Abstract and Introduction
Abstract
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.
Introduction
In 1976, Stenflo purified and characterized an immunochemically-distinct, new vitamin-K-dependent protein from bovine plasma. Since it was the third peak to elute from a di-ethylaminoethyl column, it was called protein C.
Subsequently, human protein C was isolated and thrombin was shown to convert protein C to its active form—activated protein C (APC). Subsequent studies assessing the role of protein C in critical illness created confusion regarding the terminology of endogenous protein C, APC, exogenous pooled human protein C replacement, and recombinant human-activated protein C (drotrecogin alfa [activated], Xigris, Eli Lilly, Indianapolis IN). Protein C is often confused with other proteins with similar nomenclature, such as C-reactive protein, C-peptide, protein kinase C, and surfactant protein C (Table 1). The goal of this primer is to provide clarity about the components of the protein C pathway, including the biological activity, therapeutic application, diagnostic testing, prognostic ability, and genetic polymorphisms.