Thromboplastin

Tissue factor, also called thromboplastin, factor III or cluster of differentiation (CD142) is a protein present in endothelium (subendothelial tissue), platelets, and leukocytes necessary for the initiation of thrombin formation from the zymogen prothrombin. Thrombin formation ultimately leads to the coagulation of blood.

This gene encodes 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 3 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.

Structure

The protein structure of TF consists of three domains:

• 1. a domain which is located outside the cell, this domain binds factor VIIa. The binding of VIIa to TF occurs via protein-protein interactions by both molecules.
  • Factor VIIa is a protein which consists of several domains. One of these domains, the carboxylated GLA domain, binds in the presence of calcium to negatively charged phospholipids. Binding of VIIa to negatively charged phospholipids greatly enhances the protein-protein binding of VIIa to TF.

• 2. a domain which crosses the hydrophobic membrane.

• 3. a domain of 21 amino acids length inside the cell which is involved in the signaling function of TF.

Functions

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Cytokine

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 the formation of new blood vessels (angiogenesis) and in the inhibition of the process of cell suicide (apoptosis)

Location

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 equal molar complex in the presence of calcium ions and this leads 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).

Further reading

• Gouault-Helimann M, Josso F (1980). [Initiation in vivo of blood coagulation. The role of white blood cells and tissue factor (author's transl)]. La Nouvelle presse médicale 8 (40): 3249-53.
• Mackman N (1995). Regulation of the tissue factor gene.. FASEB J. 9 (10): 883-9.
• McVey JH (2000). Tissue factor pathway.. Baillieres Best Pract. Res. Clin. Haematol. 12 (3): 361-72.
• Konigsberg W, Kirchhofer D, Riederer MA, Nemerson Y (2002). The TF:VIIa complex: clinical significance, structure-function relationships and its role in signaling and metastasis.. Thromb. Haemost. 86 (3): 757-71.
• Versteeg HH, Peppelenbosch MP, Spek CA (2002). The pleiotropic effects of tissue factor: a possible role for factor VIIa-induced intracellular signalling?. Thromb. Haemost. 86 (6): 1353-9.
• Fernandez PM, Rickles FR (2003). Tissue factor and angiogenesis in cancer.. Curr. Opin. Hematol. 9 (5): 401-6.
• Golino P (2003). The inhibitors of the tissue factor:factor VII pathway.. Thromb. Res. 106 (3): V257-65.
• Engelmann B, Luther T, Müller I (2004). Intravascular tissue factor pathway--a model for rapid initiation of coagulation within the blood vessel.. Thromb. Haemost. 89 (1): 3-8.
• Morrissey JH (2004). Tissue factor: in at the start...and the finish?. J. Thromb. Haemost. 1 (5): 878-80.
• Yu JL, May L, Klement P, et al. (2004). Oncogenes as regulators of tissue factor expression in cancer: implications for tumor angiogenesis and anti-cancer therapy.. Semin. Thromb. Hemost. 30 (1): 21-30.
• Fernandez PM, Patierno SR, Rickles FR (2004). Tissue factor and fibrin in tumor angiogenesis.. Semin. Thromb. Hemost. 30 (1): 31-44.
• Mackman N (2004). Role of tissue factor in hemostasis, thrombosis, and vascular development.. Arterioscler. Thromb. Vasc. Biol. 24 (6): 1015-22.
• Belting M, Ahamed J, Ruf W (2005). Signaling of the tissue factor coagulation pathway in angiogenesis and cancer.. Arterioscler. Thromb. Vasc. Biol. 25 (8): 1545-50.
• Engelmann B (2007). Initiation of coagulation by tissue factor carriers in blood.. Blood Cells Mol. Dis. 36 (2): 188-90.
• Furie B, Furie BC (2007). Cancer-associated thrombosis.. Blood Cells Mol. Dis. 36 (2): 177-81.
• Mackman N (2007). Alternatively spliced tissue factor - one cut too many?. Thromb. Haemost. 97 (1): 5-8.
• Wiiger MT, Prydz H (2007). The changing faces of tissue factor biology. A personal tribute to the understanding of the "extrinsic coagulation activation".. Thromb. Haemost. 98 (1): 38-42.

• OMIM 134390