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Gene Review

F3  -  coagulation factor III (thromboplastin,...

Homo sapiens

Synonyms: CD142, Coagulation factor III, TF, TFA, Thromboplastin, ...
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Disease relevance of F3

  • Tissue factor (TF), the protease receptor initiating the coagulation system, functions in vascular development, angiogenesis, and tumor cell metastasis by poorly defined molecular mechanisms [1].
  • Indeed, systemic hypercoagulability in patients with cancer and TF overexpression by cancer cells are both closely associated with tumor progression, but their causes have been elusive [2].
  • At a high dose of rLACI (800 micrograms/kg body weight), the thromboplastin-induced radioactivity increase in the lungs and the systemic fibrinogen decrease were completely suppressed [3].
  • Tissue factor (TF) has been implicated in several important biologic processes, including fibrin formation, atherogenesis, angiogenesis, and tumor cell migration [4].
  • Both TF and TFPI are major regulators of coagulation and thrombosis [5].

Psychiatry related information on F3


High impact information on F3

  • This receptor appears novel, lacking significant homology with other proteins; however, TF contains the uncommon tryptophan-lysine-serine (WKS) sequence repeated three times, a sequence we find in some serine protease-binding proteins and suggest may represent a functional sequence motif [11].
  • We identified eight patients with the lupus anticoagulant (an autoantibody acquired by some patients with systemic lupus erythematosus), by observation of an increased activated partial thromboplastin time and abnormal results on a tissue thromboplastin-inhibition test [12].
  • Group 2 (38 patients) was started on the same dose, which was then adjusted to keep the activated partial thromboplastin time between 31.5 and 36 seconds [13].
  • We conducted a study to determine whether adjustment of the dose of subcutaneous heparin to yield partial thromboplastin times in the high-normal range results in a greater reduction of postoperative deep-vein thrombosis than fixed doses of heparin [13].
  • The prolonged thromboplastin times were corrected by normal plasma and by normal plasma adsorbed with celite, but there was no mutual correction between plasmas of the patients [14].

Chemical compound and disease context of F3


Biological context of F3

  • Our goal was to investigate whether single nucleotide polymorphisms (SNP) in the TF gene (F3) are associated with plasma TF, risk, and outcome in patients with ACS [20].
  • Replacement of TF's cytoplasmic Ser residues with Asp to mimic phosphorylation enhances the interaction with ABP-280, whereas Ala mutations abolish coprecipitation of ABP-280 with immobilized TF cytoplasmic domain, and severely reduce cell spreading [1].
  • We demonstrate that immobilized ligands for TF specifically support cell adhesion, migration, spreading, and intracellular signaling, which are not inhibited by RGD peptides [1].
  • Tissue factor (TF) plays an important role in hemostasis, inflammation, angiogenesis, and the pathophysiology of atherosclerosis and cancer [21].
  • The activated partial thromboplastin time and prothrombin time of the plasma samples lengthened, possibly due to the presence of thromboplastin in circulation [3].

Anatomical context of F3


Associations of F3 with chemical compounds

  • Binding of Pg 1 to isolated TF was inhibited by 6-aminohexanoic acid and alpha-methylmannoside, suggesting that Pg 1 L-lysine binding sites and the biantennary, mannose-containing N-linked oligosaccharide chain are involved in this interaction [23].
  • Tissue factor (TF), a transmembrane receptor for the serine protease coagulation factor VII(a) (FVIIa), is the main initiator of the coagulation cascade [24].
  • Previous studies using alanine mutagenesis have identified TF residues Lys165 and Lys166 as important for factor X (FX) activation, hypothesizing either that these residues interact with phospholipid head groups or that they directly or indirectly promote macromolecular substrate binding [25].
  • Melatonin significantly decreased LPS-induced TF activity by 48% (P < 0.01) directly after exercise, and a 44% reduction was seen 2 hr later (P < 0.02) [26].
  • Tissue factor (TF) is a transmembrane glycoprotein that initiates blood coagulation when complexed with factor VIIa (FVIIa) [27].

Physical interactions of F3

  • Plasminogen bound to a site on the TF apoprotein that appears to be distinct from the binding site for factors VII and VIIa as judged by a combination of biosensor and cell assays [4].
  • These findings indicate that FVIIa protease induction of VEGF expression is mediated by thrombin and FXa generated in response to FVIIa binding to TF-expressing fibroblasts; they also exclude a direct signaling involving MAP kinase activation via the intracellular domain of TF when expressed by these cells [22].
  • Transient transfections with TF promoter constructs containing SP and EGR-1 binding sites before and after inactivation by site-directed mutagenesis revealed that Sp1 mediates basal and progestin-enhanced TF transcriptional activity [28].
  • 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 [29].
  • Exposure to functionally inactivated FVIIa did not show any effect on uPAR expression on SW979 cells despite binding to TF with higher efficiency [30].

