Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Tissue Factor

  • Elena SergeevaEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101878


Historical Background

Morawitz was the first to describe the clot-promoting substance found in tissues (tissue factor) and introduced it into his clotting theory. He proposed a clotting theory which influenced research in this field over the next 50 years.

Until 1962 12 main clotting factors were described, but their interrelationship was unknown. In 1964, Davie and Macfarlane independently formulated the “cascade theory” of in vivo clotting. Only 30 years later, in 1995, Rapaport and Rao were able to write “Thus little reason exists today to doubt that the binding of factor VII to TF and the subsequent reactions so triggered play a ‘prima ballerina’ role in the initiation of coagulation process.”

In 1987, the efficiency of purification of human tissue factor (TF) from brain and placenta was greatly improved by using a monoclonal antibody against human tissue factor on...

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  1. Annex BH, Denning SM, Channon KM. Differential expression of tissue factor protein in directional atherectomy specimens from patients with stable and unstable coronary syndromes. Circulation. 1995;91(3):619–22.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Arnaud E, Barbalat V, Nicaud V, Cambien F, Evans A, Morrison C, Arveiler D, Luc G, Ruidavets JB, Emmerich J. Polymorphisms in the 5′ regulatory region of the tissue factor gene and the risk of myocardial infarction and venous thromboembolism: the ECTIM and PATHROS studies. Etude Cas-Temoins de l’Infarctus du Myocarde. Paris Thrombosis case-control Study. Arterioscler Thromb Vasc Biol. 2000;20:892–8.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Baglia AF, Shrimpton CN, Lopez JA, Walsh PN. The glycoprotein Ib-IX-V complex mediates localization of factor XI to lipid rafts on the platelet membrane. J Biol Chem. 2003;278:21744–50.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Bajaj MS, Birktoft JJ, Steer SA, Bajaj SP. Structure and biology of tissue factor pathway inhibitor. Thromb Haemost. 2001;86:959–72.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Baker AK, WangR, Mackman N, Luyendyk JP. Rapamycin enhances LPS induction of tissue factor and tumor necrosis factor-alpha expression in macrophages by reducing IL-10 expression. Mol Immunol. 2009;46(11–12):2249–55.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Bode M, Mackman N. Regulation of tissue factor gene expression in monocytes and endothelial cells: thromboxane A2 as a new player. Vasc Pharmacol. 2014;62(2):57–62.CrossRefGoogle Scholar
  7. Borisoff JI, Spronk HM, Cate H. The hemostatic system as a modulator of atherosclerosis. N Engl J Med. 2011;364:1746–60.CrossRefGoogle Scholar
  8. Bruni F, Puccetti L, Pasqui AL, Pastorelli M, Bova G, Cercignani M, Palazzuoli A, Leo A, Auteri A. Different effect induced by treatment with several statins on monocyte tissue factor expression in hypercholesterolemic subjects. Clin Exp Med. 2003;3(1):45–53.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Butenas S, Dee JD, Mann KG. The function of factor XI in tissue factor-initiated thrombin generation. J Thromb Hemostat. 2003;1(10):2103–11.CrossRefGoogle Scholar
  10. Butenas S, Bouchard BA, Brummel-Ziedins KE, Parhami-Seren B, Mann KG. Tissue factor activity in whole blood. Blood. 2005;105(7):2764–70.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Butenas S, Orfeo T, Mann KG. Tissue factor in coagulation, which? where? when? Arterioscler Thromb Vasc Biol. 2009;29(12):1989–96.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Buzby J, Williams SA, Imfeld KL. Tissue factor inflammatory response regulated by promoter genotype and p 38 MAPK in neonatal vs. adult microvascular endothelial cells. Inflamm Res. 2014;63(4):299–308.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Calabroa P, Cirillob P, Limongellia G. Tissue factor is induced by resistin in human coronary artery endothelial cells by the NF-ĸB-dependent pathway. J Vasc Res. 2011;48(1):59–66.CrossRefGoogle Scholar
