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Acenocoumarol decreases tissue factor-dependent coagulation during systemic inflammation in humans
Ursula Hollenstein1, Monika Homoncik, Paul Knöbl
1Department 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.
Clinical Pharmacology and Therapeutics
|May 16, 2002
Summary
Acenocoumarol effectively reduced thrombin generation in a human endotoxemia model, demonstrating its utility for evaluating new anticoagulant drugs. This study highlights the model
Area of Science:
- Pharmacology
- Hematology
- Clinical Drug Development
Background:
- Coumarin derivatives are crucial for preventing thromboembolic events and serve as comparators for novel anticoagulants.
- Measuring novel anticoagulant efficacy in human models with biomarkers aids early clinical development.
- Investigated acenocoumarol's effects in experimental human endotoxemia using a tissue factor-dependent coagulation model.
Purpose of the Study:
- To evaluate the applicability of a tissue factor-dependent coagulation model for assessing anticoagulant potency.
- To investigate the effects of acenocoumarol in experimental human endotoxemia.
- To characterize the pharmacodynamics of oral anticoagulants in a human model.
Main Methods:
- Randomized, controlled, 2-by-2 factorial design study.
- Healthy volunteers received endotoxin or placebo after 18 days of acenocoumarol or placebo pretreatment.
- Measured thrombin and fibrin formation using Prothrombin fragment 1+2 (F(1+2)), soluble fibrin, and D-dimer.
Main Results:
- Acenocoumarol decreased vitamin K-dependent coagulation factors and spontaneous thrombin formation.
- Acenocoumarol significantly inhibited endotoxin-induced thrombin generation, with peak F(1+2) levels reduced from 4.1 to 1.0 nmol/L.
- Decreased soluble fibrin and D-dimer levels indicated limited disseminated intravascular coagulation propagation.
Conclusions:
- Human endotoxemia is a suitable model for measuring oral anticoagulant efficacy.
- This model can be valuable for rapid pharmacodynamic characterization of anticoagulant compounds.
- The study supports the use of this model for early-phase clinical drug development of anticoagulants.