Enzymatic interactions of F3

  • Consistently, the antibody depressed TF/FVII-catalyzed FX activation was shown on Western blotting analysis [31].

Co-localisations of F3

  • 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].
  • Furthermore, TF has been colocalized with VEGF in breast cancer, specially at sites of early angiogenesis [33].

Regulatory relationships of F3

  • Recombinant lipoprotein-associated coagulation inhibitor inhibits tissue thromboplastin-induced intravascular coagulation in the rabbit [3].
  • TF enhanced two-chain urokinase (tcuPA) activation of Glu-plasminogen, but not of miniplasminogen, in a dose-dependent, saturable manner (half maximal stimulation at 59 pmol/L) [4].
  • In contrast, TGF-beta required 4 h of priming to inhibit TF expression induced by LPS [34].
  • The increase in TF activity induced by both rsCD40L and activated platelet supernatants was inhibited by anti-CD40L antibody [35].
  • Celite activation of TAFI-deficient/FXIII-supplemented plasma showed significantly prolonged onset and duration of clot lysis compared with samples activated with TF [36].

Other interactions of F3

  • Two-hybrid screening identified actin-binding protein 280 (ABP-280) as ligand for the TF cytoplasmic domain [1].
  • The stimulatory effect of TF on plasminogen activation was confirmed when plasmin formation was examined directly on sodium dodecyl sulfate-polyacrylamide gel electrophoresis [4].
  • In this study, we have explored the ramifications of VEGF induction of tissue factor (TF) in human umbilical vein endothelial cells (HUVECs) and subsequent activation of progelatinase A [37].
  • STUDY OBJECTIVE: Cytokines increase endothelial tissue factor (TF) and tissue plasminogen activator inhibitor type-1 (PAI-1) expression in vitro [38].
  • Recombinant IL-1 beta also induced the synthesis of clotting factor VII in monocytes, thus allowing the formation of TPL-factor VII complexes, a most powerful trigger of blood clotting [39].

Analytical, diagnostic and therapeutic context of F3

  • Extracellular ligation of TF is necessary for ABP-280 binding [1].
  • Plasminogen was found to bind directly to the extracellular domain of TF apoprotein (amino acids 1-219) as determined by optical biosensor interaction analysis [4].
  • Electrophoretic mobility shift assays demonstrate the binding of Fos/Jun complexes to two TF promoter AP-1 sites in this region [40].
  • For this we investigated the effects of EP on the expression and function of tissue factor (TF), the principal initiator of coagulation activation in sepsis, in human monocytic (THP-1) cell cultures [41].
  • In a rat model of disseminated intravascular coagulation (DIC), intravenous injection of a human TF-containing thromboplastin reagent (0.5 ml/kg) resulted in an immediate death in approximately 60% of the animals and a clinical score of approximately 2 [42].


