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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1098.)
© 2003 American Heart Association, Inc.

Thrombosis

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; Pei Hua Lin; Susan T. Edwards; Paul W. Wong; Bingyan Zhu; Robert M. Scarborough; Ting Su; Zhaozhong J. Jia; Yonghong Song; Penglie Zhang; Lane Clizbe; Gary Park; Andrea Reed; Stanley J. Hollenbach; John Malinowski; Ann E. Arfsten

From Millennium Pharmaceuticals Inc, South San Francisco, Calif.

Correspondence to Uma Sinha, PhD, Millennium Pharmaceuticals, 256 E Grand Ave, South San Francisco, CA 94080. E-mail Uma.Sinha{at}mpi.com

Objective— In this 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 K_i 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 K_i using amidolytic substrates.

Key Words: factor Xa • prothrombinase • coagulation inhibitors

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