title: Crosstalk between inflammation and coagulation: the lessons of sepsis.
abstract: 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.affiliation: Center of Experimental and Molecular Medicine, University of Amsterdam, Amsterdam, The Netherlands. t.vanderpoll@amc.uva.nl
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.forename: Marcel
authors.initials: M
authors.lastname: Levi
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D001779:Blood Coagulation Factors / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D015195:Drug Design; D005342:Fibrinolysis; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D011486:Protein C / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D044462:Receptors, Proteinase-Activated / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy / Q000503:physiopathology*
chemical_list: D001779:Blood Coagulation Factors; D016207:Cytokines; D011486:Protein C; D044463:Receptor, PAR-1; D011956:Receptors, Cell Surface; D044462:Receptors, Proteinase-Activated; C091963:activated protein C receptor