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  2. Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis. Yu, J.L., May, L., Lhotak, V., Shahrzad, S., Shirasawa, S., Weitz, J.I., Coomber, B.L., Mackman, N., Rak, J.W. Blood (2005) [Pubmed]
  3. Recombinant lipoprotein-associated coagulation inhibitor inhibits tissue thromboplastin-induced intravascular coagulation in the rabbit. Day, K.C., Hoffman, L.C., Palmier, M.O., Kretzmer, K.K., Huang, M.D., Pyla, E.Y., Spokas, E., Broze, G.J., Warren, T.G., Wun, T.C. Blood (1990) [Pubmed]
  4. Tissue factor regulates plasminogen binding and activation. Fan, Z., Larson, P.J., Bognacki, J., Raghunath, P.N., Tomaszewski, J.E., Kuo, A., Canziani, G., Chaiken, I., Cines, D.B., Higazi, A.A. Blood (1998) [Pubmed]
  5. Angiotensin-converting enzyme inhibition reduces monocyte chemoattractant protein-1 and tissue factor levels in patients with myocardial infarction. Soejima, H., Ogawa, H., Yasue, H., Kaikita, K., Takazoe, K., Nishiyama, K., Misumi, K., Miyamoto, S., Yoshimura, M., Kugiyama, K., Nakamura, S., Tsuji, I. J. Am. Coll. Cardiol. (1999) [Pubmed]
  6. Intracellular and surface distribution of monocyte tissue factor: application to intersubject variability. Egorina, E.M., Sovershaev, M.A., Bjørkøy, G., Gruber, F.X., Olsen, J.O., Parhami-Seren, B., Mann, K.G., Østerud, B. Arterioscler. Thromb. Vasc. Biol. (2005) [Pubmed]
  7. Usefulness of thrombelastography for dosage monitoring of low molecular weight heparin and unfractionated heparin during hemodialysis. Shinoda, T., Arakura, H., Katakura, M., Shirota, T., Nakagawa, S. Artificial organs. (1990) [Pubmed]
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  9. Screening INR deviation of local prothrombin time systems. Poller, L. J. Clin. Pathol. (1998) [Pubmed]
  10. Near-patient testing of haemostasis in the operating theatre: an approach to appropriate use of blood in surgery. Samama, C.M., Ozier, Y. Vox Sang. (2003) [Pubmed]
  11. Molecular cloning of the cDNA for tissue factor, the cellular receptor for the initiation of the coagulation protease cascade. Morrissey, J.H., Fakhrai, H., Edgington, T.S. Cell (1987) [Pubmed]
  12. Obstetric complications associated with the lupus anticoagulant. Branch, D.W., Scott, J.R., Kochenour, N.K., Hershgold, E. N. Engl. J. Med. (1985) [Pubmed]
  13. Adjusted versus fixed-dose subcutaneous heparin in the prevention of deep-vein thrombosis after total hip replacement. Leyvraz, P.F., Richard, J., Bachmann, F., Van Melle, G., Treyvaud, J.M., Livio, J.J., Candardjis, G. N. Engl. J. Med. (1983) [Pubmed]
  14. The Passovoy defect: further characterization of a hereditary hemorrhagic diathesis. Hougie, C., Mc Pherson, R.A., Brown, J.E., Lakin-Thomas, P.L., Melaragno, A., Aronson, L., Baugh, R.F. N. Engl. J. Med. (1978) [Pubmed]
  15. Intravenous recombinant soluble human thrombomodulin prevents venous thrombosis in a rat model. Solis, M.M., Cook, C., Cook, J., Glaser, C., Light, D., Morser, J., Yu, S.C., Fink, L., Eidt, J.F. J. Vasc. Surg. (1991) [Pubmed]
  16. Effects of all-trans-retinoic acid and arsenic trioxide on the hemostatic disturbance associated with acute promyelocytic leukemia. Zhao, W., Wang, H., Wang, X., Wu, F., Guo, W., Qu, B., Shen, Z., Wang, Z. Thromb. Res. (2001) [Pubmed]
  17. Progesterone increases tissue factor gene expression, procoagulant activity, and invasion in the breast cancer cell line ZR-75-1. Kato, S., Pinto, M., Carvajal, A., Espinoza, N., Monso, C., Sadarangani, A., Villalon, M., Brosens, J.J., White, J.O., Richer, J.K., Horwitz, K.B., Owen, G.I. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  18. Identification of a novel human tissue factor splice variant that is upregulated in tumor cells. Chand, H.S., Ness, S.A., Kisiel, W. Int. J. Cancer (2006) [Pubmed]
  19. Biological mechanisms underlying the clinical effects of mifepristone (RU 486) on the endometrium. Papp, C., Schatz, F., Krikun, G., Hausknecht, V., Lockwood, C.J. Early pregnancy (Online) (2000) [Pubmed]
  20. Genetic variations in the tissue factor gene are associated with clinical outcome in acute coronary syndrome and expression levels in human monocytes. Mälarstig, A., Tenno, T., Johnston, N., Lagerqvist, B., Axelsson, T., Syvänen, A.C., Wallentin, L., Siegbahn, A. Arterioscler. Thromb. Vasc. Biol. (2005) [Pubmed]
  21. 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]
