Tissue factor

Tissue factor, also called platelet tissue factor, factor III, thromboplastin, or CD142 is a is_associated_with::protein present in subendothelial tissue and is_associated_with::leukocytes necessary for the initiation of is_associated_with::thrombin formation from the is_associated_with::zymogen is_associated_with::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
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. 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 is_associated_with::exon 5 is absent and exon 4 is spliced directly to exon 6.

Coagulation


TF is the cell surface receptor for the is_associated_with::serine protease factor VIIa.

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

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

Cytokine signaling
TF is related to a protein family known as the is_associated_with::cytokine receptor class II family. The members of this receptor family are activated by is_associated_with::cytokines. Cytokines are small proteins that can influence the behavior of is_associated_with::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 is_associated_with::angiogenesis and is_associated_with::apoptosis.

Structure
The protein structure of TF consists of three domains:


 * 1) a domain which is located outside the cell, this domain binds is_associated_with::factor VIIa. The binding of VIIa to TF occurs via protein-protein interactions by both molecules.
 * 2) Factor VIIa is a protein which consists of several domains. One of these domains, the carboxylated is_associated_with::GLA domain, binds in the presence of calcium to negatively charged is_associated_with::phospholipids. Binding of VIIa to negatively charged phospholipids greatly enhances  the protein-protein binding of VIIa to TF.
 * 3) a domain which crosses the hydrophobic membrane.
 * 4) a domain of 21 amino acids length inside the cell which is involved in the signaling function of TF.

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. is_associated_with::smooth muscle cells) and cells surrounding blood vessels (e.g. is_associated_with::fibroblasts). This can change when the blood vessel is damaged by for example physical injury or rupture of is_associated_with::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 is_associated_with::tumor necrosis factor-alpha (TNF-alpha). Another cell type that expresses TF on the cell surface in inflammatory conditions is the is_associated_with::monocyte (a white blood cell).

Thromboplastin
Historically, is_associated_with::thromboplastin was a lab reagent, usually derived from placental sources, used to assay is_associated_with::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. Partial thromboplastin 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 is the combination of both phospholipids and tissue factor, both needed in the activation of the extrinsic pathway, and partial thromboplastin is just phospholipids without tissue factor. Tissue factor is not needed to activate the intrinsic pathway.

Interactions
Tissue factor has been shown to interact with is_associated_with::Factor VII.