TABLE 3.
Summary data from select studies reporting on DOAC neutralization studies
| Study | Summary of findings | Comments/author conclusions |
|---|---|---|
| DOAC‐Stop | ||
| Exner et al 2018 26 | DOAC‐Stop tested on normal and a range of abnormal plasmas using aPTT, dRVVT, PT/INR, including LA samples. DOAC‐Stop found to remove dabigatran, apixaban, rivaroxaban and edoxaban with minimal effect on any of the (mainly clotting) tests | Original description of DOAC‐Stop, and indeed any DOAC‐neutralization for LA testing (and other coagulation assays) |
| Jacquemin et al 2018 27 | Assessed DOAC‐Stop compared with idarucizumab, a humanized antibody fragment that binds dabigatran and acts as an in vivo antidote. DOAC‐Stop as effective as idarucizumab to neutralize dabigatran in a variety of assays and did not interfere with detection of LA | Idarucizumab would represent a very expensive way to neutralize dabigatran for laboratory tests |
| Kopatz et al 2018 28 | Normal pooled plasma spiked with apixaban, dabigatran, edoxaban, or rivaroxaban assessed for thrombin generation in the presence and absence of DOAC‐Stop. DOAC‐Stop effectively removed DOACs, but leaving the DOAC‐Stop‐treated plasma slightly more procoagulant | Although not related to LA, “a minor DOAC‐independent increase in thrombin generation response in the DOAC‐Stop‐treated sample should be taken into account” in relation to other potential hemostasis test results |
| Exner et al 2019 29 | This study aimed to investigate the specificity of an DOAC‐Stop on a range of other anticoagulants using the aPTT. In addition to extracting DOACs, DOAC‐Stop also bound argatroban and lepirudin, but had no effect on heparin, enoxaparin or danaparoid. Among other aPTT‐inhibiting agents, DOAC‐Stop also extracted protamine, aprotinin, and polymyxin | Important follow‐up study, showing additional potential utility for DOAC‐Stop, as well as potential confounders |
| Platton and Hunt 30 | Investigated DOAC‐Stop effects on a range of hemostasis assays on plasmas collected from patients on rivaroxaban or apixaban and enabled more accurate interpretation of coagulation assays (PT, aPTT, DOAC‐specific anti‐Xa assay, factor VIII, and dRVVT) before and after sample treatment | DOAC‐Stop significantly removed the effects of rivaroxaban and apixaban and reduced the number of false‐positive LA interpretations with rivaroxaban. There was no effect on results from patients not anticoagulated. Complete reversal of the anti‐Xa effect did not occur in every sample |
| Ząbczyk et al 31 | Assessed the impact of DOAC‐Stop, reversing in vitro effects of DOACs, on LA testing in 75 anticoagulated VTE patients (50 on rivaroxaban, 20 on dabigatran, and 5 on apixaban) | Authors concluded that DOAC‐Stop did not adversely influence LA testing in APS patients, and effectively reduced plasma DOAC concentrations leading to appropriate dRVVT results in up to 97% of VTE patients |
| Favaloro et al 2019 33 | Assessed cross‐laboratory (n = 82) testing of four samples to investigate whether rivaroxaban‐induced interference in LA testing could be neutralized: (A) A pool of normal plasma (LA‐negative control); (B) sample A spiked with rivaroxaban (200 ng/ml) to create rivaroxaban‐induced interference (LA “false”‐positive sample); (C) sample B subsequently treated with a commercial DOAC‐neutralizer (DOAC‐Stop); (D) sample B treated with andexanet alfa (200 μg/ml) | DOAC‐Stop was able to neutralize the false LA activity induced by rivaroxaban. In contrast, although andexanet alfa negated the rivaroxaban‐prolonged LA ratio, it did not fully correct clot times, leaving some residual LA interference, and requiring additional testing to investigate prolonged clotting times |
