on May 15, 2003
Published online before print May 15, 2003, doi: 10.1161/01.ATV.0000077248.22632.88
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Submitted on April 16, 2003
Accepted on May 2, 2003
Inhibition of Purified Factor Xa Amidolytic Activity May Not Be Predictive of Inhibition of In Vivo Thrombosis. Implications for Identification of Therapeutically Active Inhibitors
Uma Sinha *;
From Millennium Pharmaceuticals Inc, South San Francisco, Calif.
* To whom correspondence should be addressed. E-mail: Uma.Sinha{at}mpi.com.
Objective--In thi study we test the hypothesis that blood/plasma-based prothrombinase assays, rather than inhibition of purified factor Xa (fXa), are predictive of in vivo antithrombotic activity.
Methods and Results--Six fXa inhibitors with equivalent nanomolar Ki were studied in thrombin generation assays using human plasma/blood and endogenous macromolecular substrate. In all assays, benzamidine inhibitors were more potent (100 to 800 nmol/L) than the aminoisoquinolines (5 to 58 µmol/L) or neutral inhibitors (3 to10 µmol/L). A similar rank order of compound inhibition was also seen in purified prothrombinase assays as well as in a rabbit model of deep vein thrombosis.
Conclusions--Assays using prothrombinase with protein substrates are better predictors of in vivo efficacy than fXa Ki using amidolytic substrates.
Key words: factor Xa • prothrombinase • coagulation inhibitors
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