  14. Camerer E, Huang W, Coughlin SR. Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa. PNAS. 2000;97(10):5255–60.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Camici GG, Steffel J, Amanovic I, Breitenstein A, Baldinger J, Keller S, Lüscher TF, Tanner FC. Rapamycin promotes arterial thrombosis in vivo: implications for everolimus and zotarolimus eluting stents. Eur Heart J. 2010;31(2):236–42.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Campo G, Valgimigli M, Ferraresi P. Tissue factor and coagulation factor VII levels during acute myocardial infarction. Arterioscler Thromb Vasc Biol. 2006;26(12):2800–6.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Caterina R. Inflammation and thrombosis. Proceedings of the ESC Congress; 2015.Google Scholar
  18. Chen C. C, Chen, N, Lau L. F. The angiogenic factors Cyr61 and connective tissue growth factor induce adhesive signaling in primary human skin fibroblasts. J Biol Chem. 2001;276, 13, 10443–52PubMedPubMedCentralCrossRefGoogle Scholar
  19. Chu AJ. Tissue factor mediates inflammation. Arch Biochem Biophys. 2005;440(2):123–32.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Chu AJ. Role of tissue factor in thrombosis. Coagulation-inflammation-thrombosis circuit. Front Biosci. 2006;(11):256–71.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Chu AJ. Tissue factor, blood coagulation, and beyond: an overview. Int J Inflamm. 2011; 2011. Article ID. 367284. p 30.Google Scholar
  22. Coughlin SR. Thrombin signalling & protease activated receptors. Nature. 2000;407(6801):258–64.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Demetz G, Ott I. The interface between inflammation and coagulation in cardiovascular disease. Int J Inflamm. 2012. Article ID. 860301. p. 8.Google Scholar
  24. Dietzen DJ, Page KL, Tetzloff TA. Lipid rafts are necessary for tonic inhibition of cellular tissue factor procoagulant activity. Blood. 2004;103(8):3038–44.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Drake TA, Morrissey JH, Edgington TS. Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis. Am J Pathol. 1989;134:1087–97.PubMedPubMedCentralGoogle Scholar
  26. Eddleston M, de la Torre JC, Oldstone MB. Astrocytes are the primary source of tissue factor in the murine central nervous system: a role for astrocytes in cerebral hemostasis. J Clin Invest. 1993;92(1):349–58.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Edgington TS, Mackman N, Brand K. The structural biology of expression and function of tissue factor. Thromb Haemost. 1991;66:67–79.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Evangelista FC, Rios DR, Ribeiro DD. Lack of association between potential prothrombotic genetic risk factors and arterial and venous thrombosis. Genet Mol Res. 2015;14(3):9585–94.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Falciani M, Gori AM, Fedi S, Chiarugi L, Simonetti I, Dabizzi RP, Prisco D, Pepe G, Abbate R, Gensini GF. Elevated tissue factor and tissue factor pathway inhibitor circulating levels in ischaemic heart disease patients. Thromb Haemost. 1998;79:495–9.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Fiore MM, Neuenschwander PF, Morrissey JH. The biochemical basis for the apparent defect of soluble mutant tissue factor in enhancing the proteolytic activities of factor VIIa. J Biol Chem. 1994;269(1):143–9.PubMedPubMedCentralGoogle Scholar
  31. Fisher KL, Gorman CM, Vehar GA, O’Brien DP, Lawn RM. Cloning and expression of human tissue factor cDNA. Thromb Res. 1987;48:89–99.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Freeburn JC, Wallace JM, Strain JJ, Sinnamon DG, Craig BM, Johnson D, Gilmore WS. Monocyte tissue factor-like activity in post myocardial infarction patients. Br J Haematol. 1998;102:605–8.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Giesen PL, Rauch U, Bohrmann B, Kling D, Roque M, Fallon JT, Badimon JJ, Himber J, Riederer MA, Nemerson Y. Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci USA. 1999a;96:2311–5.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Giesen PL, Rauch U, Bohrmann B. Blood-borne tissue factor: another view of thrombosis. PNAS. 1999b;96(5):2311–5.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Habis M, Gonzalez C, Jacq L, Pezzano M, Schaison F, Lardoux H. Hemostasis disturbances in myocardial ischemia. Ann Cardiol Angeiol. 2000;49(8):480–7.Google Scholar
