Acenocoumarol decreases tissue factor-dependent coagulation during systemic inflammation in humans.
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.
Hollenstein
Ursula
U
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.
Homoncik
Monika
M
Knöbl
Paul
P
Pernerstorfer
Thomas
T
Graggaber
Johann
J
Eichler
Hans-Georg
HG
Handler
Sylvia
S
Jilma
Bernd
B
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*
D000925:Anticoagulants; D015415:Biomarkers; D005338:Fibrin Fibrinogen Degradation Products; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D011516:Prothrombin; D013925:Thromboplastin; D015942:Factor VIIa; D000074:Acenocoumarol