Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

Editor-in-Chief: Plebani, Mario

Ed. by Gillery, Philippe / Greaves, Ronda / Lackner, Karl J. / Lippi, Giuseppe / Melichar, Bohuslav / Payne, Deborah A. / Schlattmann, Peter


IMPACT FACTOR 2018: 3.638

CiteScore 2018: 2.44

SCImago Journal Rank (SJR) 2018: 1.191
Source Normalized Impact per Paper (SNIP) 2018: 1.205

Online
ISSN
1437-4331
See all formats and pricing
More options …
Volume 57, Issue 6

Issues

Danger of false negative (exclusion) or false positive (diagnosis) for ‘congenital thrombophilia’ in the age of anticoagulants

Emmanuel J. Favaloro
  • Corresponding author
  • Haematology, Institute of Clinical Pathology and Medical Research, NSW Health Pathology, Westmead Hospital, Westmead, NSW 2145, Australia
  • Sydney Centres for Thrombosis and Haemostasis, Sydney, NSW, Australia, Phone: +612 8890 6618
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2018-11-29 | DOI: https://doi.org/10.1515/cclm-2018-1041

Abstract

Background

Most guidelines and experts recommend against performance of thrombophilia testing in general, and specifically against testing patients on pharmacological anticoagulants, due to substantially increased risk of false positive identification. For example, vitamin K antagonist (VKA) therapy affects protein C (PC) and protein S (PS), as well as some clotting assays (e.g. as used to investigate activated PC resistance [APCR]). Although heparin may also affect clotting assays, most commercial methods contain neutralisers to make them ‘insensitive’ to therapeutic levels. Direct oral anticoagulants (DOACs) also affect a wide variety of thrombophilia assays, although most reported data has employed artificial in vitro spiked samples.

Methods

In the current report, data from our facility for the past 2.5 years has been assessed for all ‘congenital thrombophilia’ related tests, as evaluated against patient anticoagulant status. We processed 10,571 ‘thrombophilia’ related test requests, including antithrombin (AT; n=3470), PC (n=3569), PS (n=3585), APCR (n=2359), factor V Leiden (FVL; n=2659), and prothrombin gene mutation (PGM; n=2103).

Results

As expected, VKA therapy affected PC and PS, and despite manufacturer claims, also APCR. Most assays, as suggested by manufacturers, were largely resistant to heparin therapy. DOACs’ use was associated with falsely low APCR ratios (i.e. FVL-like effect) and somewhat unexpectedly, anti-Xa agents apixaban and rivaroxaban were also associated with lower AT and higher PS values.

Conclusions

It is concluded that ex-vivo data appears to confirm the potential for both false positive and false negative ‘thrombophilia’ events in patients on anticoagulant (including DOAC) treatment.

Keywords: activated protein C resistance; anticoagulant therapy; antithrombin; direct oral anticoagulants; laboratory practice; protein C; protein S; thrombophilia

References

  • 1.

    Favaloro EJ, Pasalic L, Lippi G. Replacing warfarin therapy with the newer direct oral anticoagulants, or simply a growth in anticoagulation therapy? Implications for pathology testing. Pathology 2017;49:639–43.Web of SciencePubMedCrossrefGoogle Scholar

  • 2.

    Favaloro EJ, Pasalic L, Curnow J, Lippi G. Laboratory monitoring or measurement of direct oral anticoagulants (DOACs): advantages, limitations and future challenges. Curr Drug Metab 2017;18:598–608.PubMedWeb of ScienceGoogle Scholar

  • 3.

    Lippi G, Franchini M, Favaloro EJ. Pharmacogenetics of vitamin K antagonists: useful or hype? Clin Chem Lab Med 2009;47:503–15.Web of SciencePubMedGoogle Scholar

  • 4.

    Bonar R, Favaloro EJ. Explaining and reducing the variation in inter-laboratory reported values for international normalised ratio. Thromb Res 2016;150:22–9.PubMedWeb of ScienceGoogle Scholar

  • 5.

    Steinberg BA, Shrader P, Thomas L, Ansell J, Fonarow GC, Gersh BJ, et al. Off-label dosing of non-vitamin K antagonist oral anticoagulants and adverse outcomes: The ORBIT-AF II registry. J Am Coll Cardiol 2016;68:2597–604.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 6.

    Baglin T, Gray E, Greaves M, Hunt BJ, Keeling D, Machin S, et al. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol 2010;149:209–20.Web of ScienceCrossrefPubMedGoogle Scholar

  • 7.

    Graham N, Rashiq H, Hunt BJ. Testing for thrombophilia: clinical update. Br J Gen Pract 2014;64:e120–2.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 8.

    Howard LS, Hughes RJ. NICE guideline: management of venous thromboembolic diseases and role of thrombophilia testing. Thorax 2013;68:391–3.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 9.

    De Stefano V, Rossi E. Testing for inherited thrombophilia and consequences for antithrombotic prophylaxis in patients with venous thromboembolism and their relatives. A review of the guidelines from scientific societies and working groups. Thromb Haemost 2013;110:697–705.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 10.

