Comprehensive review of the impact of direct oral anticoagulants on thrombophilia diagnostic tests: Practical recommendations for the laboratory

Abstract

There is a laboratory and clinical need to know the impact of direct oral anticoagulants (DOACs) on diagnostic tests to avoid misinterpretation of results. Although the regulatory labelling documents provide some information about the influences of each DOAC on diagnostic tests, these are usually limited to some of the most common tests and no head to head comparison is available. In this paper, we report the impact of DOACs on several thrombophilia tests, including assessment of antithrombin, protein S and protein C activity assays, detection of activated protein C resistance and assays used for lupus anticoagulant. Results are compared and discussed with data obtained from literature. The final goal of this comprehensive review is to provide practical recommendations for laboratories to avoid misdiagnosis due to oral direct factor Xa (FXa) or IIa (FIIa) inhibitors. Overall, oral direct FXa (apixaban, betrixaban, edoxaban and rivaroxaban) and FIIa (dabigatran) antagonists may affect clot‐based thrombophilia diagnostic tests resulting in false‐positive or false‐negative results. An effect on FIIa‐based thrombophilia diagnostic tests is observed with dabigatran but not with anti‐FXa DOACs and conversely for FXa‐based thrombophilia diagnostic tests. No impact was observed with antigenic/chromogenic methods for the assessment of protein S and C activity. In conclusion, interpretation of thrombophilia diagnostic tests results should be done with caution in patients on DOACs. The use of a device/chemical compound able to remove or antagonize the effect of DOACs or the development of new diagnostic tests insensitive to DOACs should be considered to minimize the risk of false results.

2021 Update of the International Council for Standardization in Haematology Recommendations for Laboratory Measurement of Direct Oral Anticoagulants

“…It has been widely shown that DOACs may interfere with coagulation testing, even at low DOAC concentrations. 37 Thus, even trough collections aimed to minimize DOAC concentration may be inadequate to completely eliminate drug interference in certain assays. 37 To ensure an undetectable DOAC concentration, a delay of 3 days or more (depending on DOAC, renal function and clinical situations) between the last intake and testing could be necessary.…”

“…37 Thus, even trough collections aimed to minimize DOAC concentration may be inadequate to completely eliminate drug interference in certain assays. 37 To ensure an undetectable DOAC concentration, a delay of 3 days or more (depending on DOAC, renal function and clinical situations) between the last intake and testing could be necessary. A longer delay is likely necessary for lupus anticoagulant (LA) testing with dilute Russell viper venom time (dRVVT) tests, due to the interference that may still be present when DOAC concentration is below the lower limit of quantification of the anti-Xa-based method (anti-Xa).…”

“…[59][60][61][62] As such, caution should be used when performing and interpreting the results from any coagulation-related test from a DOAC-treated patient. 37…”

Review of coagulation preanalytical variables with update on the effect of direct oral anticoagulants

“…However, identification of the lupus anticoagulant, a chronometric or clot-based assay, for the require diagnosis of APS, 38 can be challenging in the presence of DOACs, given their interference in these assays. [39][40][41][42][43] Current recommendations suggest that LA testing should not be performed in patients on DOACs, but also indicate the potential use of DOAC neutralizing agents (Table 3) to mitigate their effect on these tests require further investigation. 44 The use of activated charcoal has been demonstrated to be an effective means of neutralizing most DOACs to near nonmeasurable levels.…”

“…Perhaps, the most interesting consideration for testing patients on DOACs is those patients suspected for high‐risk (triple positivity) antiphospholipid antibody syndrome (APS), as treatment using rivaroxaban in this patient population has demonstrated to be not as effective as warfarin, and thus these patients may be considered for alternative anticoagulant therapy, 37 but further studies are warranted. However, identification of the lupus anticoagulant, a chronometric or clot‐based assay, for the require diagnosis of APS, 38 can be challenging in the presence of DOACs, given their interference in these assays 39‐43 . Current recommendations suggest that LA testing should not be performed in patients on DOACs, but also indicate the potential use of DOAC neutralizing agents (Table 3) to mitigate their effect on these tests require further investigation 44 …”