Initiation of coagulation cascade

Initiation of coagulation cascade The initiation phase of coagulation proceeds through the tissue factor (TF)-mediated generation of a small amount of thrombin on the plasma membrane surfaces of TF-bearing cells (e.g., fibroblasts, smooth muscle cells and pericytes) (reviewed by Rao LVM & Pendurthi UR 2012; Grover SP & Mackman N 2018). Additionally, activated cells (e.g., polarized macrophages) and apoptotic cells, along with certain cancer cells, release TF-bearing extracellular vesicles (EVs) with procoagulant activity (Hohensinner PJ et al., 2021; reviewed by Hisada Y et al., 2022; Sachetto ATA et al., 2023). TF is predominantly maintained in a cryptic, coagulant-inactive state on the surfaces of resting cells or EVs (Schecter AD et al. 1997; Bach RR 2006; Kothari H et al. 2013; Grover SP & Mackman N 2018). Upon tissue injury or inflammation TF is converted into its procoagulant isoform at the membrane surface. Ca²⁺-dependent exposure of phosphatidylserine (PS), hydrolysis of sphingomyelin (SM) and thiol-disulfide exchange within TF are thought to synergistically contribute to the activation of TF on the outer plasma membrane (Langer F & Ruf W 2014; Ansari SA et al. 2019). Activated TF becomes exposed to circulating blood and the extracellular part of TF binds both the zymogen factor VII (FVII) and its active serine protease form FVIIa with very high affinity and specificity (Vadivel K& Bajaj SP 2012; Prasad R & Sen P 2018). The TF:FVIIa complex initiates the coagulation protease cascade by converting zymogens FIX and FX to active proteases FIXa and FXa, which are involved in the generation of thrombin. Aberrant expression of TF is associated with various coagulopathies. For example, the procoagulant properties of EVs bearing TF may contribute to thrombosis and disseminated intravascular coagulation in pathophysiologic conditions such as cancer, sepsis, and infection (reviewed by Mackman N et al., 2021; Hisada Y et al., 2022; Sachetto ATA et al., 2023).