Tissue factor explained

Tissue factor, also called platelet tissue factor or Coagulation factor III,^[1] is a protein present in subendothelial tissue and leukocytes which plays a major role in coagulation and, in humans, is encoded by F3 gene. Its role in the blood clotting is the initiation of thrombin formation from the zymogen prothrombin. Thromboplastin defines the cascade that leads to the activation of factor X—the tissue factor pathway. In doing so, it has replaced the previously named extrinsic pathway in order to eliminate ambiguity.

Function

The F3 gene encodes tissue factor also known as coagulation factor III, which is a cell surface glycoprotein. This factor enables cells to initiate the blood coagulation cascades, and it functions as the high-affinity receptor for the coagulation factor VII. The resulting complex provides a catalytic event that is responsible for initiation of the coagulation protease cascades by specific limited proteolysis. Unlike the other cofactors of these protease cascades, which circulate as nonfunctional precursors, this factor is a potent initiator that is fully functional when expressed on cell surfaces. There are three distinct domains of this factor: extracellular, transmembrane, and cytoplasmic. This protein is the only one in the coagulation pathway for which a congenital deficiency has not been described.^[2] In addition to the membrane-bound tissue factor, soluble form of tissue factor was also found which results from alternatively spliced tissue factor mRNA transcripts, in which exon 5 is absent and exon 4 is spliced directly to exon 6.^{[3] [4]}

Coagulation

Tissue factor (TF) is the cell surface receptor for the serine protease factor VIIa.

The best known function of tissue factor is its role in blood coagulation. The complex of TF with factor VIIa catalyzes the conversion of the inactive protease factor X into the active protease factor Xa.

Together with factor VIIa, tissue factor forms the extrinsic pathway of coagulation. This is opposed to the intrinsic (amplification) pathway, which involves both activated factor IX and factor VIII. Both pathways lead to the activation of factor X (the common pathway), which combines with activated factor V in the presence of calcium and phospholipid to produce thrombin (thromboplastin activity).

Cytokine signaling

TF is related to a protein family known as the cytokine receptor class II family. The members of this receptor family are activated by cytokines. Cytokines are small proteins that can influence the behavior of white blood cells. Binding of VIIa to TF has also been found to start signaling processes inside the cell. The signaling function of TF/VIIa plays a role in angiogenesis and apoptosis. Pro-inflammatory and pro-angiogenic responses are activated by TF/VIIa-mediated cleavage by the protease-activated receptor 2 (PAR2).^[5] EphB2 and EphA2 of the Eph tyrosine kinase receptor (RTK) family can also be cleaved by TF/VIIa.^[6]

Structure

Tissue factor belongs to the cytokine receptor protein superfamily and consists of three domains:^[7]

1. an extracellular domain, which consists of two fibronectin type III modules whose hydrophobic cores merge in the domain-domain interface. This serves as a (probably rigid) template for factor VIIa binding.
2. a transmembrane domain.
3. a cytosolic domain of 21 amino acids length inside the cell which is involved in the signaling function of TF.

Note that one of factor VIIa's domains, GLA domain, binds in the presence of calcium to negatively charged phospholipids, and this binding greatly enhances factor VIIa binding to tissue factor.

Tissue distribution

Some cells release TF in response to blood vessel damage (see next paragraph) and some do only in response to inflammatory mediators (endothelial cells/macrophages).

TF is expressed by cells which are normally not exposed to flowing blood, such as sub-endothelial cells (e.g. smooth muscle cells) and cells surrounding blood vessels (e.g. fibroblasts). This can change when the blood vessel is damaged by, for example, physical injury or rupture of atherosclerotic plaques. Exposure of TF-expressing cells during injury allows the complex formation of TF with factor VII. Factor VII and TF form an equimolar complex in the presence of calcium ions, leading to the activation of factor VII on a membrane surface.

The inner surface of the blood vessel consists of endothelial cells. Endothelial cells do not express TF except when they are exposed to inflammatory molecules such as tumor necrosis factor-alpha (TNF-alpha). Another cell type that expresses TF on the cell surface in inflammatory conditions is the monocyte (a white blood cell).

