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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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Endothelial cell surface area per ml of blood. Adapted from Busch et al [6].
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Figure 2: Endothelial cell surface area per ml of blood. Adapted from Busch et al [6].

Mentions: Activated Protein C is particularly important in the microcirculation [3]. Although the number of thrombomodulin molecules per endothelial cell is approximately constant, the local concentration of thrombomodulin is determined by the number of endothelial cells that are in contact with the blood. Because the endothelial cell surface area per unit blood volume is much greater in the microcirculation (approximately 3000-5000 cm2 of endothelium/ml blood) than in larger blood vessels (approximately 1.5 cm2/ml) (Fig. 2) [6], there is a correspondingly high concentration of thrombomodulin in the normal microvasculature (approximately 500 nmol/l) as compared with the larger vessels (approximately 0.1-0.2 nmol/l). As a result, thrombin is rapidly removed from the microcirculation as it is bound to thrombomodulin. This suggests that the Activated Protein C system is uniquely poised to regulate coagulopathies in the microcirculation, and this has been confirmed in clinical studies [7].


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

Esmon CT - Crit Care (2001)

Endothelial cell surface area per ml of blood. Adapted from Busch et al [6].
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Endothelial cell surface area per ml of blood. Adapted from Busch et al [6].
Mentions: Activated Protein C is particularly important in the microcirculation [3]. Although the number of thrombomodulin molecules per endothelial cell is approximately constant, the local concentration of thrombomodulin is determined by the number of endothelial cells that are in contact with the blood. Because the endothelial cell surface area per unit blood volume is much greater in the microcirculation (approximately 3000-5000 cm2 of endothelium/ml blood) than in larger blood vessels (approximately 1.5 cm2/ml) (Fig. 2) [6], there is a correspondingly high concentration of thrombomodulin in the normal microvasculature (approximately 500 nmol/l) as compared with the larger vessels (approximately 0.1-0.2 nmol/l). As a result, thrombin is rapidly removed from the microcirculation as it is bound to thrombomodulin. This suggests that the Activated Protein C system is uniquely poised to regulate coagulopathies in the microcirculation, and this has been confirmed in clinical studies [7].

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