sequestered tissue factor -> tissue factor

Stable Identifier
Reaction [transition]
Homo sapiens
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Tissue factor (TF), also known as thromboplastin or CD142, is an integral transmembrane glycoprotein, that functions as a co-factor for coagulation factor VII (FVII) and FVIIa (Broze GJ et al. 1985; Nemerson Y & Repke D 1985; Rao LV & Rapaport SI 1988). The TF:FVIIa complex is the primary activator of the coagulation protease cascade. The formation of TF:FVIIa complex triggers the coagulation cascade by activating both FIX and FX through their limited proteolysis. TF is expressed on the surface of several cell types located in subendothelial structures throughout the vasculature, and it is normally not in contact with circulating blood, where other coagulation factors are present in their inactivated forms (Drake TA et al. 1989; Wilcox JN et al. 1989; Fleck RA et al. 1990). Cells that are normally not exposed to the flowing blood, such as smooth muscle cells, constitutively express TF on their surface (Drake TA et al. 1989; Fleck RA et al. 1990). Upon vascular injury, through physical damage of the endothelial layer of the blood vessel, TF becomes exposed to circulating blood and the extracellular part of TF binds FVII with very high affinity and specificity. Infectious and inflammatory disease conditions induce TF expression, either in circulating blood cells or vascular endothelial cells, by activation of TF gene transcription (van den Eijnden MM et al. 1997; Osterud B & Bjorklid E 2012). Induced expression of TF by monocytes in response to infection is thought to be a part of the innate immune response to limit the dissemination of pathogens by trapping them inside clots (van der Poll T & Herwald H 2014).

Irrespective of the cellular source of TF and whether it is induced or constitutively expressed, most of the TF expressed on the surfaces of resting cells exists in a cryptic coagulant-inactive state (Schecter AD et al. 1997; Bach RR 2006; Kothari H et al. 2013; Grover SP & Mackman N 2018). The encrypted TF can bind to FVIIa, but the assembled TF:FVIIa complex fails to activate FIX and FX (Rao LV & Pendurthi UR 2012). Activation or disruption of cells markedly enhances cell surface TF procoagulant activity without altering TF antigen levels at the cell surface (‘decryption’). Several mechanisms have been proposed for TF decryption on cell surfaces, and out of them, externalization of phosphatidylserine (PS) to the outer leaflet and PDI-mediated thiol-disulfide exchange pathways that affect the allosteric disulfide bond in TF seem most likely (Rao LV & Pendurthi UR 2012; Grover SP & Mackman N 2018; Ansari SA et al. 2019). The presence of a high molar concentration of sphingomyelin (SM) in the outer leaflet of the plasma membrane inhibits TF procoagulant activity on the cell surface, thus maintaining TF in an encrypted state in resting cells (Wang J et al. 2017). Acid-sphingomyelinase (ASM)-mediated hydrolysis of SM following cell injury removes the inhibitory effect of SM on TF activity, thus leading to TF decryption (Wang J, et al. 2017; Ansari SA et al. 2019). It has been suggested that the coordinated effects of SM hydrolysis, PS externalization and thiol-disulphide exchange pathways are responsible for full cellular activation of TF (Ansari SA et al. 2019). However, molecular links among various pathways of TF decryption are not fully known yet. The Reactome event describes exposure of TF sequestered in the wall of a blood vessel to flowing blood.

Literature References
PubMed ID Title Journal Year
2704749 Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque

Wilcox, JN, Smith, KM, Schwartz, SM, Gordon, D

Proc Natl Acad Sci U S A 1989
23006890 Regulation of tissue factor coagulant activity on cell surfaces

Rao, LV, Pendurthi, UR

J. Thromb. Haemost. 2012
23621622 Analysis of tissue factor expression in various cell model systems: cryptic vs. active

Kothari, H, Pendurthi, UR, Rao, LV

J. Thromb. Haemost. 2013
29437578 Tissue Factor: An Essential Mediator of Hemostasis and Trigger of Thrombosis

Grover, SP, Mackman, N

Arterioscler. Thromb. Vasc. Biol. 2018
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