulable state in patients with the antiphospholipid syndrome. Thromb Haemost 1998; 79: 276-81.
  • 140 Jacobsen EM, Sandset PM, Wisloff F. Do antiphospholipid antibodies interfere with tissue factor pathway inhibitor?. Thromb Res 1999; 94: 213-20.
  • 141 Ariens RA, Alberio G, Moia M, Mannucci PM. Low levels of heparinreleasable tissue factor pathway inhibitor in young patients with thrombosis. Thromb Haemost 1999; 81: 203-7.
  • 142 Holst J, Lindblad B, Bergqvist D, Nordfang O, Ostergaard PB, Petersen JR, Nielsen G, Hedner U. Antithromboitc effect of recombinant truncated tissue factor pathway inhibitor (TFPI 1-161) in experimental venous thrombosis – a comparison with low moleuclar weight heparin. Thromb Haemost 1994; 71: 214-9.
  • 143 Chouhan VD, Comerota AJ, Sun L, Harada R, Gaughan JP, Rao AK. Inhibition of tissue factor pathway during intermittent pneumatic compression: A possible mechanism for antithrombotic effect. Arterioscler Thromb Vasc Biol 1999; 19: 2812-7.
  • 144 Osterud B, Flaegstad T. Increased thromboplastin activity in monocytes of patients with meningococcal infection: related to an unfavorable prognosis. Thromb Haemost 1983; 49: 5-7.
  • 145 Taylor Jr FB. Studies on the inflammatory-coagulant axis in the baboon response to E. coli: regulatory roles of proteins C, S, C4b, BP and of inhibitors of tissue factor. Prog Clin Biol Res 1994; 388: 175-94.
  • 146 Shimura M, Wada H, Nakasaki T, Hiyoyama K, Mori Y, Nishikawa M, Deguchi H, Deguchi K, Gabazza EC, Shiku H. Increased truncated form of plasma tissue factor pathway inhibitor levels in patients with disseminated intravascular coagulation. Am J Hematol 1999; 60: 94-8.
  • 147 Iversen N, Strekerud FG, Abildgaard U. Tissue factor pathway inhibitor (TFPI) in disseminated intravascular coagulation: low levels of the activated factor X-TFPI complex. Blood Coagul Fibrinolysis 2000; 11: 591-8.
  • 148 Asakura H, Ontachi Y, Mizutani T, Kato M, Saito M, Morishita E, Yamazaki M, Suga Y, Takami A, Miyamoto K, Nakao S. Elevated levels of free tissue factor pathway inhibitor antigen in cases of disseminated intravascular coagulation caused by various underlying diseases. Blood Coagul Fibrinolysis 2001; 12: 1-8.
  • 149 Creasey AA, Chang ACK, Feigen L, Wun TC, Taylor Jr FB, Hinshaw LB. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J Clin Invest 1993; 91: 2850-60.
  • 150 Taylor FB, Chang AC, Peer G, Li A, Ezban M, Hedner U. Active site inhibited factor VIIa (DEGR VIIa) attenuates the coagulant and inter-leukin-6 and -8, but not tumor necrosis factor, responses of the baboon to LD100 Escherichia coli . Blood 1998; 91: 1609-15.
  • 151 Carr C, Bild GS, Chang ACK, Peer GT, Palmier MO, Frazier RB, Gustafson ME, Wun TC, Creasey AA, Hinshaw LB, Taylor Jr FB, Galluppi GR. Recombinant E. coli-derived tissue factor pathway inhibitor reduces coagulopathic and lethal effects in the baboon gram-negative model of septic shock. Circ Shock 1995; 44: 126-37.
  • 152 Johnson K, Aarden L, Choi Y, de Groot E, Creasey A. The proinflamma-tory cytokine response to coagulation and endotoxin in whole blood. Blood 1996; 87: 5051-60.
  • 153 Park CT, Creasey AA, Wright SD. Tissue factor pathway inhibitor blocks cellular effects of endotoxin by binding to endotoxin and interfering with transfer to CD14. Blood 1997; 89: 4268-74.
  • 154 de Jonge E, Dekkers PE, Creasey AA, Hack CE, Paulson SK, Karim A, Kesecioglu J, Levi M, van Deventer SJ, van Der Poll T. Tissue factor pathway inhibitor dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia. Blood 2000; 95: 1124-9.
  • 155 Bone RC, Francis PB, Pierce AK. Intravascular coagulation associated with the adult respiratory distress syndrome. Am J Med 1976; 61: 585-9.
  • 156 Idell S, James KK, Levin EG, Schwartz BS, Manchanda N, Maunder RJ, Martin TR, McLarty J, Fair DS. Local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome. J Clin Invest 1989; 84: 695-705.
  • 157 Sabharwal AK, Bajaj SP, Ameri A, Tricomi SM, Hyers TM, Dahms TE, Taylor FB, Bajaj MS. Tissue factor pathway inhibitor and von Willebrand factor antigen levels in adult respiratory distress syndrome and in a primate model of sepsis. Am J Respir Crit Care Med 1995; 151: 758-67.
