Thomas Eller1, Tobias Flieder2, Vanessa Fox2, Tatjana Gripp2, Marcus Dittrich3, Joachim Kuhn2, Susanne Alban4, Cornelius Knabbe2, Ingvild Birschmann2. 1. Labor Krone GbR, Siemensstrasse, Bad Salzuflen, Germany. 2. Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Institut für Laboratoriums- und Transfusionsmedizin, Georgstrasse, Bad Oeynhausen, Germany. 3. Department of Bioinformatics, Biocenter, University of Würzburg, Am Hubland, Würzburg, Germany. 4. Pharmaceutical Institute, Christian-Albrechts University of Kiel, Gutenbergstr, Kiel, Germany.
Abstract
Objectives: The three direct oral anticoagulants (DOACs) dabigatran, apixaban and rivaroxaban are now widely used in clinical practice. For patients requiring perioperative interruption of DOACs, heparin bridging is still under discussion. Here we show, for the first time, the influence of concomitantly used DOACs and heparins on laboratory assays. Methods: For spiking experiments, 10 healthy donors and nine patients treated with DOACs were investigated. The measurement of DOACs and heparins was performed with routine methods on the ACL TOP [HEMOCLOT ® direct thrombin inhibitor (CoaChrom Diagnostica, Austria), COAMATIC ® Heparin (Chromogenix, USA) calibrated with rivaroxaban, apixaban, unfractionated heparin (UFH) and low molecular weight heparin (LMWH), additionally PT reagent RecombiPlasTin 2G and aPTT reagent SynthASil (Instrumentation Laboratory, Germany)] and the DOACs were additionally quantified with liquid chromatography-mass spectrometry. A linear regression model has been used to estimate the effect of DOAC prestimulation. Results: No influence of dabigatran could be demonstrated in the anti-Xa testing methods for LMWH, UFH, rivaroxaban or apixaban. All FXa-inhibiting drugs affected all the anti-Xa testing methods in their own specific ways. Compared with heparin alone, measurement of heparins in samples with a basic concentration of DOACs (200 ng/ml) displays a more dramatic increase. Samples of patients with therapeutic intake of DOACs spiked with UFH and LMWH showed the expected pharmacokinetic profiles, but increased pharmacodynamic effects. Conclusions: Direct thrombin and FXa inhibitors exhibit distinct effects on assay results when used concomitantly with heparins. These interactions must be considered in the interpretation of assay results during bridging therapy.
Objectives: The three direct oral anticoagulants (DOACs) dabigatran, apixaban and rivaroxaban are now widely used in clinical practice. For patients requiring perioperative interruption of DOACs, heparin bridging is still under discussion. Here we show, for the first time, the influence of concomitantly used DOACs and heparins on laboratory assays. Methods: For spiking experiments, 10 healthy donors and nine patients treated with DOACs were investigated. The measurement of DOACs and heparins was performed with routine methods on the ACL TOP [HEMOCLOT ® direct thrombin inhibitor (CoaChrom Diagnostica, Austria), COAMATIC ® Heparin (Chromogenix, USA) calibrated with rivaroxaban, apixaban, unfractionated heparin (UFH) and low molecular weight heparin (LMWH), additionally PT reagent RecombiPlasTin 2G and aPTT reagent SynthASil (Instrumentation Laboratory, Germany)] and the DOACs were additionally quantified with liquid chromatography-mass spectrometry. A linear regression model has been used to estimate the effect of DOAC prestimulation. Results: No influence of dabigatran could be demonstrated in the anti-Xa testing methods for LMWH, UFH, rivaroxaban or apixaban. All FXa-inhibiting drugs affected all the anti-Xa testing methods in their own specific ways. Compared with heparin alone, measurement of heparins in samples with a basic concentration of DOACs (200 ng/ml) displays a more dramatic increase. Samples of patients with therapeutic intake of DOACs spiked with UFH and LMWH showed the expected pharmacokinetic profiles, but increased pharmacodynamic effects. Conclusions: Direct thrombin and FXa inhibitors exhibit distinct effects on assay results when used concomitantly with heparins. These interactions must be considered in the interpretation of assay results during bridging therapy.