Neutralising rivaroxaban induced interference in laboratory testing for lupus anticoagulant (LA): A comparative study using DOAC Stop and andexanet alfa

Favaloro, Emmanuel J.; Gilmore, Grace; Arunachalam, Sandya; Mohammed, Soma; Baker, Ross

doi:10.1016/j.thromres.2019.05.013

Cited by 50 publications

(97 citation statements)

References 25 publications

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“…This sample formed the ‘rivaroxaban + DOAC Stop’ treatment sample. The ICPMR laboratory confirmed that the rivaroxaban was neutralized in this sample prior to lyophilization and cross‐laboratory testing. A final ~1/3 aliquot of the rivaroxaban‐treated sample was instead additionally treated with andexanet alfa (kindly donated by the manufacturer, Portola Pharmaceuticals Inc) and used at a final concentration of 200 μg/mL, as selected based on considerations previously described . This final sample formed the ‘rivaroxaban + andexanet alfa’ treatment sample.…”

Section: Methodssupporting

confidence: 87%

“…DOAC Stop has been assessed for DOAC neutralization in several studies, but mostly related to assessment of thrombophilia, 18,19,[26][27][28][29][30][31] and included in only a few studies related to factor assays. 30,32 To our knowledge, no study has previously assessed the effect of andexanet alfa on factor levels and DOAC interference.…”

Section: Discussionmentioning

confidence: 99%

“…Third, we have restricted assessment to a single concentration of andexanet alfa; however, we believe this to be potentially reflective of a genuine treatment value if an ex vivo sample could be obtained, 19 and higher concentrations of andexanet do not substantially further neutralize rivaroxaban detected by anti-FXa testing ( Figure S1; Ref. 19 ). Fourth, we did not separately assess individual combinations of reagents/instruments in order to provide any further specific detail around reagent-related differences.…”

Section: Discussionmentioning

confidence: 99%

“…Samples were coded to preserve sample blinding; coding was different to that of the previous LA‐based study, in case participants for the current study also participated in the prior study. Samples were later commercially lyophilized by Australian Scientific Enterprise and sent as sample sets, together with instructions and data sheets for completion, to participant laboratories who derived from those already enrolled in the FVIII and FIX external quality assessment (EQA) programme of the RCPAQAP (Royal College of Pathologists of Australasia) .…”

Section: Methodsmentioning

confidence: 99%

“…Samples were coded to preserve sample blinding; coding was different to that of the previous LA-based study, 19 in case participants for the current study also participated in the prior study. Samples were later commercially lyophilized by Australian…”

Section: Code Used In Fviii and Fix Exercise Identity In Current Reportmentioning

confidence: 99%

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Reducing the effect of DOAC interference in laboratory testing for factor VIII and factor IX: A comparative study using DOAC Stop and andexanet alfa to neutralize rivaroxaban effects

et al. 2020

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Introduction Investigation of factors (F) VIII and IX is common, with testing important for diagnosis or exclusion of haemophilia A or B, associated acquired conditions and factor inhibitors. Rivaroxaban, a common direct anti‐Xa agent, causes significant interference in clotting assays, including substantial false reduction of factor levels. Aim To assess whether rivaroxaban‐induced interference of FVIII and FIX testing could be neutralized. Materials and methods An international, cross‐laboratory exercise for FVIII (n = 84) and FIX (n = 74), using four samples: (A) pool of normal plasma; (B) pool spiked with rivaroxaban (200 ng/mL); (C) rivaroxaban sample subsequently treated with ‘DOAC Stop’ and; (D) rivaroxaban sample treated with andexanet alfa (200 μg/mL). Testing performed blind to sample type. Results All laboratories reported normal FIX and 94% reported normal FVIII in the pool sample. Instead, 55% and 95%, respectively, reported abnormal FIX and FVIII levels for the rivaroxaban sample. DOAC Stop treatment evidenced a correction in most laboratories (100% reported normal FIX and 86% normal FVIII). Andexanet alfa provided intermediate results, with many laboratories still reporting abnormal results (59% for FVIII, 18% for FIX). We also identified reagent‐specific issues. Conclusions As expected, rivaroxaban caused false low values of FVIII and FIX. This might lead to increased testing to identify the cause of low factor levels and potentially lead to false identification of (mild) haemophilia A or B if unrecognized by clinicians/laboratories. DOAC Stop effectively neutralized the rivaroxaban effect, but andexanet alfa less so, with reagent‐related effects evident, and thus, false low values sometimes persisted.

