What is the role of the protein C system in the pathophysiology of disseminated intravascular coagulation (DIC)?

Updated: Dec 06, 2020
  • Author: Marcel M Levi, MD; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP  more...
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Impaired functioning of the protein C pathway is mainly due to down-regulation of thrombomodulin expression or its inactivation by cellular reactive oxygen species on endothelial cells by proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin (IL)–1b. [28] This downregulation has been confirmed in studies in patients with meningococcal sepsis.

In combination with low levels of zymogen protein C (due to mechanisms similar to those described for antithrombin), this process results in diminished protein C activation, which will enhance the procoagulant state. Protein C levels are further reduced via consumption, extravascular leakage, renal loss, and reduced hepatic production and by a reduction in circulating free protein S. The availability of protein S to serve as a cofactor for activated protein C is regulated by the degree it is bound to the complement protein C4B-binding protein.

Animal experiments involving severe inflammation-induced coagulation activation convincingly show that compromising the protein C system results in increased morbidity and mortality, whereas restoring adequate functioning of activated protein C improves survival and organ failure. Experiments show that mice with a 1-allele targeted deletion of the protein C gene (resulting in heterozygous protein C deficiency) have more severe DIC and organ dysfunction and a higher mortality than wild-type littermates.

Besides being implicated in the physiologic regulation of thrombin formation, activated protein C probably also has important inflammation-modulating effects, which may be of relevance in the pathogenesis of DIC.

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