title: Acenocoumarol decreases tissue factor-dependent coagulation during systemic inflammation in humans.
abstract: BACKGROUND
  Coumarin derivatives are still widely used for prophylaxis of thromboembolic events and therefore represent important comparator substances for new anticoagulants. Measurement of the efficacy of such novel compounds in a human coagulation model with adequate biomarkers could be useful for early-phase clinical drug development. To evaluate the applicability of a well-established model of tissue factor-dependent coagulation for defining anticoagulant potency, we investigated the effects of acenocoumarol in experimental human endotoxemia.
  
  
  METHODS
  In a randomized, controlled, 2-by-2 factorial design, healthy volunteers received an infusion of 2 ng/kg endotoxin or placebo after 18 days of pretreatment with acenocoumarol or placebo. Prothrombin fragment 1+2 (F(1+2)), soluble fibrin, and D-dimer were used as markers of thrombin and fibrin formation.
  
  
  RESULTS
  As expected, pretreatment with acenocoumarol decreased vitamin K-dependent coagulation factors, but it also decreased spontaneous thrombin formation. Acenocoumarol inhibited endotoxin-induced thrombin generation as measured by F(1+2) levels: endotoxin infusion increased F(1+2) levels 8-fold-from 0.5 to 4.1 nmol/L-in the placebo group, whereas peak F(1+2) levels reached only 1.0 nmol/L in subjects after acenocoumarol pretreatment. This inhibition was also reflected in decreased formation of soluble fibrin and decreased D-dimer levels, showing that depletion of endogenous coagulation factors limits the propagation of nonovert disseminated intravascular coagulation.
  
  
  CONCLUSIONS
  Human endotoxemia is a suitable tool for measurement of the efficacy of oral anticoagulants and therefore may become a valuable addition for expeditious pharmacodynamic characterization of lead compounds with anticoagulant potency.
authors.affiliation: Department of Clinical Pharmacology, Internal Medicine I, Division of Infectious Diseases, Clinical Institute of Medical and Chemical Laboratory Diagnostics, University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: Ursula
authors.initials: U
authors.lastname: Hollenstein
authors.forename: Monika
authors.initials: M
authors.lastname: Homoncik
authors.forename: Paul
authors.initials: P
authors.lastname: Knöbl
authors.forename: Thomas
authors.initials: T
authors.lastname: Pernerstorfer
authors.forename: Johann
authors.initials: J
authors.lastname: Graggaber
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Eichler
authors.forename: Sylvia
authors.initials: S
authors.lastname: Handler
authors.forename: Bernd
authors.initials: B
authors.lastname: Jilma
mesh_terms: D000074:Acenocoumarol / Q000627:therapeutic use*; D000328:Adult; D000704:Analysis of Variance; D000925:Anticoagulants / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001780:Blood Coagulation Tests / Q000706:statistics & numerical data; D016001:Confidence Intervals; D019281:Dimerization; D004311:Double-Blind Method; D019446:Endotoxemia / Q000097:blood*; D015942:Factor VIIa / Q000378:metabolism; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000097:blood; D007262:Infusions, Intravenous; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D010446:Peptide Fragments / Q000097:blood; D010865:Pilot Projects; D010976:Platelet Count; D011516:Prothrombin / Q000378:metabolism; D012995:Solubility; D018709:Statistics, Nonparametric; D013925:Thromboplastin / Q000502:physiology*
chemical_list: D000925:Anticoagulants; D015415:Biomarkers; D005338:Fibrin Fibrinogen Degradation Products; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D011516:Prothrombin; D013925:Thromboplastin; D015942:Factor VIIa; D000074:Acenocoumarol