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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   *
1   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
2   Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
,
Calvin H. Yeh   *
1   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
2   Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
3   Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
,
Brian J. Dale
2   Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
4   School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
,
Beverly A. Leslie
1   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
2   Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
,
Alan R. Stafford
1   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
2   Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
,
James C. Fredenburgh
1   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
2   Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
,
Jack Hirsh
1   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
,
Jeffrey I. Weitz
1   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
2   Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
3   Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
› Author Affiliations Funding C.H.Y. is supported by a doctoral scholarship from the Canadian Institutes of Health Research. B.J.D is supported by a Scientific Education Grant from the Australasian Society of Thrombosis and Haemostasis. P.Y.K. is supported by the Hamilton Health Sciences Early Career Award and the New Investigator Fund. J.I.W. holds the Canada Research Chair (Tier I) in Thrombosis and the Heart and Stroke Foundation J. Fraser Mustard Chair in Cardiovascular Research at McMaster University.
Further Information

Publication History

16 January 2018

26 March 2018

Publication Date:
29 May 2018 (online)

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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 Ki 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 (Ki 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

Authors' Contributions

P.Y.K designed experiments, performed modeling and data analysis, and wrote the manuscript. C.H.Y. and B.J.D. designed and performed experiments, analyzed and interpreted data, and wrote the manuscript. B.A.L. and A.R.S. performed experiments. J.C.F., J.H., and J.I.W. designed experiments, interpreted data, and wrote the manuscript.


* These authors contributed equally.


Supplementary Material

 

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