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

Giuseppe Lippi; Camilla Mattiuzzi; Emmanuel J. Favaloro

doi:10.1515/dx-2014-0054

Article Open Access

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

Giuseppe Lippi , Camilla Mattiuzzi and Emmanuel J. Favaloro

Published/Copyright: September 25, 2014

Published by

Become an author with De Gruyter Brill

Submit Manuscript Author Information Explore this Subject

From the journal Diagnosis Volume 1 Issue 4

Keywords: apixaban; dabigatran; direct oral anticoagulants; rivaroxaban; thrombophilia

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.

	Dabigatran	Rivaroxaban	Apixaban
Peek levels	64–443 ng/mL	170–400 ng/mL	100–300 ng/mL
Antithrombin^a	No (using factor X-based chromogenic assays)	No (using thrombin-based chromogenic assays)	No (using thrombin-based chromogenic assays)
Protein C^b	No (using chromogenic assays)	No (using chromogenic assays)	No (using chromogenic assays)
Protein S^b (free)	No (using immunoassays)	No (using immunoassays)	No (using immunoassays)
APCr	Yes	Variable	No (up to 447 ng/mL)
dRVVT	Yes	Yes	Yes

^aAn effect is, however, predicable using factor X-based chromogenic assays in patients taking FXa inhibitors, and FII-based chromogenic assays in patients taking FIIa inhibitors. ^bAn effect is, however, likely using clot-based Protein C and Protein S assays. APCr, activated protein C resistance; DRVVT, dilute Russell’s Viper Venom Time.

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.

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: glippi@ao.pr.it, ulippi@tin.it; and Laboratory of Clinical Chemistry and Hematology, Academic Hospital of Parma, Parma, Italy

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.

References

1. Chandrashekar V. Thrombophilia testing and diagnostic dilemma – a tertiary centre experience. Diagnosis 2014;1:249–50.10.1515/dx-2014-0020Search in Google Scholar PubMed

2. Favaloro EJ, Mohammed S, Pati N, Manyuk H, McDonald D. A clinical audit of congenital thrombophilia investigation in tertiary practice. Pathology 2011;43:266–72.10.1097/PAT.0b013e328344e5fcSearch in Google Scholar PubMed

3. Adcock DM, Gosselin R, Kitchen S, Dwyre DM. The effect of dabigatran on select specialty coagulation assays. Am J Clin Pathol 2013;139:102–9.10.1309/AJCPY6G6ZITVKPVHSearch in Google Scholar PubMed

4. 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;9:133–9.10.1111/j.1538-7836.2010.04098.xSearch in Google Scholar PubMed

5. Mani H, Hesse C, Stratmann G, Lindhoff-Last E. Ex vivo effects of low-dose rivaroxaban on specific coagulation assays and coagulation factor activities in patients under real life conditions. Thromb Haemost 2013;109:127–36.10.1160/TH12-04-0228Search in Google Scholar PubMed

6. Douxfils J, Chatelain C, Chatelain B, Dogné JM, Mullier F. Impact of apixaban on routine and specific coagulation assays: a practical laboratory guide. Thromb Haemost 2013;110:283–94.10.1160/TH12-12-0898Search in Google Scholar PubMed

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;38:269–74.10.1007/s11239-014-1082-5Search in Google Scholar PubMed

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].10.1055/s-0034-1381233Search in Google Scholar PubMed

9. Favaloro EJ, Lippi G, Koutts J. Laboratory testing of anticoagulants: the present and the future. Pathology 2011;43:682–92.10.1097/PAT.0b013e32834bf5f4Search in Google Scholar PubMed

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

Published Online: 2014-9-25

Published in Print: 2014-12-1

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.