  • 158 Bajaj MS, Tricomi SM. Plasma levels of the three endothelial-specific proteins von Willebrand factor, tissue factor pathway inhibitor, and thrombomodulin do not predict the development of acute respiratory distress syndrome. Intensive Care Med 1999; 25: 1259-66.
  • 159 Rao LV. Tissue factor as a tumor procoagulant. Cancer Metastasis Rev 1992; 11: 249-66.
  • 160 Lindahl AK, Sandset PM, Abildgarrd U. Indices of hyper-coagulation in cancer as compared with those in acute inflammation and acute infarction. Haemostasis 1990; 20: 253-62.
  • 161 Callander NS, Varki N, Rao LV. Immunohistochemical indentification of tissue factor in solid tumors. Cancer 1992; 70: 1194-201.
  • 162 Kakkar AK, DeRuvo N, Chinswangwatanakul V, Tebbutt S, Williamson RC. Extrinsic-pathway activation in cancer with high factor VIIa and tissue factor. Lancet 1995; 346: 1004-5.
  • 163 Iversen N, Lindahl AK, Abildgaard U. Elevated TFPI in malignant disease: relation to cancer type and hypercoagulation. Br J Haematol 1998; 102: 889-95.
  • 164 Matsuo T, Koide M, Kario K, Suzuki S, Matsuo M. Extrinsic coagulation factors and tissue factor pathway inhibitor in end-stage chronic renal failure. Haemostasis 1997; 27: 163-7.
  • 165 Inoue A, Wada H, Takagi M, Yamamuro M, Mukai K, Nakasaki T, Shimura M, Hiyoyama K, Deguchi H, Gabazza EC, Mori Y, Mishikawa M, Deguchi K, Shiku H. Hemostatic abnormalities in patients with thrombotic complications on maintenance hemodialysis. Clin Appl Thromb Hemost 2000; 6: 100-3.
  • 166 Ariens RA, Moia M, Rivolta E, Ponticelli C, Mannucci PM. High levels of tissue factor pathway inhibitor in patients with nephrotic proteinuria. Thromb Haemost 1999; 82: 1020-3.
  • 167 Cunningham MA, Ono T, Hewiston TD, Tipping PG, Becker GJ, Holds-worth SR. Tissue factor pathway inhibitor expression in human crescentic glomerulonephritis. Kidney Int 1999; 55: 1311-8.
  • 168 Callander NS, Rao LV, Nordfang O, Sandset PM, Warn-Cramer B, Rapa-port SI. Mechanism of binding of recombinant extrinsic pathway inhibitor (rEPI) to cultured cell surfaces. Evidence that rEPI can bind to and inhibit factor VIIa-tissue factor complex in the absence of factor Xa. J Biol Chem 1992; 267: 876-82.
  • 169 Abraham E. Tissue factor inhibition and clinical trial results of tissue factor pathway inhibitor in sepsis. Crit Care Med 2000; 28: S31-3.
  • 170 Mueller BM, Reisfeld RA, Edgington TS, Ruf W. Expression of tissue factor by melanoma cells promotes efficient hematogenous metastasis. Proc Natl Acad Sci USA 1992; 89: 11832-6.
  • 171 Bromberg ME, Konisberg WH, Madison JF, Pawashe A, Garen A. Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation. Proc Natl Acad Sci USA 1995; 92: 8205-9.
  • 172 Fischer EG, Riewald M, Huang HY, Miyagi Y, Kubota Y, Mueller BM, Ruf W. Tumor cell adhesion and migration supported by interaction of a receptor-protease complex with its inhibitor. J Clin Invest 1999; 104: 1213-21.
  • 173 Rao CN, Gomez DE, Woodley DT, Thorgeirsson UP. Partial characterization of novel serine proteinase inhibitors from human umbilical vein endothelial cells. Arch Biochem Biophys 1995; 319: 55-62.
  • 174 Carmeliet P, Mackman N, Moons L, Luther T, Gressens P, Van Vlaenderen I, Demunck H, Kasper M, Breier G, Evrard P, Muller M, Risau W, Edgington T, Collen D. Role of tissue factor in embryonic blood vessel development. Nature 1996; 383: 73-5.
  • 175 Zhang Y, Deng Y, Luther T, Muller M, Ziegler R, Waldherr R, Stern DM, Nawroth PP. Tissue factor controls the balance of angiogenic and anti-angiogenic properties of tumor cells in mice. J Clin Invest 1994; 94: 1320-7.
  • 176 Sato Y, Asada Y, Marutsuka K, Hatakeyama K, Kamikubo Y, Sumiyoshi A. Tissue factor pathway inhibitor inhibits aortic smooth muscle cell migration induced by tissue factor/factor VIIa complex. Thromb Haemost 1997; 78: 1138-41.
  • 177 Chang J-Y, Monroe DM, Oliver JA, Roberts HR. TFPI , a second product from the mouse tissue factor pathway inhibitor (TFPI) Gene. Thromb Haemost 1999; 81: 45-9.