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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

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Volume 57, Issue 6


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



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.


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).


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.


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


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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.

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