Acenocoumarol decreases tissue factor-dependent coagulation during systemic inflammation in humans

• Published in: Clinical pharmacology and therapeutics Vol. 71; no. 5; p. 368
• Main Authors: Hollenstein, Ursula, Homoncik, Monika, Knöbl, Paul, Pernerstorfer, Thomas, Graggaber, Johann, Eichler, Hans-Georg, Handler, Sylvia, Jilma, Bernd
• Format: Journal Article
• Language: English
• Published: United States 01.05.2002
• Subjects: Acenocoumarol - therapeutic use; Adult; Analysis of Variance; Anticoagulants - therapeutic use; Biomarkers - blood; Blood Coagulation Tests - statistics & numerical data; Confidence Intervals; Dimerization; Double-Blind Method; Endotoxemia - blood; Factor VIIa - metabolism; Fibrin Fibrinogen Degradation Products - metabolism; Humans; Inflammation - blood; Infusions, Intravenous; Lipopolysaccharides - administration & dosage; Male; Peptide Fragments - blood; Pilot Projects; Platelet Count; Prothrombin - metabolism; Solubility; Statistics, Nonparametric; Thromboplastin - physiology
• ISSN: 0009-9236
• DOI: 10.1067/mcp.2002.123596

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. 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. 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. 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.