Mechanistic Basis for the Differential Effects of Rivaroxaban and Apixaban on Global Tests of Coagulation

Paul Y. Kim; Calvin H. Yeh; Brian J. Dale; Beverly A. Leslie; Alan R. Stafford; James C. Fredenburgh; Jack Hirsh; Jeffrey I. Weitz

doi:10.1055/s-0038-1649507

TH Open, Inhaltsverzeichnis

CC-BY 4.0 · TH Open 2018; 02(02): e190-e201
DOI: 10.1055/s-0038-1649507

Original Article

Georg Thieme Verlag KG Stuttgart · New York

Mechanistic Basis for the Differential Effects of Rivaroxaban and Apixaban on Global Tests of Coagulation

Paul Y. Kim^*

¹Department of Medicine, McMaster University, Hamilton, Ontario, Canada

²Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada

,

Calvin H. Yeh^*

¹Department of Medicine, McMaster University, Hamilton, Ontario, Canada

²Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada

³Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada

,

Brian J. Dale

²Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada

⁴School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia

,

Beverly A. Leslie

¹Department of Medicine, McMaster University, Hamilton, Ontario, Canada

²Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada

,

Alan R. Stafford

¹Department of Medicine, McMaster University, Hamilton, Ontario, Canada

²Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada

,

James C. Fredenburgh

¹Department of Medicine, McMaster University, Hamilton, Ontario, Canada

²Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada

,

Jack Hirsh

¹Department of Medicine, McMaster University, Hamilton, Ontario, Canada

,

Jeffrey I. Weitz

¹Department of Medicine, McMaster University, Hamilton, Ontario, Canada

²Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada

³Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada

› Institutsangaben

Abstract

Rivaroxaban and apixaban are both small molecules that reversibly inhibit factor Xa. Compared with rivaroxaban, apixaban has minimal effects on the prothrombin time and activated partial thromboplastin time. To investigate this phenomenon, we used a factor Xa-directed substrate in a buffer system. Although rivaroxaban and apixaban inhibited factor Xa with similar K_i values at equilibrium, kinetic measurements revealed that rivaroxaban inhibited factor Xa up to 4-fold faster than apixaban (p < 0.001). Using a discontinuous chromogenic assay to monitor thrombin production by prothrombinase in a purified system, rivaroxaban was 4-fold more potent than apixaban (K_i values of 0.7 ± 0.3 and 2.9 ± 0.5 nM, respectively; p = 0.02). Likewise, in thrombin generation assays in plasma, rivaroxaban prolonged the lag time and suppressed endogenous thrombin potential to a greater extent than apixaban. To characterize how the two inhibitors differ in recognizing factor Xa, inhibition of prothrombinase was monitored in real-time using a fluorescent probe for thrombin. The data were fit using a mixed-inhibition model and the individual association and dissociation rate constants were determined. The association rates for the binding of rivaroxaban to either free factor Xa or factor Xa incorporated into the prothrombinase complex were 10- and 1,193-fold faster than those for apixaban, respectively, whereas dissociation rates were about 3-fold faster. Collectively, these findings suggest that rivaroxaban and apixaban differ in their capacity to inhibit factor Xa and provide a plausible explanation for the observation that rivaroxaban has a greater effect on global tests of coagulation than apixaban.

Keywords

DOAC - inhibition kinetics - coagulation assays - coagulation inhibitors

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