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The normal role of Activated Protein C in maintaining homeostasis and its relevance to critical illness.

Esmon CT - Crit Care (2001)

Bottom Line: Thrombin is a multifunctional protein, with procoagulant, inflammatory and anticoagulant effects.When the level of thrombomodulin or Protein C is reduced in sepsis there is a vicious cycle of coagulation and inflammation, with potentially lethal consequences.In vitro studies and animal models have shown that Activated Protein C blunts the inflammatory and coagulant response to sepsis through a variety of mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Howard Hughes Medical Institute, Oklahoma City 73104, USA. Charles-Esmon@omrf.ouhsc.edu

ABSTRACT
Thrombin is a multifunctional protein, with procoagulant, inflammatory and anticoagulant effects. Binding of thrombin to thrombomodulin results in activation of Protein C and initiation of the Activated Protein C anticoagulant pathway, a process that is augmented by the endothelial cell Protein C receptor (EPCR). Activated Protein C has demonstrated antithrombotic, anti-inflammatory, and profibrinolytic properties. Its antithrombotic activity is particularly important in the microcirculation, and Protein C deficiency is associated with microvascular thrombosis. Activated Protein C has also been shown to modulate inflammation. When the level of thrombomodulin or Protein C is reduced in sepsis there is a vicious cycle of coagulation and inflammation, with potentially lethal consequences. In vitro studies and animal models have shown that Activated Protein C blunts the inflammatory and coagulant response to sepsis through a variety of mechanisms.

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Cellular and humoral responses to nM concentrations of thrombin. EC, endothelial cell; PAF, platelet-activating factor; PDGF, platelet-derived growth factor; PMN, polymorphonuclear leukocyte; TGF, transforming growth factor. Adapted from Esmon [1].
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Figure 1: Cellular and humoral responses to nM concentrations of thrombin. EC, endothelial cell; PAF, platelet-activating factor; PDGF, platelet-derived growth factor; PMN, polymorphonuclear leukocyte; TGF, transforming growth factor. Adapted from Esmon [1].

Mentions: The initiation of coagulation, especially in severe sepsis, is probably mediated by the induction of tissue factor (TF) expression by endotoxin. This leads to the activation of factor X, which then combines with factor Va to convert prothrombin to thrombin. Although thrombin is usually considered to have purely procoagulant activity, it is in fact a multifunctional protein that has some important homeostatic anticoagulant effects (Fig. 1) [1]. One of its main functions is to bind to thrombomodulin, which is expressed on the endothelial cell surface. Thrombomodulin is the major physiologic buffer for the procoagulant effects of thrombin in normal vessels [2,3]. Because thrombomodulin binds to the same site on thrombin that would normally bind to fibrinogen, platelets or factor V, all of these functions are blocked. Instead, the thrombin-thrombomodulin complex activates Protein C (through a different site on the thrombin molecule), resulting in initiation of the Activated Protein C pathway [3]. This process is augmented by the EPCR [4,5]. Activated Protein C must dissociate from EPCR before it can bind to Protein S and function as an effective anticoagulant through the inactivation of factor Va.


The normal role of Activated Protein C in maintaining homeostasis and its relevance to critical illness.

Esmon CT - Crit Care (2001)

Cellular and humoral responses to nM concentrations of thrombin. EC, endothelial cell; PAF, platelet-activating factor; PDGF, platelet-derived growth factor; PMN, polymorphonuclear leukocyte; TGF, transforming growth factor. Adapted from Esmon [1].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3300084&req=5

Figure 1: Cellular and humoral responses to nM concentrations of thrombin. EC, endothelial cell; PAF, platelet-activating factor; PDGF, platelet-derived growth factor; PMN, polymorphonuclear leukocyte; TGF, transforming growth factor. Adapted from Esmon [1].
Mentions: The initiation of coagulation, especially in severe sepsis, is probably mediated by the induction of tissue factor (TF) expression by endotoxin. This leads to the activation of factor X, which then combines with factor Va to convert prothrombin to thrombin. Although thrombin is usually considered to have purely procoagulant activity, it is in fact a multifunctional protein that has some important homeostatic anticoagulant effects (Fig. 1) [1]. One of its main functions is to bind to thrombomodulin, which is expressed on the endothelial cell surface. Thrombomodulin is the major physiologic buffer for the procoagulant effects of thrombin in normal vessels [2,3]. Because thrombomodulin binds to the same site on thrombin that would normally bind to fibrinogen, platelets or factor V, all of these functions are blocked. Instead, the thrombin-thrombomodulin complex activates Protein C (through a different site on the thrombin molecule), resulting in initiation of the Activated Protein C pathway [3]. This process is augmented by the EPCR [4,5]. Activated Protein C must dissociate from EPCR before it can bind to Protein S and function as an effective anticoagulant through the inactivation of factor Va.

Bottom Line: Thrombin is a multifunctional protein, with procoagulant, inflammatory and anticoagulant effects.When the level of thrombomodulin or Protein C is reduced in sepsis there is a vicious cycle of coagulation and inflammation, with potentially lethal consequences.In vitro studies and animal models have shown that Activated Protein C blunts the inflammatory and coagulant response to sepsis through a variety of mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Howard Hughes Medical Institute, Oklahoma City 73104, USA. Charles-Esmon@omrf.ouhsc.edu

ABSTRACT
Thrombin is a multifunctional protein, with procoagulant, inflammatory and anticoagulant effects. Binding of thrombin to thrombomodulin results in activation of Protein C and initiation of the Activated Protein C anticoagulant pathway, a process that is augmented by the endothelial cell Protein C receptor (EPCR). Activated Protein C has demonstrated antithrombotic, anti-inflammatory, and profibrinolytic properties. Its antithrombotic activity is particularly important in the microcirculation, and Protein C deficiency is associated with microvascular thrombosis. Activated Protein C has also been shown to modulate inflammation. When the level of thrombomodulin or Protein C is reduced in sepsis there is a vicious cycle of coagulation and inflammation, with potentially lethal consequences. In vitro studies and animal models have shown that Activated Protein C blunts the inflammatory and coagulant response to sepsis through a variety of mechanisms.

Show MeSH
Related in: MedlinePlus