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Recombinant human activated protein C: current insights into its mechanism of action.

Levi M, van der Poll T - Crit Care (2007)

Bottom Line: Administration of recombinant human activated protein C (rhAPC) may correct the dysregulated anticoagulant mechanism and prevent propagation of thrombin generation and formation of microvascular thrombosis.Furthermore, it may simultaneously modulate the inflammatory response.It is likely that the beneficial effect of rhAPC observed in experimental and clinical studies of severe sepsis results from a combination of mechanisms that modulate the entangled processes of coagulation and inflammation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands. m.m.levi@amc.uva.nl

ABSTRACT
Impairment of the protein C pathway plays a central role in the pathogenesis of sepsis. Administration of recombinant human activated protein C (rhAPC) may correct the dysregulated anticoagulant mechanism and prevent propagation of thrombin generation and formation of microvascular thrombosis. Furthermore, it may simultaneously modulate the inflammatory response. It is likely that the beneficial effect of rhAPC observed in experimental and clinical studies of severe sepsis results from a combination of mechanisms that modulate the entangled processes of coagulation and inflammation. This review presents an analysis of the various mechanisms of action of rhAPC in sepsis.

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The protein C system. The solid arrows indicate the mechanisms by which the protein C system is impaired in sepsis.
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Figure 1: The protein C system. The solid arrows indicate the mechanisms by which the protein C system is impaired in sepsis.

Mentions: Activated protein C (APC) appears to play a central role in the pathogenesis of sepsis and associated organ dysfunction. There is ample evidence that insufficient functioning of the protein C pathway contributes to the derangement of coagulation observed in sepsis [5,6]. The protein C system is summarized in Figure 1. The circulating zymogen protein C is activated by the endothelial cell bound thrombomodulin once this is activated by thrombin [7]. APC acts in concert with its co-factor, protein S, and can proteolytically degrade the cofactors Va and VIIIa, which are essential for coagulation; APC is therefore an effective anticoagulant. The endothelial protein C receptor (EPCR) not only accelerates activation of protein C several fold but it also serves as a receptor for APC, and binding of APC to EPCR may amplify its anticoagulant and anti-inflammatory effects [8]. A recent study [9] demonstrated that exposure of cultured endothelial cells to APC results in release of microparticles that contain EPCR, but the relevance of that observation to coagulation or inflammation is not yet clear.


Recombinant human activated protein C: current insights into its mechanism of action.

Levi M, van der Poll T - Crit Care (2007)

The protein C system. The solid arrows indicate the mechanisms by which the protein C system is impaired in sepsis.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2230607&req=5

Figure 1: The protein C system. The solid arrows indicate the mechanisms by which the protein C system is impaired in sepsis.
Mentions: Activated protein C (APC) appears to play a central role in the pathogenesis of sepsis and associated organ dysfunction. There is ample evidence that insufficient functioning of the protein C pathway contributes to the derangement of coagulation observed in sepsis [5,6]. The protein C system is summarized in Figure 1. The circulating zymogen protein C is activated by the endothelial cell bound thrombomodulin once this is activated by thrombin [7]. APC acts in concert with its co-factor, protein S, and can proteolytically degrade the cofactors Va and VIIIa, which are essential for coagulation; APC is therefore an effective anticoagulant. The endothelial protein C receptor (EPCR) not only accelerates activation of protein C several fold but it also serves as a receptor for APC, and binding of APC to EPCR may amplify its anticoagulant and anti-inflammatory effects [8]. A recent study [9] demonstrated that exposure of cultured endothelial cells to APC results in release of microparticles that contain EPCR, but the relevance of that observation to coagulation or inflammation is not yet clear.

Bottom Line: Administration of recombinant human activated protein C (rhAPC) may correct the dysregulated anticoagulant mechanism and prevent propagation of thrombin generation and formation of microvascular thrombosis.Furthermore, it may simultaneously modulate the inflammatory response.It is likely that the beneficial effect of rhAPC observed in experimental and clinical studies of severe sepsis results from a combination of mechanisms that modulate the entangled processes of coagulation and inflammation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands. m.m.levi@amc.uva.nl

ABSTRACT
Impairment of the protein C pathway plays a central role in the pathogenesis of sepsis. Administration of recombinant human activated protein C (rhAPC) may correct the dysregulated anticoagulant mechanism and prevent propagation of thrombin generation and formation of microvascular thrombosis. Furthermore, it may simultaneously modulate the inflammatory response. It is likely that the beneficial effect of rhAPC observed in experimental and clinical studies of severe sepsis results from a combination of mechanisms that modulate the entangled processes of coagulation and inflammation. This review presents an analysis of the various mechanisms of action of rhAPC in sepsis.

Show MeSH
Related in: MedlinePlus