Global coagulation tests: their applicability for measuring direct factor Xa- and thrombin inhibition and reversal of anticoagulation by prothrombin complex concentrate

Jasper Dinkelaar; Sanne Patiwael; Job Harenberg; Anja Leyte; Herm Jan M. Brinkman

doi:10.1515/cclm-2014-0307

Article

Global coagulation tests: their applicability for measuring direct factor Xa- and thrombin inhibition and reversal of anticoagulation by prothrombin complex concentrate

Jasper Dinkelaar , Sanne Patiwael , Job Harenberg , Anja Leyte and Herm Jan M. Brinkman

Published/Copyright: June 5, 2014

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From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 52 Issue 11

Abstract

Background: Specific mass spectrometry and direct activated factor X (Xa)- and thrombin inhibition assays do not allow determination of the reversal of anticoagulant effects of non-vitamin K direct oral anticoagulants (NOACs) by prothrombin complex concentrate (PCC). The objective of this study was the evaluation of the applicability of a variety of commercially available global coagulation assays in analyzing the reversal of NOAC anticoagulation by PCC.

Methods: Plasma and whole blood were spiked with apixaban or dabigatran and PCC was added to these samples. Prothrombin time (PT), modified PT (mPT), activated partial prothrombin time (APTT), thrombography (CAT method) and thromboelastography (ROTEM, TEG) were performed.

Results: Assays triggered by contact activation (APTT, INTEM) did not show inhibitor reversal by PCC. Assays triggered by tissue factor (TF) showed NOAC type and NOAC concentration dependent anticoagulation reversal effects of PCC ranging from partial normalization to overcorrection of the following parameters: clotting or reaction time (PT, mPT TEG-TF, EXTEM, FIBTEM); angle in thromboelastography (TEG-TF); thrombin generation (CAT) lag time, endogenous thrombin potential (ETP) and peak thrombin. Extent of reversal was assay reagent dependent. ETP (5 pM TF) was the only parameter showing complete reversal of anticoagulation by PCC for all NOACs ranging from 200 to 800 μg/L.

Conclusions: ETP fits with the concept that reversal assessment of NOAC anticoagulation by PCC should be based on measurements on the clotting potential or thrombin generating potential of the plasma or whole blood patient sample. Low sensitivity of ETP for NOACs and its correlation with bleeding are issues that remain to be resolved.

Keywords: apixaban; blood coagulation tests; clotting time; dabigatran; reversal of oral anticoagulation; thrombin generation; thromboelastography

Corresponding author: Herm Jan M. Brinkman, Department of Plasma Proteins, Sanquin Research, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands, Phone: +31 205123151, E-mail: h.brinkman@sanquin.nl

Acknowledgments

N. Alleyne, M. Michel and V. Strijbis are acknowledged for excellent technical assistance. Dr. R. Krämer kindly provided purified dabigatran.

Conflict of interest statement

Authors’ conflict of interest disclosure: All other authors stated that there are no conflicts of interest regarding the publication of this article. Research funding and authors’ employment played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Research funding: J. Harenberg receives a grant from Dietmar Hopp Foundation for determination of anticoagulant effects of NOAC in different matrices.

Employment or leadership: H.J.M. Brinkman and S. Patiwael are employed by Sanquin, manufacturer of Cofact.

Honorarium: None declared.

Authors’ contribution: J. Dinkelaar: Designed and performed research, wrote the paper. S. Patiwael: Performed research. J. Harenberg: Designed research, wrote the paper. A. Leyte: Designed research, wrote the paper. H.J.M. Brinkman: Designed and performed research, wrote the paper.

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Received: 2014-3-19

Accepted: 2014-5-13

Published Online: 2014-6-5

Published in Print: 2014-11-19

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Articles in the same Issue

https://doi.org/10.1515/cclm-2014-0307

Keywords for this article

apixaban; blood coagulation tests; clotting time; dabigatran; reversal of oral anticoagulation; thrombin generation; thromboelastography