  36. He WJ, Hu Y, Zhang XP, Hong M, Guo T, Wei WN, Song SJ. Activated protein C ratio, plasma tissue factor activity and activated factor VII in Chinese patients with coronary heart disease. Eur J Med Res. 2008;13(2):47–51.PubMedPubMedCentralGoogle Scholar
  37. Hembrough TA, Swartz GM, Papathanassiu A, Vlasuk GP, Rote WE, Green SJ, Pribluda VS. Tissue factor/factor VIIa inhibitors block angiogenesis and tumor growth through a nonhemostatic mechanism. Cancer Res. 2003.;63(11):2997–3000.Google Scholar
  38. Hembrough TA, Ruiz JF, Swerdlow BM, Swartz GM, Hammers HJ, Zhang L, Plum SM, Williams MS, Strickland DK, Pribluda VS. Identification and characterization of a very low density lipoprotein receptor-binding peptide from tissue factor pathway inhibitor that has antitumor and antiangiogenic activity. Blood. 2004;103(9):3374–80.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Henriksson CE, Klingenberg O, Hellum M, Landsverk KS, Joø GB, Westvik AB, Kierulf P. Calcium ionophore-induced de-encryption of tissue factor in monocytes is associated with extensive cell death. Thromb Res. 2007;119(5):621–30.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Hobbs JE, Zakarija A, Cundiff DL, Doll JA, Hymen E, Cornwell M, Crawford SE, Liu N, Signaevsky M, Soff GA. Alternatively spliced human tissue factor promotes tumor growth and angiogenesis in a pancreatic cancer tumor model. Thromb Res. 2007;120:S13–S21.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Huisse MG, Ajzenberg N, Feldman L, Guillin MC, Steg PG. Microparticle-linked tissue factor activity and increased thrombin activity play a potential role in fibrinolysis failure in ST-segment elevation myocardial infarction. Thromb Haemost. 2009;101:734–40.PubMedPubMedCentralGoogle Scholar
  42. Kambas K, Markiewski MM, Pneumatikos IA, Rafail SS, Theodorou V, Konstantonis D, Kourtzelis I, Doumas MN, Magotti P, Deangelis RA, Lambris JD, Ritis KD. C5a and TNF-alpha up-regulate the expression of tissue factor in intra-alveolar neutrophils of patients with the acute respiratory distress syndrome. J Immunol. 2008;180(11):7368–75.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Kim J, Min JK, Park JA, et al. Receptor activator of nuclear factor kappa B ligand is a novel inducer of tissue factor in macrophages. J Circ Res. 2010;107(7):871–6.CrossRefGoogle Scholar
  44. Koh KK, Chung WJ, Ahn JY, Han SH, Kang WC, Seo YH, Ahn TH, Choi IS, Shin EK. Angiotensin II type 1 receptor blockers reduce tissue factor activity and plasminogen activator inhibitor type-1 antigen in hypertensive patients: a randomized, double-blind, placebo-controlled study. Atherosclerosis. 2004;177(1):155–60.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Kostakoua P, Kolovoua K, Anagnostopoulou K. Efficacy of simvastatin or ezetimibe on tissue factor, von Willebrand’s factor and C-reactive protein in patients with hypercholesterolaemia. Arch Cardiovasc Dis. 2010;103(1):26–32.CrossRefGoogle Scholar
  46. Lopez-Pedrera C, Barbarroja N, Dorado G, et al. Tissue factor as an effector of angiogenesis and tumor progression in hematological malignancies. Leukemia. 2006;20(8):1331–40.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Mackman N. Regulation of the tissue factor gene. Thromb Haemost. 1997;78(1):747–54.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Mackman N. Role of tissue factor in hemostasis, thrombosis, and vascular development. Arteriosclero Thromb Vasc Biol. 2004;24(6):1015–22.CrossRefGoogle Scholar
  49. Mackman N. The role of tissue factor and factor VIIa in hemostasis. Anesth Analg. 2009;108(5):1447–52.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Mackman N, Parker JC. Tissue factor in the myocardium. Proceedings of the 18 Frontiers in Cardiovascullar Biology Congress; 2014.Google Scholar
