Coagulation proteased-induced extracellular vesicles: Their potential effects on coagulation and inflammation

Coagulation proteases, in addition to playing an essential role in blood coagulation, often influence diverse cellular functions by inducing specific signaling pathways via the activation of protease-activated receptors (PARs). PAR activation-induced cellular effects are known to be cell-specific as PARs are expressed selectively in specific cell types. However, a growing body of evidence indicates that coagulation protease-induced PAR activation in a specific cell type could affect cellular responses in other cell types via communicating through extracellular vesicles (EVs) as coagulation proteases induced-PAR signaling could promote the release of EVs in various cell types. EVs are membrane-enclosed nanosized vesicles that facilitate intercellular communication by transferring bioactive molecules, such as proteins, lipids, mRNAs, and microRNAs, from donor cells to recipient cells. Our recent findings established that factor VIIa (FVIIa) promotes the release of EVs from vascular endothelium via endothelial cell protein C receptor-dependent activation of PAR1-mediated biased signaling. FVIIa-released EVs exhibit procoagulant activity and cytoprotective responses both in vitro and in vivo model systems. This review discusses how factor VIIa and other coagulation proteases activate PAR-mediated cell signaling and trigger the release of EVs. The review specifically discusses how FVIIa-released EVs are enriched with phosphatidylserine and anti-inflammatory miRNAs and the impact of FVIIa-released EVs on hemostasis in therapeutic settings. The review also briefly highlights the therapeutic potential of FVIIa-released EVs in treating bleeding and inflammatory disorders, such as hemophilic arthropathy and sepsis.