Thromboplastin

Historically, thromboplastin was a lab reagent, usually derived from placental sources, used to assay prothrombin times (PT time). Thromboplastin, by itself, could activate the extrinsic coagulation pathway. When manipulated in the laboratory, a derivative could be created called partial thromboplastin, which was used to measure the intrinsic pathway. This test is called the aPTT, or activated partial thromboplastin time. It was not until much later that the subcomponents of thromboplastin and partial thromboplastin were identified. Thromboplastin contains phospholipids as well as tissue factor, both of which are needed in the activation of the extrinsic pathway, whereas partial thromboplastin does not contain tissue factor. Tissue factor is not needed to activate the intrinsic pathway.

Interactions

Tissue factor has been shown to interact with Factor VII.^{[8] [9]}

See also

• Hemostasis

Further reading

• Gouault-Helimann M, Josso F . [Initiation in vivo of blood coagulation. The role of white blood cells and tissue factor (author's transl)] . La Nouvelle Presse Medicale . 8 . 40 . 3249–3253 . October 1979 . 392457 .
• Mackman N . Regulation of the tissue factor gene . FASEB Journal . 9 . 10 . 883–889 . July 1995 . 7615158 . 10.1096/fasebj.9.10.7615158 . 23822012 . free .
• McVey JH . Tissue factor pathway . Bailliere's Best Practice & Research. Clinical Haematology . 12 . 3 . 361–372 . September 1999 . 10856975 . 10.1053/beha.1999.0030 .
• Konigsberg W, Kirchhofer D, Riederer MA, Nemerson Y . The TF:VIIa complex: clinical significance, structure-function relationships and its role in signaling and metastasis . Thrombosis and Haemostasis . 86 . 3 . 757–771 . September 2001 . 11583305 . 10.1055/s-0037-1616129 . 28579579 .
• Versteeg HH, Peppelenbosch MP, Spek CA . The pleiotropic effects of tissue factor: a possible role for factor VIIa-induced intracellular signalling? . Thrombosis and Haemostasis . 86 . 6 . 1353–1359 . December 2001 . 11776298 . 10.1055/s-0037-1616734 . 10976556 .
• Fernandez PM, Rickles FR . Tissue factor and angiogenesis in cancer . Current Opinion in Hematology . 9 . 5 . 401–406 . September 2002 . 12172458 . 10.1097/00062752-200209000-00003 . 2736760 .
• Golino P . The inhibitors of the tissue factor:factor VII pathway . Thrombosis Research . 106 . 3 . V257–V265 . May 2002 . 12356487 . 10.1016/S0049-3848(02)00079-8 .
• Engelmann B, Luther T, Müller I . Intravascular tissue factor pathway--a model for rapid initiation of coagulation within the blood vessel . Thrombosis and Haemostasis . 89 . 1 . 3–8 . January 2003 . 12540946 . 10.1055/s-0037-1613535 . 32138198 .
• Morrissey JH . Tissue factor: in at the start...and the finish? . Journal of Thrombosis and Haemostasis . 1 . 5 . 878–880 . May 2003 . 12871349 . 10.1046/j.1538-7836.2003.00219.x . 39106656 . free .
• Yu JL, May L, Klement P, Weitz JI, Rak J . Oncogenes as regulators of tissue factor expression in cancer: implications for tumor angiogenesis and anti-cancer therapy . Seminars in Thrombosis and Hemostasis . 30 . 1 . 21–30 . February 2004 . 15034795 . 10.1055/s-2004-822968 . 260317043 .
• Fernandez PM, Patierno SR, Rickles FR . Tissue factor and fibrin in tumor angiogenesis . Seminars in Thrombosis and Hemostasis . 30 . 1 . 31–44 . February 2004 . 15034796 . 10.1055/s-2004-822969 . 260320942 .
• Mackman N . Role of tissue factor in hemostasis, thrombosis, and vascular development . Arteriosclerosis, Thrombosis, and Vascular Biology . 24 . 6 . 1015–1022 . June 2004 . 15117736 . 10.1161/01.ATV.0000130465.23430.74 . free .
• Belting M, Ahamed J, Ruf W . Signaling of the tissue factor coagulation pathway in angiogenesis and cancer . Arteriosclerosis, Thrombosis, and Vascular Biology . 25 . 8 . 1545–1550 . August 2005 . 15905465 . 10.1161/01.ATV.0000171155.05809.bf . 1785798 . free .
• Engelmann B . Initiation of coagulation by tissue factor carriers in blood . Blood Cells, Molecules & Diseases . 36 . 2 . 188–190 . 2007 . 16473535 . 10.1016/j.bcmd.2005.12.020 .
• Furie B, Furie BC . Cancer-associated thrombosis . Blood Cells, Molecules & Diseases . 36 . 2 . 177–181 . 2007 . 16490369 . 10.1016/j.bcmd.2005.12.018 .
• Mackman N . Alternatively spliced tissue factor - one cut too many? . Thrombosis and Haemostasis . 97 . 1 . 5–8 . January 2007 . 17200762 . 10.1160/th06-11 .
• Wiiger MT, Prydz H . The changing faces of tissue factor biology. A personal tribute to the understanding of the "extrinsic coagulation activation" . Thrombosis and Haemostasis . 98 . 1 . 38–42 . July 2007 . 17597988 . 10.1160/th07-04-0289 . 32384175 . free .

