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Protein C in critical illness
Henry J Mann1, Mary A Short, Douglas E Schlichting
1College of Pharmacy, Center for Excellence in Critical Care, University of Minnesota, Minneapolis, MN 55455, USA. HMann@umn.edu
Insights
Low protein C levels are common in severe sepsis and correlate with worse outcomes. The protein C pathway is crucial for regulating critical illness responses.
Area of Science:
- Biochemistry
- Hematology
- Critical Care Medicine
Background:
- Protein C is a vitamin K-dependent plasma protein with anticoagulant and anti-inflammatory properties.
- The protein C pathway plays a vital role in regulating coagulation and inflammatory responses.
- Impaired protein C activation is observed in critical illnesses like severe sepsis.
Purpose of the Study:
- To assess the role of protein C in critical illness.
- To elucidate the mechanisms by which protein C modulates coagulation and inflammation.
- To investigate the correlation between protein C levels and patient outcomes in critical illness.
Main Methods:
- Review of existing literature on protein C function and its role in critical illness.
- Analysis of the biochemical pathways involved in protein C activation and function.
- Correlation analysis of protein C levels with morbidity and mortality in sepsis patients.
Main Results:
- Protein C activation to activated protein C (APC) requires thrombin bound to thrombomodulin.
- APC inactivates coagulation factors Va and VIIIa, reducing thrombin generation and inflammation.
- APC exhibits anti-inflammatory, cytoprotective, and barrier-protective activities through cell signaling.
- Protein C levels are significantly reduced in severe sepsis due to impaired production and increased degradation.
- Low protein C levels (<85% of patients) are strongly correlated with increased morbidity and mortality in sepsis.
Conclusions:
- The protein C pathway is a critical homeostatic regulator with multifaceted roles in critical illness.
- Protein C concentration is inversely correlated with morbidity and mortality in sepsis and other critical conditions.
- Maintaining adequate protein C levels may be crucial for improving outcomes in critical illness.
Purpose:
The role of protein C in critical illness is assessed.
Summary:
Conversion of protein C to activated protein C (APC) requires thrombin and thrombomodulin. When thrombin is not bound to thrombomodulin, it can convert fibrinogen to fibrin, factor V to factor Va, and factor VIII to factor VIIIa but will not convert protein C to APC. When thrombin is bound to thrombomodulin, it can convert protein C to APC but cannot convert fibrinogen, factor V, or factor VIII. Activation of protein C is accelerated by the presence of endothelial protein C receptors. In conjunction with protein S, APC limits coagulation by inactivating factors Va and VIIIa, which decreases thrombin-mediated inflammation. By inhibiting the formation of thrombin and the release of proinflammatory cytokines, APC reduces the inflammatory response to infection. By inducing cell signaling, APC directly modulates the cellular response to infection, resulting in antiinflammatory, cytoprotective, and barrier-protective activities. APC is metabolized by protease inhibitors and other proteins in the plasma. Conversion of protein C to APC is impaired in severe sepsis. During severe sepsis, endogenous levels of the inactive precursor protein C are reduced because of decreased production by the liver and degradation by enzymes. More than 85% of patients with severe sepsis have low levels of protein C. Absolute levels of protein C correlate with morbidity and mortality outcomes of the sepsis population, regardless of age, infecting microorganism, presence of shock, disseminated intravascular coagulation, degree of hypercoagulation, or severity of illness.
Conclusion:
The protein C pathway is a natural homeostatic regulator with multiple mechanisms of action. Blood protein C concentration is inversely correlated with morbidity and mortality in sepsis and other critical illness.
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