Tissue factor (TF), also known as thromboplastin, factor III (FIII) 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 initiates the coagulation protease cascade by converting the zymogens FIX and FX to the active proteases FIXa and FXa. TF is expressed on the surface of several cell types, such as smooth muscle cells, 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). 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 to initiate the clotting cascade. Besides, microbial infection and inflammatory response can induce TF expression in circulating blood cells and vascular endothelial cells (van den Eijnden MM et al. 1997; Osterud B & Bjorklid E 2012). It is believed that the induced expression of TF by monocytes in response to infection may help to limit the dissemination of pathogens by trapping them inside clots (van der Poll T & Herwald H 2014).

The vast majority of the TF expressed on the surfaces of resting cells is maintained in a cryptic coagulant-inactive state (Schecter AD et al. 1997; Bach RR 2006; Kothari H et al. 2013; Grover SP & Mackman N 2018). This cryptic TF can bind to FVIIa, but the formed TF:FVIIa complex fails to activate FIX and FX (Rao LV & Pendurthi UR 2012). Upon tissue injury or inflammation TF is converted into its procoagulant isoform at the cell surface. Several mechanisms have been proposed for TF activation or decryption. These include Ca2+-dependent exposure of phosphatidylserine (PS) on the outer plasma membrane as a result of reduced flippase activity, protein disulfide isomerase (PDI)-mediated thiol-disulfide exchange reaction that affects the allosteric disulfide bond in TF (Rao LV & Pendurthi UR 2012; Grover SP & Mackman N 2018; Ansari SA et al. 2019). In addition, the presence of sphingomyelin (SM) in the outer leaflet of the plasma membrane inhibits TF procoagulant activity on the cell surface of resting cells (Wang J et al. 2017). Acid-sphingomyelinase (ASM)-mediated hydrolysis of SM 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 SM hydrolysis, PS externalization and thiol-disulphide exchange pathways synergistically contribute to the activation of TF (Langer F & Ruf W 2014; Ansari SA et al. 2019).

The Reactome event describes exposure of TF sequestered in the wall of a blood vessel to flowing blood.