The protein C pathway and sepsis

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Abstract

After the discovery of the key components of the protein C (PC) pathway a beneficial effect on survival of the infusion of activated protein C (APC) in animal models of sepsis was demonstrated, leading to the development of recombinant human activated protein C (rh-APC) as a therapeutic agent. It soon became clear that rather than the anticoagulant and profibrinolytic activities of APC, its anti-inflammatory and cytoprotective properties played a major role in the treatment of patients with severe sepsis. Such properties affect the response to inflammation of endothelial cells and leukocytes and are exerted through binding of APC to at least five receptors with intracellular signaling. The main APC protective mechanism involves binding of the Gla-domain to the endothelial protein C receptor (EPCR) and cleavage of protease activated receptor 1 (PAR-1), eliciting suppression of proinflammatory cytokines synthesis and of intracellular proapoptotic pathways and activation of endothelial barrier properties. However, thrombin cleaves PAR-1 with much higher catalytic efficiency, followed by pro-inflammatory, pro-apoptotic and barrier disruptive intracellular signaling, and it is unclear how APC can exert a protective activity through the cleavage of PAR-1 when thrombin is also present in the same environment. Interestingly, in endothelial cell cultures, PAR-1 cleavage by thrombin results in anti-inflammatory and barrier protective signaling provided occupation of EPCR by the PC gla-domain, raising the possibility that the beneficial effects of rh-APC might be recapitulated in vivo by administration of h-PC zymogen to patients with severe sepsis. Recent reports of h-PC infusion in animal models of sepsis support this hypothesis.

Original languageEnglish
Pages (from-to)296-300
Number of pages5
JournalThrombosis Research
Volume129
Issue number3
DOIs
Publication statusPublished - Mar 2012

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Protein C
Sepsis
PAR-1 Receptor
Thrombin
Anti-Inflammatory Agents
Endothelial Cells
Animal Models
Enzyme Precursors
Human Development
Occupations
Anticoagulants
Carrier Proteins
Leukocytes
Cell Culture Techniques
Cytokines
Inflammation

ASJC Scopus subject areas

  • Hematology

Cite this

The protein C pathway and sepsis. / Della Valle, Patrizia; Pavani, Giulia; D'Angelo, Armando.

In: Thrombosis Research, Vol. 129, No. 3, 03.2012, p. 296-300.

Research output: Contribution to journalArticle

Della Valle, Patrizia ; Pavani, Giulia ; D'Angelo, Armando. / The protein C pathway and sepsis. In: Thrombosis Research. 2012 ; Vol. 129, No. 3. pp. 296-300.
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