Chest
The Protein C Pathway
Section snippets
The Activation Complex
The key feature of the protein C pathway resides in the ability of the pathway to respond to the presence of thrombin. As the thrombin concentration rises, much of the thrombin binds to thrombomodulin, primarily on the endothelial cell surface (Fig 1), leading to the activation of protein C.
Protein C activation is enhanced approximately 20-fold in vivo when protein C is bound to the endothelial cell protein C receptor (EPCR).2 Relative to free thrombin, thrombin bound to thrombomodulin is
Other Functions of the Activation Complex
Thrombomodulin is a complex molecule with multiple distinct domains (Fig 2). Different functions have been ascribed to these domains. The N-terminal domain has sequence similarity to the lectins, which are carbohydrate-binding proteins, and is not involved in protein C activation. The lectin domain has been shown to have anti-inflammatory activity.10 Whether infused, added as the soluble isolated domain, or present on cellular thrombomodulin (ie, native), the presence of the domain
Functions of APC
In addition to inactivating factors Va and VIIIa (Fig 1),2425 APC has been shown to have anti-inflammatory, antiapoptotic, and anticoagulant activity at the cellular level. The antiapoptotic activity appears to be mediated, at least in part, by the APC-EPCR complex cleaving PAR-1. Since EPCR is expressed primarily on endothelium,26 but PAR is located on many cells, the EPCR dependence probably allows for preferential activation of this receptor on endothelium,5 thereby avoiding platelet and
Physiology of the Protein C Pathway
Thrombomodulin is located on the endothelium; in general, the number of copies per endothelial cell appear by immunohistochemistry to vary < 10-fold among vascular beds (the brain microcirculation being an exception, where thrombomodulin expression is very low).31 From simple geometry, the endothelial cell to blood volume ratio increases hundreds of fold as blood moves from the large vessels to the capillaries. Assuming 100,000 copies of thrombomodulin per endothelial cell, a reasonable
Down-regulation
Both thrombomodulin and EPCR can be down-regulated at the transcriptional level by inflammatory cytokines like IL-1β and TNF-α.1638 In addition, thrombomodulin activity can be dramatically reduced by oxidants released from leukocytes.39 Finally, leukocyte elastase rapidly releases soluble forms of thrombomodulin40 that have considerably less activity than the cellular form because they no longer have the EPCR acceleration effect and they do not contain the chondroitin for high-affinity thrombin
The Protein C Pathway in Sepsis
The combined anticoagulant and anti-inflammatory activities of APC have been recognized for a long time as an attractive combination for treating severe sepsis. In initial studies in baboons, APC was shown to prevent death from infusion of normally lethal concentrations of E coli. APC infusion was associated with a reduced drop in BP, decreased markers of inflammation, and a decreased coagulant response.46 When endogenous protein C activation was prevented, the animals responded to low-level E
Summary
The protein C pathway is important for the negative control of both coagulation and inflammation. The recently described inhibition of apoptosis by APC may be particularly important in the treatment of ischemic diseases. Modulation of the pathway can be therapeutically beneficial. Furthermore, the pathway may be down-regulated in a variety of disease states to such an extent that the down-regulation contributes to the severity of the disease. Future studies will likely provide new methods to
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Chest
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Thrombin has dual trypsin-like and chymotrypsin-like specificity
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2024, Research and Practice in Thrombosis and HaemostasisDesign and characterization of novel activated protein C variants for the proteolysis of cytotoxic extracellular histone H3
2023, Journal of Thrombosis and HaemostasisMonitoring prothrombin activation in plasma through loss of Förster resonance energy transfer
2023, Journal of Thrombosis and Haemostasis
Dr. Esmon holds patents and licenses related to the use of protein C and activated protein C in the treatment of sepsis and thrombosis, as well as patents related to diagnostic aspects of defects in the protein C pathway.