  51. Malarstig A, Tenno T, Johnston N. Genetic variations in the tissue factor gene are associated with clinical outcome in acute coronary syndrome and expression levels in human monocytes. Arterioscler Thromb Vasc Biol. 2005;25(12):2667–72.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Mallat Z, Besnard S, Duriez M, et al. Protective role of interleukin-10 in atherosclerosis. Circ Res. 1999;85(8):17–24.CrossRefGoogle Scholar
  53. Maly M, Vojacek J, Hrabos V. Tissue factor, tissue factor pathway inhibitor and cytoadhesive molecules in patients with an acute coronary syndrome. Physiol Res. 2003;52:719–28.PubMedPubMedCentralGoogle Scholar
  54. Mariani G, Bernardi F, Bertina R. Serum phospholipids are the main environmental determinants of activated factor VII in the most common FVII genotype. Haematologica. 1999;84:620–6.PubMedPubMedCentralGoogle Scholar
  55. Martinez-Sales V, Vila V, Ferrando M, Reganon E. Atorvastatin neutralises the thrombin-induced tissue factor expresion in endothelial cells via geranylgeranyl pyrophosphate. Cytotechnology. 2011;63(1):1–5.PubMedPubMedCentralCrossRefGoogle Scholar
  56. Misumi K, Ogawa H, Yasue H, et al. Comparison of plasma tissue factor levels in unstable and stable angina pectoris. Am J Cardiol. 1998;81(1):22–6.PubMedPubMedCentralCrossRefGoogle Scholar
  57. Moons AH, Levi M, Peters RJ. Tissue factor and coronary artery disease. Cardiovasc Res. 2002;53(2):313–25.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Morange PE, Blankenberg S, Alessi MC, Bickel C, Rupprecht HJ, Schnabel R, Lubos E, Munzel T, Peetz D, Nicaud V. Prognostic value of plasma tissue factor and tissue factor pathway inhibitor for cardiovascular death in patients with coronary artery disease: the AtheroGene study. J Thromb Haemost. 2007;5:475–82.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Morel O, Pereira B, Averous G. Increased levels of procoagulant tissue factor-bearing microparticles within the occluded coronary artery of patients with ST-segment elevation myocardial infarction: Role of endothelial damage and leukocyte activation. Atherosclerosis. 2009;204(2):636–41.PubMedPubMedCentralCrossRefGoogle Scholar
  60. Morrissey JH, Fakhrai H, Edgington TS. Molecular cloning of the cDNA for tissue factor, the cellular receptor for the initiation of the coagulation protease cascade. Cell. 1987;50:129–35.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Muller YA, Ultsch MH, Kelley RF, de Vos AM. Structure of the extracellular domain of human tissue factor: location of the factor VIIa binding site. Biochemistry. 1994;33(36):10864–70.PubMedPubMedCentralCrossRefGoogle Scholar
  62. Opstad TB, Pettersen AA, Weiss T. Gender differences of polymorphisms in the TF and TFPI genes, as related to phenotypes in patients with coronary heart disease and type-2 diabetes. Thromb J. 2010;8:7.PubMedPubMedCentralCrossRefGoogle Scholar
  63. Ott I. Tissue factor in acute coronary syndromes. Semin Vasc Med. 2003;3:185–92.PubMedPubMedCentralCrossRefGoogle Scholar
  64. Ott I, Koch W, von Beckerath N. Tissue factor promotor polymorphism-603 A/G is associated with myocardial infarction. Atherosclerosis. 2004;177(1):189–91.PubMedPubMedCentralCrossRefGoogle Scholar
  65. Piazza L, Ridker PM. Is venous thromboembolism a chronic inflammatory disease? Clin Chem. 2015;61:313–6.PubMedPubMedCentralCrossRefGoogle Scholar
  66. Ray B, Chetter IC, Lee HL, Ettelaie C, PT MC. Plasma tissue factor is a predictor for restenosis after femoropopliteal angioplasty. Br J Surg. 2007;94(9):1092–5.PubMedPubMedCentralCrossRefGoogle Scholar
  67. Reny JL, Laurendeau I, Fontana P. The TF-603A/G gene promoter polymorphism and circulating monocyte tissue factor gene expression in healthy volunteers. Thromb Haemost. 2004;91(2):248–54.PubMedPubMedCentralGoogle Scholar
  68. Rickles FR, Patierno S, Fernandez PM. Tissue factor, thrombin, and cancer. Chest. 2003;124(3):58–68.CrossRefGoogle Scholar
  69. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999;340(2):115–26.CrossRefPubMedPubMedCentralGoogle Scholar
