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Crosstalk between Inflammation and Coagulation: The Lessons of Sepsis.
MedLine Citation:
PMID:  22272914     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Sepsis results in the concurrent activation of inflammatory and procoagulant pathways. Bacterial products and proinflammatory cytokines trigger the coagulation system primarily via induction of tissue factor. During sepsis, activation of coagulation is accompanied by impaired function of major anticoagulant mechanisms, including antithrombin, the protein C system and fibrinolysis. Protease activated receptors (PARs) form the molecular connection between coagulation and inflammation, and especially PAR1 seems to play an eminent role in sepsis pathogenesis. Activated protein C (APC) can cleave PAR1 when associated with either the endothelial protein C receptor (EPCR) or CD11b/CD18, resulting in broad cytoprotective effects mediated by sphingosine 1 phosphate (S1P) receptor 1 (S1P1). In contrast, activation of PAR1 by high dose thrombin results in barrier disruptive effects in endothelial cells via an S1P3 dependent mechanism. Recombinant APC protects against mortality in experimental endotoxemia and sepsis by effects that can be mediated by either EPCR - PAR1 dependent (endothelial cells, dendritic cells) or CD11b/CD18 - PAR1 dependent (macrophages) mechanisms. These protective APC effects do not rely on the anticoagulant properties of this protein. APC mutants that lack anticoagulant properties but retain the capacity to activate PAR1 are promising new drugs for sepsis treatment.
Authors:
Tom van der Poll; Marcel Levi
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-1-20
Journal Detail:
Title:  Current vascular pharmacology     Volume:  -     ISSN:  1875-6212     ISO Abbreviation:  -     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-1-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101157208     Medline TA:  Curr Vasc Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Infectious Diseases, Tropical Medicine & AIDS, Academic Medical Center, Meibergdreef 9, Room G2-130, 1105 AZ Amsterdam, The Netherlands. t.vanderpoll@amc.uva.nl.
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