  22. Vascular endothelial growth factor production by fibroblasts in response to factor VIIa binding to tissue factor involves thrombin and factor Xa. Ollivier, V., Chabbat, J., Herbert, J.M., Hakim, J., de Prost, D. Arterioscler. Thromb. Vasc. Biol. (2000) [Pubmed]
  23. Tissue factor is the receptor for plasminogen type 1 on 1-LN human prostate cancer cells. Gonzalez-Gronow, M., Gawdi, G., Pizzo, S.V. Blood (2002) [Pubmed]
  24. Factor VIIa induces tissue factor-dependent up-regulation of interleukin-8 in a human keratinocyte line. Wang, X., Gjernes, E., Prydz, H. J. Biol. Chem. (2002) [Pubmed]
  25. Substrate recognition by tissue factor-factor VIIa. Evidence for interaction of residues Lys165 and Lys166 of tissue factor with the 4-carboxyglutamate-rich domain of factor X. Huang, Q., Neuenschwander, P.F., Rezaie, A.R., Morrissey, J.H. J. Biol. Chem. (1996) [Pubmed]
  26. The in vivo effect of melatonin on cellular activation processes in human blood during strenuous physical exercise. Johe, P.D., Østerud, B. J. Pineal Res. (2005) [Pubmed]
  27. Formation of tissue factor-factor VIIa-factor Xa complex prevents apoptosis in human breast cancer cells. Jiang, X., Guo, Y.L., Bromberg, M.E. Thromb. Haemost. (2006) [Pubmed]
  28. Progestin-regulated expression of tissue factor in decidual cells: implications in endometrial hemostasis, menstruation and angiogenesis. Schatz, F., Krikun, G., Caze, R., Rahman, M., Lockwood, C.J. Steroids (2003) [Pubmed]
  29. 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]
  30. Enhanced expression of urokinase receptor induced through the tissue factor-factor VIIa pathway in human pancreatic cancer. Taniguchi, T., Kakkar, A.K., Tuddenham, E.G., Williamson, R.C., Lemoine, N.R. Cancer Res. (1998) [Pubmed]
  31. Anticoagulant potential of an antibody against factor VII. Chu, A.J., Mathews, S.T. J. Surg. Res. (2003) [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. Pentoxifylline inhibits hypoxia-induced upregulation of tumor cell tissue factor and vascular endothelial growth factor. Amirkhosravi, A., Meyer, T., Warnes, G., Amaya, M., Malik, Z., Biggerstaff, J.P., Siddiqui, F.A., Sherman, P., Francis, J.L. Thromb. Haemost. (1998) [Pubmed]
  34. Inhibition of tissue factor surface expression in human peripheral blood monocytes exposed to cytokines. Ernofsson, M., Tenno, T., Siegbahn, A. Br. J. Haematol. (1996) [Pubmed]
  35. Platelet-CD40 ligand interaction with melanoma cell and monocyte CD40 enhances cellular procoagulant activity. Amirkhosravi, A., Amaya, M., Desai, H., Francis, J.L. Blood Coagul. Fibrinolysis (2002) [Pubmed]
  36. Contact activation prolongs clot lysis time in human plasma: role of thrombin-activatable fibrinolysis inhibitor and Factor XIII. Nielsen, V.G., Steenwyk, B.L., Gurley, W.Q. J. Heart Lung Transplant. (2006) [Pubmed]
  37. Vascular endothelial growth factor induces tissue factor and matrix metalloproteinase production in endothelial cells: conversion of prothrombin to thrombin results in progelatinase A activation and cell proliferation. Zucker, S., Mirza, H., Conner, C.E., Lorenz, A.F., Drews, M.H., Bahou, W.F., Jesty, J. Int. J. Cancer (1998) [Pubmed]
  38. The tissue factor and plasminogen activator inhibitor type-1 response in pediatric sepsis-induced multiple organ failure. Green, J., Doughty, L., Kaplan, S.S., Sasser, H., Carcillo, J.A. Thromb. Haemost. (2002) [Pubmed]
  39. Cytokine-induced procoagulant activity in monocytes and endothelial cells. Further enhancement by cyclosporine. Carlsen, E., Flatmark, A., Prydz, H. Transplantation (1988) [Pubmed]
  40. PML/RARalpha plays a role for basal activity and retinoid-induced repression of the tissue factor promoter in acute promyelocytic leukemia cells. Tenno, T., Oberg, F., Mackman, N., Nilsson, K., Siegbahn, A. Thromb. Haemost. (2003) [Pubmed]
  41. Ethyl pyruvate exerts combined anti-inflammatory and anticoagulant effects on human monocytic cells. van Zoelen, M.A., Bakhtiari, K., Dessing, M.C., Van't Veer, C., Spek, C.A., Tanck, M., Meijers, J.C., van der Poll, T. Thromb. Haemost. (2006) [Pubmed]
  42. Amplified anticoagulant activity of tissue factor-targeted thrombomodulin. In-vivo validation of a tissue factor-neutralizing antibody fused to soluble thrombomodulin. Wang, Y.X., Wu, C., Vincelette, J., Martin-McNulty, B., Alexander, S., Larsen, B., Light, D.R., McLean, K. Thromb. Haemost. (2006) [Pubmed]
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