  70. Ruf W, Rehemtulla A, Morrissey JH, Edgington TS. Phospholipid independent and dependent interactions required for tissue factor receptor and cofactor function. J Biol Chem. 1991;266(4):2158–66.PubMedPubMedCentralGoogle Scholar
  71. Scarpati EM, Wen D, Broze GJ, Miletich JP, Flandermeyer RR, Siegel NR, Sadler JE. Human tissue factor: cDNA sequence and chromosome localizatopn of the gene. Biochemistry. 1987;26:5234–8.PubMedPubMedCentralCrossRefGoogle Scholar
  72. Seljeflot I, Hurlen M, Hole T, Arnesen H. Soluble tissue factor as predictor of future events in patients with acute myocardial infarction. Thromb Res. 2003;111:369–72.PubMedPubMedCentralCrossRefGoogle Scholar
  73. Smith A, Hurlen M, Hole T, Arnesen H. Which hemostatic markers add to the predictive value of conventional risk factors for coronary heart disease and ischemic stroke? The Caerphilly Study. Circulation. 2005;112(20):3080–7.PubMedPubMedCentralCrossRefGoogle Scholar
  74. Soejima H, Ogawa H, Yasue H. Heightened tissue factor associated with tissue factor pathway inhibitor and prognosis in patients with unstable angina. Circulation. 1999;99(22):2908–13.PubMedPubMedCentralCrossRefGoogle Scholar
  75. Spicer EK, Horton R, Bloem L. Isolation of cDNA clones coding for human tissue factor: primary structure of the protein and cDNA. PNAS. 1987;84(15):5148–52.PubMedPubMedCentralCrossRefGoogle Scholar
  76. Stampfuss JJ, Censarek P, Bein D. Membrane environment rather than tissue factor expression determines thrombin formation triggered by monocytic cells undergoing apoptosis. J Leukoc Biol. 2008;83(6):1379–81.PubMedPubMedCentralCrossRefGoogle Scholar
  77. Steffel J, Lüscher TF, Tanner FC. Tissue factor in cardiovascular diseases: molecular mechanisms and clinical implications. Circulation. 2006;113(5):722–31.PubMedPubMedCentralCrossRefGoogle Scholar
  78. Stojkovic S. IL-33 induces tissue factor in human endothelial cells – impact on atherosclerotic plague thrombotic potential. Proceedings of the 18 Frontiers in Cardiovascullar Biology Congress; 2014.Google Scholar
  79. Suefuji H, Ogawa H, Yasue H, Kaikita K, Soejima H, Motoyama T, Mizuno Y, Oshima S, Saito T, Tsuji I, Kumeda K, Kamikubo Y, Nakamura S. Increased plasma tissue factor levels in acute myocardial infarction. Am Heart J. 1997;134(2 Pt 1):253–9.PubMedPubMedCentralCrossRefGoogle Scholar
  80. Tremoli E, Camera M, Toschi V, Colli S. Tissue factor in atherosclerosis. Atherosclerosis. 1999;144(2):273–83.PubMedPubMedCentralCrossRefGoogle Scholar
  81. von der Thüsen JH, Kuiper J, van Berkel TJ, Biessen EA. Interleukins in atherosclerosis: molecular pathways and therapeutic potential. Pharmacol. Rev. 2003;55(1):133–66.PubMedPubMedCentralCrossRefGoogle Scholar
  82. Walsh PN. Roles of factor XI, platelets and tissue factor-initiated blood coagulation. J Thromb Haemost. 2003;1(10):2081–6.PubMedPubMedCentralCrossRefGoogle Scholar
  83. Wilcox JN, Smith KM, Schwartz SM, Gordon D, Wilcox JN. Localization of tissue factor in the normal vessel wall and the atherosclerotic plaque. Proc Natl Acad Sci. 1989;84(8):2839–43.CrossRefGoogle Scholar
  84. Zhu T, Mancini JA, Sapieha P, Yang C, Joyal JS, Honoré JC, Leduc M, Zaniolo K, Hardy P, Shao Z, Fan L, Hou X, Rivard GE, Chemtob S. Cortactin activation by FVIIa/tissue factor and PAR2 promotes endothelial cell migration. Am J Physiol Regul Integr Comp Physiol. 2011;300(3):R577–85.PubMedPubMedCentralCrossRefGoogle Scholar
  85. Zwicker JI, Trenor CC, Furie BC, Furie B. Tissue factor-bearing microparticles and thrombus formation. Arterioscler. Thromb Vasc Biol. 2011;31(4):728–33.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Гpaциaнcкий HA. Hecтaбильнaя cтeнoкapдия – ocтpый кopoнapный cиндpoм. III. Пpeдупpeждeниe oбocтpeний ишeмичecкoй бoлeзни cepдцa. Cтaтины и aнтибиoтики. Кapдиoлoгия. 1997;37(11):4–17.Google Scholar

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Authors and Affiliations

  1. 1.I.P. Pavlov 1st Saint Petersburg State Medical UniversitySt. PetersburgRussia
  2. 2.Federal Almazov North-West Research CentreSt. PetersburgRussia