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Official Journal of the Society to Improve Diagnosis in Medicine (SIDM)

Editor-in-Chief: Graber, Mark L. / Plebani, Mario

Ed. by Argy, Nicolas / Epner, Paul L. / Lippi, Giuseppe / McDonald, Kathryn / Singh, Hardeep

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Thrombophilia testing in patients taking direct oral anticoagulants. Handle with care

Giuseppe Lippi
  • Corresponding author
  • U.O. Diagnostica Ematochimica, Azienda Ospedaliero-Universitaria di Parma, Via Gramsci, 14, 43126 – Parma, Italy
  • Laboratory of Clinical Chemistry and Hematology, Academic Hospital of Parma, Parma, Italy
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Camilla Mattiuzzi / Emmanuel J. Favaloro
  • Institute of Clinical Pathology and Medical Research (ICPMR), Department of Haematology, Pathology West, Westmead Hospital, Westmead, NSW, Australia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2014-09-25 | DOI: https://doi.org/10.1515/dx-2014-0054

To the Editor,

We read with interest the recent letter of Chandrashekar, who further emphasized that results of thrombophilia testing may be confounded by the incident administration of oral vitamin K antagonists (VKAs), and that this potential interference may be detected by elevated prothrombin time (PT) and activated partial thromboplastin time (APTT) [1]. This was also seen in work previously published by one of us [2], where an alarming 80% of so-called low protein C, protein S and/or antithrombin levels in diagnostic test practice derived from cases likely to be on conventional anticoagulant therapy (VKAs or heparin) at the time of testing. Thus, there is ample evidence that blood sampling for thrombophilia screening should be avoided in patients taking conventional anticoagulants such as VKAs. However, differing and more complex conclusions may need to be applied to the direct oral anticoagulants (DOACs), either the activated factor II (FIIa) inhibitor dabigatran or the activated factor X (FXa) inhibitors rivaroxaban, apixaban and edoxaban. This is an important consideration, given the ever-increasing number of patients taking these agents.

With the only exception of edoxaban, the influence of these novel and largely clinically effective therapeutic agents on conventional hemostasis assays has been thoughtfully investigated over the past few years [3–7], and the main findings are summarized in Table 1. In brief, none of the recommended tests for assessment of protein C (chromogenic) or protein S (free) has proven to be significantly biased by the presence of DOACs, even at the peek levels of the drugs [8]. However, the same will not apply to clot-based assays for protein C and protein S. As regards antithrombin, this parameter can be assessed by means of FX-based chromogenic assays in patients taking FIIa inhibitors, and by means of FII-based chromogenic assays in patients taking FXa inhibitors, respectively. However, utilising FX-based chromogenic assays in patients taking FXa inhibitors, and FII-based chromogenic assays in patients taking FIIa inhibitors will be problematic and lead to false identification of deficiencies. The activated protein C resistance (APCr) assay exhibits a variable method-dependent prolongation with dabigatran and rivaroxaban, and a significant prolongation with apixaban at concentrations that were approximately 50% higher than the upper peak level. Also predictable, since it is a clot-based assay, is that the dilute Russell’s Viper Venom Time (dRVVT) shows a high degree of dose-dependent bias, so that this test has even been recently proposed to enable screening the anticoagulant effect of all DOACs [9, 10].

Table 1

Influence of dabigatran, rivaroxaban and apixaban on thrombophilia testing.

According to the available evidence published so far, it can hence be concluded that thrombophilia testing in patients taking direct oral anticoagulants should be handled with much care, and unless laboratories and clinicians understand the variable effects of these drugs on hemostasis tests, the false identification of thrombophilia defects will be entirely feasible.


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    Adcock DM, Gosselin R, Kitchen S, Dwyre DM. The effect of dabigatran on select specialty coagulation assays. Am J Clin Pathol 2013;139:102–9.Web of ScienceGoogle Scholar

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    Hillarp A, Baghaei F, Fagerberg Blixter I, Gustafsson KM, Stigendal L, Sten-Linder M, et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost 2011;9:133–9.CrossrefWeb of ScienceGoogle Scholar

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  • 7.

    Lippi G, Ardissino D, Quintavalla R, Cervellin G. Urgent monitoring of direct oral anticoagulants in patients with atrial fibrillation: a tentative approach based on routine laboratory tests. J Thromb Thrombolysis 2014;38:269–74.Web of ScienceGoogle Scholar

  • 8.

    Lippi G, Favaloro EJ, Mattiuzzi C. Combined administration of antibiotics and direct oral anticoagulants: a renewed indication for laboratory monitoring? Semin Thromb Hemost 2014 Jun 11. [Epub ahead of print].Google Scholar

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    Favaloro EJ, Lippi G, Koutts J. Laboratory testing of anticoagulants: the present and the future. Pathology 2011;43:682–92.Web of ScienceCrossrefGoogle Scholar

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    Favaloro EJ, Lippi G. The new oral anticoagulants and the future of haemostasis laboratory testing. Biochem Med (Zagreb) 2012;22:329–41.CrossrefGoogle Scholar

About the article

Corresponding author: Prof. Giuseppe Lippi, U.O. Diagnostica Ematochimica, Azienda Ospedaliero-Universitaria di Parma, Via Gramsci, 14, 43126 – Parma, Italy, Phone: +0039-0521-703050, +0039-0521-703791, E-mail: , ; and Laboratory of Clinical Chemistry and Hematology, Academic Hospital of Parma, Parma, Italy

Published Online: 2014-09-25

Published in Print: 2014-12-01

Conflict of interest statement

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) 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.

Citation Information: Diagnosis, Volume 1, Issue 4, Pages 311–312, ISSN (Online) 2194-802X, ISSN (Print) 2194-8011, DOI: https://doi.org/10.1515/dx-2014-0054.

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©2014, Lippi et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License. BY-NC-ND 3.0

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