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Section: Methodssupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Code Used In Fviii and Fix Exercise Identity In Current Reportmentioning

confidence: 99%

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Reducing the effect of DOAC interference in laboratory testing for factor VIII and factor IX: A comparative study using DOAC Stop and andexanet alfa to neutralize rivaroxaban effects

et al. 2020

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The Russell viper venom time (RVVT) test for investigation of lupus anticoagulant (LA)

Favaloro

2019

American J Hematol

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Lupus anticoagulants (LAs) are a laboratory representation of the clinical syndrome of antiphospholipid syndrome (APS), and can also arise in other pathological states. Laboratory testing for LA is complex and three separate recent guidelines have been published. One test, the Russell viper venom time (RVVT), is the mandated laboratory test for inclusion in LA identification/exclusion in all three guidance documents. This is because the the RVVT is recognized to have great sensitivity for LA, with this generally recognized to be greater than that of most other LA screening assays. However, the RVVT is also very sensitive to the presence of many anticoagulant drugs, which diminishes its specificity for LA. Various strategies can be used to improve LA specificity and reduce anticoagulant assay interference.

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The effect of unfractionated heparin, enoxaparin, and danaparoid on lupus anticoagulant testing: Can activated carbon eliminate false‐positive results?

Kesel

Devreese

2020

Research and Practice in Thrombosis and Haemostasis

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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractBackground: Heparins and heparinoids interfere with functional clotting assays used for lupus anticoagulant (LAC) detection. However, current guidelines for LAC testing do not provide clear guidance on this matter. Objectives:We aimed to assess to effect of unfractionated heparin (UFH), enoxaparin, and danaparoid on LAC assays over broad anti-Xa activity ranges and to evaluate whether activated carbon (AC) is able to neutralize these effects.Methods: UFH (0.1-3.0 IU/mL), enoxaparin (0.2-2.9 IU/mL), and danaparoid (0.6-2.2 IU/mL) were spiked to normal pooled plasma. AC was added at multiple activity levels. Anti-Xa assays and LAC tests were performed on all samples using Stago analyzers and reagents.Results: Abnormal activated partial thromboplastin time (APTT) screening and mixing tests were obtained at the lowest levels for all compounds. Abnormal APTT confirmation tests were seen from 2.5 and 1.9 anti-Xa IU/mL for enoxaparin and danaparoid, respectively. Abnormal dilute Russell's viper venom test (dRVVT) screening tests were obtained from 1.6, 1.4, and 1.1 anti-Xa IU/mL for UFH, enoxaparin, and danaparoid, respectively. Mixing tests were abnormal from 2.5 and 1.3 anti-Xa IU/mL for enoxaparin and danaparoid, respectively. Abnormal dRVVT confirmation results were seen for danaparoid only from 1.9 anti-Xa IU/mL. AC was unable to neutralize anti-Xa activity in plasma and overcome the effect of the tested anticoagulants on LAC assays but may cause prolongation of APTT clotting times.Conclusions: UFH, enoxaparin, and danaparoid clearly affected LA tests; however, false-positive LAC conclusions were obtained at supratherapeutic enoxaparin and danaparoid levels only. AC may prolong APTT screen clotting times, requiring 3-step testing to avoid potential misdiagnosis of LAC. K E Y W O R D Scarbon, danaparoid, enoxaparin, heparin, lupus coagulation inhibitor

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Neutralising rivaroxaban induced interference in laboratory testing for lupus anticoagulant (LA): A comparative study using DOAC Stop and andexanet alfa

Cited by 50 publications

References 25 publications

Reducing the effect of DOAC interference in laboratory testing for factor VIII and factor IX: A comparative study using DOAC Stop and andexanet alfa to neutralize rivaroxaban effects

Reducing the effect of DOAC interference in laboratory testing for factor VIII and factor IX: A comparative study using DOAC Stop and andexanet alfa to neutralize rivaroxaban effects

The Russell viper venom time (RVVT) test for investigation of lupus anticoagulant (LA)

The effect of unfractionated heparin, enoxaparin, and danaparoid on lupus anticoagulant testing: Can activated carbon eliminate false‐positive results?

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