    Carroll BJ, Piazza G. Hypercoagulable states in arterial and venous thrombosis: When, how, and who to test? Vasc Med 2018;23:388–99.CrossrefWeb of SciencePubMedGoogle Scholar

  • 11.

    Ormesher L, Simcox LE, Tower C, Greer IA. ‘To test or not to test’, the arguments for and against thrombophilia testing in obstetrics. Obstet Med 2017;10:61–6.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 12.

    Gosselin RC, Adcock DM, Bates SM, Douxfils J, Favaloro EJ, Gouin-Thibault I, et al. International Council for Standardization in Haematology (ICSH) recommendations for laboratory measurement of direct oral anticoagulants. Thromb Haemost 2018;118:437–50.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 13.

    Bonar R, Favaloro EJ, Mohammed S, Pasalic L, Sioufi J, Marsden K. The effect of dabigatran on haemostasis tests: a comprehensive assessment using in-vitro and ex-vivo samples. Pathology 2015;47:355–64.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 14.

    Bonar R, Favaloro EJ, Mohammed S, Ahuja M, Pasalic L, Sioufi J, et al. The effect of the direct factor Xa inhibitors apixaban and rivaroxaban on haemostasis tests: a comprehensive assessment using in vitro and ex vivo samples. Pathology 2016;48:60–71.Web of ScienceCrossrefPubMedGoogle Scholar

  • 15.

    Favaloro EJ, Orsag I, Bukuya M, McDonald D. A nine-year retrospective assessment of laboratory testing for activated protein C resistance: evolution of a novel approach to thrombophilia investigations. Pathology 2002;34:348–55.CrossrefGoogle Scholar

  • 16.

    Mohammed S, Favaloro EJ. Laboratory testing for activated protein C resistance (APCR). Methods Mol Biol 2017;1646:137–43.PubMedCrossrefGoogle Scholar

  • 17.

    Favaloro EJ. Diagnostic issues in Thrombophilia: a laboratory scientist’s view. Semin Thromb Hemost 2005;31:11–6.CrossrefPubMedGoogle Scholar

  • 18.

    Favaloro EJ, McDonald D. Futility of testing for factor V Leiden. Blood Trans 2012;10:260–3.Google Scholar

  • 19.

    Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, et al. Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost 2009;7:1737–40.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 20.

    Exner T, Michalopoulos N, Pearce J, Xavier R, Ahuja M. Simple method for removing DOACs from plasma samples. Thromb Res 2018;163:117–22.CrossrefWeb of SciencePubMedGoogle Scholar

  • 21.

    Mou E, Kwang H, Hom J, Shieh L, Kumar A, Richman I, et al. Magnitude of potentially inappropriate thrombophilia testing in the inpatient hospital setting. J Hosp Med 2017;12:735–8.Web of SciencePubMedCrossrefGoogle Scholar

  • 22.

    Cox N, Johnson SA, Vazquez S, Fleming RP, Rondina MT, Kaplan D, et al. Patterns and appropriateness of thrombophilia testing in an academic medical center. J Hosp Med 2017;12:705–9.CrossrefWeb of ScienceGoogle Scholar

  • 23.

    Shen YM, Tsai J, Taiwo E, Gavva C, Yates SG, Patel V, et al. Analysis of thrombophilia test ordering practices at an academic center: a proposal for appropriate testing to reduce harm and cost. PLoS One 2016;11:e0155326.CrossrefWeb of ScienceGoogle Scholar

  • 24.

    Kwon AJ, Roshal M, DeSancho MT. Clinical adherence to thrombophilia screening guidelines at a major tertiary care hospital. J Thromb Haemost 2016;14:982–6.Web of ScienceCrossrefGoogle Scholar

  • 25.

    Lippi G. Thrombophilia testing. Useful or hype? Clin Chem Lab Med 2014;52:467–9.PubMedWeb of ScienceGoogle Scholar

  • 26.

    Franchini M. The utility of thrombophilia testing. Clin Chem Lab Med 2014;52:495–7.Web of SciencePubMedGoogle Scholar

  • 27.

    Favaloro EJ. The futility of thrombophilia testing. Clin Chem Lab Med 2014;52:499–503.PubMedWeb of ScienceGoogle Scholar

About the article

Received: 2018-09-21

Accepted: 2018-11-05

Published Online: 2018-11-29

Published in Print: 2019-05-27


Author contributions: The author has 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: Clinical Chemistry and Laboratory Medicine (CCLM), Volume 57, Issue 6, Pages 873–882, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/cclm-2018-1041.

Export Citation

©2019 Walter de Gruyter GmbH, Berlin/Boston.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

[1]
Rita Selby and Carolyne Elbaz
Journal of Thrombosis and Haemostasis, 2019, Volume 17, Number 9, Page 1443
[3]
Riddhi Virparia, Luigi Brunetti, Stuart Vigdor, and Christopher D. Adams
Journal of Thrombosis and Thrombolysis, 2019
[4]
Sally Cox‐Morton, Stephen MacDonald, and Will Thomas
British Journal of Haematology, 2019

Comments (0)

Please log in or register to comment.
Log in