title: Endotoxaemia induces resistance to activated protein C in healthy humans.
abstract: Systemic inflammation activates the tissue factor/factor VIIa complex (TF/FVIIa), leading to a procoagulant state, which may be enhanced by impairment of physiological anticoagulant pathways, such as the protein C system. Besides impaired protein C activation, resistance to activated protein C (APC) may occur. We studied the effect of endotoxemia on APC resistance, analysed its determinants and evaluated the effect of TF/FVIIa inhibition on endotoxin-induced APC resistance. Sixteen healthy male volunteers participated in the study, eight receiving endotoxin alone and eight receiving the combination of endotoxin and recombinant Nematode Anticoagulant Protein c2 (rNAPc2), a potent inhibitor of TF/FVIIa. Parameters of coagulation were subsequently studied. The sensitivity to APC was determined by two tests: a test based on the endogenous thrombin potential and a test based on the activated partial thromboplastin time. In response to endotoxemia, both tests detected a transient APC resistance that was predominantly mediated by an increase in factor VIII and was not influenced by TF/FVIIa inhibition. In vitro tests confirmed that an increase in factor VIII induced APC resistance, as measured by both tests. This finding suggests that APC resistance might play a role in the procoagulant state occurring during human endotoxemia.
authors.affiliation: Department of Intensive Care, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands. a.c.depont@amc.uva.nl
authors.forename: Anne-Cornélie J M
authors.initials: AC
authors.lastname: de Pont
authors.forename: Kamran
authors.initials: K
authors.lastname: Bakhtiari
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Hutten
authors.forename: Evert
authors.initials: E
authors.lastname: de Jonge
authors.forename: George P
authors.initials: GP
authors.lastname: Vlasuk
authors.forename: William E
authors.initials: WE
authors.lastname: Rote
authors.forename: Marcel
authors.initials: M
authors.lastname: Levi
authors.forename: Harry R
authors.initials: HR
authors.lastname: Büller
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Meijers
mesh_terms: D020016:Activated Protein C Resistance / Q000097:blood / Q000209:etiology*; D000293:Adolescent; D000328:Adult; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests / Q000379:methods; D019446:Endotoxemia / Q000097:blood / Q000150:complications*; D005165:Factor V / Q000494:pharmacology; D005169:Factor VIII / Q000494:pharmacology; D015942:Factor VIIa / Q000037:antagonists & inhibitors / Q000378:metabolism; D015801:Helminth Proteins / Q000494:pharmacology; D006801:Humans; D008297:Male; D010314:Partial Thromboplastin Time; D011486:Protein C; D011994:Recombinant Proteins / Q000494:pharmacology; D012307:Risk Factors; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D015801:Helminth Proteins; D011486:Protein C; D011994:Recombinant Proteins; C400226:anti-coagulant protein C2, Ancylostoma caninum; D005165:Factor V; D005169:Factor VIII; D013925:Thromboplastin; D015942:Factor VIIa