Tissue factor

Tissue factor, also called platelet tissue factor or Coagulation factor III, 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.

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. 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.

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).

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). EphB2 and EphA2 of the Eph tyrosine kinase receptor (RTK) family can also be cleaved by TF/VIIa.

Tissue factor belongs to the cytokine receptor protein superfamily and consists of three domains:

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.