External links

• • —March 2006
• PDBe-KB provides an overview of all the structure information available in the PDB for Human Tissue factor

Notes and References

1. Zhou RF, Liu Y, Wang YX, Mo W, Yu M . Coagulation factor III (tissue factor) is required for vascularization in zebrafish embryos . Genetics and Molecular Research . 10 . 4 . 4147–4157 . October 2011 . 22057990 . 10.4238/2011.October.31.2 .
2. Web site: Entrez Gene: F3 coagulation factor III (thromboplastin, tissue factor).
3. Guo W, Wang H, Zhao W, Zhu J, Ju B, Wang X . Effect of all-trans retinoic acid and arsenic trioxide on tissue factor expression in acute promyelocytic leukemia cells . Chinese Medical Journal . 114 . 1 . 30–34 . January 2001 . 11779431 .
4. Bogdanov VY, Balasubramanian V, Hathcock J, Vele O, Lieb M, Nemerson Y . Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein . Nature Medicine . 9 . 4 . 458–462 . April 2003 . 12652293 . 10.1038/nm841 . 13173744 .
5. Ruf W, Disse J, Carneiro-Lobo TC, Yokota N, Schaffner F . Tissue factor and cell signalling in cancer progression and thrombosis . Journal of Thrombosis and Haemostasis . 9 . Suppl 1 . 306–315 . July 2011 . 21781267 . 3151023 . 10.1111/j.1538-7836.2011.04318.x .
6. Eriksson O, Ramström M, Hörnaeus K, Bergquist J, Mokhtari D, Siegbahn A . The Eph tyrosine kinase receptors EphB2 and EphA2 are novel proteolytic substrates of tissue factor/coagulation factor VIIa . The Journal of Biological Chemistry . 289 . 47 . 32379–32391 . November 2014 . 25281742 . 4239594 . 10.1074/jbc.M114.599332 . free .
7. Muller YA, Ultsch MH, de Vos AM . The crystal structure of the extracellular domain of human tissue factor refined to 1.7 A resolution . Journal of Molecular Biology . 256 . 1 . 144–159 . February 1996 . 8609606 . 10.1006/jmbi.1996.0073 .
8. Carlsson K, Freskgård PO, Persson E, Carlsson U, Svensson M . Probing the interface between factor Xa and tissue factor in the quaternary complex tissue factor-factor VIIa-factor Xa-tissue factor pathway inhibitor . European Journal of Biochemistry . 270 . 12 . 2576–2582 . June 2003 . 12787023 . 10.1046/j.1432-1033.2003.03625.x . free .
9. Zhang E, St Charles R, Tulinsky A . Structure of extracellular tissue factor complexed with factor VIIa inhibited with a BPTI mutant . Journal of Molecular Biology . 285 . 5 . 2089–2104 . February 1999 . 9925787 . 10.1006/jmbi.1998.2452 .