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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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Primate model of sepsis. (a) Lethal E. coli infusion alone. (b) Lethal E.coli plus Activated Protein C infusion. SGPT, serum glutamic pyruvic transaminase (indicator of liver damage). Adapted from Taylor et al [11].
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Figure 5: Primate model of sepsis. (a) Lethal E. coli infusion alone. (b) Lethal E.coli plus Activated Protein C infusion. SGPT, serum glutamic pyruvic transaminase (indicator of liver damage). Adapted from Taylor et al [11].

Mentions: A primate model was used in the initial study undertaken to investigate this possibility [11]. In animals infused with a lethal Escherichia coli dose alone, Protein C and fibrinogen levels fell, liver damage occurred (Fig. 5a), and the animals died within 24-32 h. In contrast, organ damage was prevented in animals given a lethal dose of E. coli plus an infusion of Activated Protein C (Fig. 5b). Importantly, it was shown that animals could still be rescued if Activated Protein C was given 2-3 h after the lethal E. coli dose was administered. Similarly, when animals were given a sublethal dose of E. coli and Protein C activation was blocked with an antibody, mimicking the clinical situation in a patient with sepsis and low Protein C levels, the sublethal bacterial dose became lethal, with complete fibrinogen consumption, a disseminated intravascular coagulation-like syndrome, organ failure, and a full-blown septic shock-like response (Fig. 6) [11].


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

Esmon CT - Crit Care (2001)

Primate model of sepsis. (a) Lethal E. coli infusion alone. (b) Lethal E.coli plus Activated Protein C infusion. SGPT, serum glutamic pyruvic transaminase (indicator of liver damage). Adapted from Taylor et al [11].
© Copyright Policy
Related In: Results  -  Collection

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

Figure 5: Primate model of sepsis. (a) Lethal E. coli infusion alone. (b) Lethal E.coli plus Activated Protein C infusion. SGPT, serum glutamic pyruvic transaminase (indicator of liver damage). Adapted from Taylor et al [11].
Mentions: A primate model was used in the initial study undertaken to investigate this possibility [11]. In animals infused with a lethal Escherichia coli dose alone, Protein C and fibrinogen levels fell, liver damage occurred (Fig. 5a), and the animals died within 24-32 h. In contrast, organ damage was prevented in animals given a lethal dose of E. coli plus an infusion of Activated Protein C (Fig. 5b). Importantly, it was shown that animals could still be rescued if Activated Protein C was given 2-3 h after the lethal E. coli dose was administered. Similarly, when animals were given a sublethal dose of E. coli and Protein C activation was blocked with an antibody, mimicking the clinical situation in a patient with sepsis and low Protein C levels, the sublethal bacterial dose became lethal, with complete fibrinogen consumption, a disseminated intravascular coagulation-like syndrome, organ failure, and a full-blown septic shock-like response (Fig. 6) [11].

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