The protein C pathways

Abstract

Purpose of reviewTo provide an overview of the state-of-the-art in protein C (PC) pathway research. Recent findingsThe PC pathway is crucial for maintaining hemostasis to prevent venous thromboembolism. This is evident from genetic mutations that result in impaired PC pathway activity and contribute to increased venous thromboembolism risk in affected individuals. In addition to its anticoagulant role, activated PC (APC) also mediates a complex, pleiotropic role in the maintenance of vascular cell health, which it achieves via antiinflammatory and antiapoptotic cell signaling on endothelial cells. Emerging data have demonstrated that cell signaling by APC, mediated by multiple receptor interactions on different cell types, also confers cytoprotective and anti-inflammatory benefits. Defects in both arms of the PC pathway are associated with increased susceptibility to thrombo-inflammatory disease in various preclinical thrombotic, proinflammatory and neurological disease models. Moreover, recent studies have identified attenuation of anticoagulant PC pathway activity as an exciting therapeutic opportunity to promote hemostasis in patients with inherited or acquired bleeding disorders.

Tissue factor-dependent colitogenic CD4+ T cell thrombogenicity is regulated by activated protein C signalling

“…APC signalling is typically mediated by activation of protease-activated receptors (PARs), in particular PAR1 and PAR3. PAR signalling by APC typically requires APC co-localisation via binding to a co-receptor, most commonly EPCR 49 .…”

“…APC signalling is typically mediated by activation of protease-activated receptors (PARs), in particular PAR1 and PAR3. PAR signalling by APC typically requires APC co-localisation via binding to a co-receptor, most commonly EPCR 49 . Notably, disruption of APC generation or activity has been shown to contribute to T cell-mediated inflammatory diseases 28–30 .…”

Global trends and hotspots of ulcerative colitis based on bibliometric and visual analysis from 1993 to 2022

“…Inflammation, susceptibility, and venous thromboembolism are associated with developing and progressing UC. [ 19 , 20 ] Inflammation, a hallmark of UC, can contribute to the development of thrombosis, a key event in the pathogenesis of venous thromboembolism. Furthermore, the presence of susceptibility factors, encompassing both genetic and environmental influences, significantly contributes to the onset of UC and its associated complications, such as venous thromboembolism.…”

The intersection of coagulation activation and inflammation after injury: What you need to know

“…Activated protein C also has a cytoprotective role, primarily through the endothelial protein C receptor and protease activated receptor 1. This effect is incompletely understood but involves promotion of the endothelial barrier, inhibition of proinflammatory mediators, and decreased expression of vascular adhesion molecules with reduction of leukocyte adhesion and chemotaxis 66 . Severe injury is associated with significant early elevation of activated protein C levels, and this finding is associated with alterations in clotting factor activity, with the net result of increased coagulopathy and decreased clot strength as well as increased fibrinolysis and fibrinogen depletion.…”