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

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. A...

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Autores principales: Kim, Paul Y., Yeh, Calvin H., Dale, Brian J., Leslie, Beverly A., Stafford, Alan R., Fredenburgh, James C., Hirsh, Jack, Weitz, Jeffrey I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Georg Thieme Verlag KG 2018
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524873/
https://www.ncbi.nlm.nih.gov/pubmed/31249942
http://dx.doi.org/10.1055/s-0038-1649507
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author Kim, Paul Y.
Yeh, Calvin H.
Dale, Brian J.
Leslie, Beverly A.
Stafford, Alan R.
Fredenburgh, James C.
Hirsh, Jack
Weitz, Jeffrey I.
author_facet Kim, Paul Y.
Yeh, Calvin H.
Dale, Brian J.
Leslie, Beverly A.
Stafford, Alan R.
Fredenburgh, James C.
Hirsh, Jack
Weitz, Jeffrey I.
author_sort Kim, Paul Y.
collection PubMed
description 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.
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spelling pubmed-65248732019-06-27 Mechanistic Basis for the Differential Effects of Rivaroxaban and Apixaban on Global Tests of Coagulation Kim, Paul Y. Yeh, Calvin H. Dale, Brian J. Leslie, Beverly A. Stafford, Alan R. Fredenburgh, James C. Hirsh, Jack Weitz, Jeffrey I. TH Open 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. Georg Thieme Verlag KG 2018-05-29 /pmc/articles/PMC6524873/ /pubmed/31249942 http://dx.doi.org/10.1055/s-0038-1649507 Text en https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Kim, Paul Y.
Yeh, Calvin H.
Dale, Brian J.
Leslie, Beverly A.
Stafford, Alan R.
Fredenburgh, James C.
Hirsh, Jack
Weitz, Jeffrey I.
Mechanistic Basis for the Differential Effects of Rivaroxaban and Apixaban on Global Tests of Coagulation
title Mechanistic Basis for the Differential Effects of Rivaroxaban and Apixaban on Global Tests of Coagulation
title_full Mechanistic Basis for the Differential Effects of Rivaroxaban and Apixaban on Global Tests of Coagulation
title_fullStr Mechanistic Basis for the Differential Effects of Rivaroxaban and Apixaban on Global Tests of Coagulation
title_full_unstemmed Mechanistic Basis for the Differential Effects of Rivaroxaban and Apixaban on Global Tests of Coagulation
title_short Mechanistic Basis for the Differential Effects of Rivaroxaban and Apixaban on Global Tests of Coagulation
title_sort mechanistic basis for the differential effects of rivaroxaban and apixaban on global tests of coagulation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524873/
https://www.ncbi.nlm.nih.gov/pubmed/31249942
http://dx.doi.org/10.1055/s-0038-1649507
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