| Favresse et al 2018 34 | Investigated the effect of DOAC‐Stop on thrombophilia assays (antithrombin, protein S, protein C, LA, APCR) using 135 DOAC‐treated patients (38 apixaban, 40 dabigatran, 15 edoxaban, and 42 rivaroxaban) and 20 control patients. DOAC‐Stop treatment was mostly effective to overcome the effect of DOACs on aPTT‐LA and dRVVT tests. False‐positive results (up to 75%) from DOACs observed with LA tests fell to zero after DOAC‐Stop treatment, regardless of the DOAC considered | Authors concluded that DOAC‐Stop appeared to be an effective and simple way to overcome the interference of DOAC on coagulation tests and should facilitate the interpretation of thrombophilia screening tests in patients taking DOACs |
| Slavik et al 2019 35 | Evaluated the effectiveness of DOAC‐Stop using 60 (20 apixaban, 20 dabigatran, and 20 rivaroxaban) patients treated with DOACs and using high‐performance liquid chromatography‐coupled tandem mass spectrometry. DOAC‐Stop eliminated dabigatran from 99.5%, rivaroxaban from 97.9%, and apixaban from 97.1% of samples | Authors concluded that residual DOAC amounts did not exceed 2.7 ng/ml for dabigatran, 10.9 ng/ml for rivaroxaban, or 13.03 ng/ml for apixaban, “which are safe values that do not affect either screening or special coagulation tests” |
| De Kesel and Devreese 2020 38 | Assessed the ability of DOAC‐Stop to overcome DOAC interference in LA assays in a representative patient cohort (DOAC, n = 43; VKA, n = 2; heparins, n = 21; no anticoagulants, n = 63). Also, apixaban (30–933 ng/ml), edoxaban (31–1060 ng/ml), rivaroxaban (35–1020 ng/ml), and dabigatran (20–360 ng/ml) were spiked to normal plasma | Authors concluded that DOAC‐Stop limits DOAC interference in LA assays, but that DOAC measurements should be performed in treated samples because incomplete removal may occur. Applying DOAC‐Stop to VKA‐ or heparin‐containing, or non‐anticoagulated samples may lead to erroneous LA results. Therefore, DOAC‐Stop should only be used in plasma from DOAC‐treated patients |
| Monteyne et al 2020 39 | Comparative study of DOAC‐Stop and DOAC‐Remove on a range of assays, including the aPTT, in the absence of DOACs | “aPTT results should be interpreted carefully after treatment with DOAC Stop/Remove as there is a risk for falsely prolonged clotting times” |
| Riva et al 2021 40 | Assessed the effect of DOAC‐Stop on a range of assays (including aPTT and dRVVT) using plasma spiked with various DOACs or parenteral agents | False‐positive LA results obtained with rivaroxaban were normalized with DOAC‐Stop. No effect was observed on the indirect factor Xa inhibitors |
| Baker et al 2021 41 | Authors aimed to evaluate DOAC‐Stop for the removal of DOAC interference in LA testing in 73 samples from patients on DOAC therapy, along with samples from 40 LA positive and negative control patients not on therapy, using aPTT, SCT, and dRVVT. DOAC‐Stop markedly reduced DOAC interference from test samples but had no effect on LA testing in the absence of DOAC therapy, permitting the identification of all LA positive and negative controls | Authors concluded that DOAC‐Stop removed false positives and false negatives resulting from DOAC interference and allowed the identification of patients meeting criteria for the diagnosis of APS by LA testing, as well as the detection of patients on rivaroxaban who are triple positive for APS |
| Úlehlová et al 2021 42 | 31 patient samples spiked with dabigatran, rivaroxaban, or apixaban using concentrations that influenced LA screening tests and thus mask the presence of LA. DOAC levels before and after DOAC‐Stop were determined by functional assays and LC‐MS analysis. The results of LA‐positive samples show significant differences between functional tests and the LC‐MS method both before and after DOAC binding | The presence of LA affects the determination of DOAC by functional tests, and in such cases, it is necessary to use LC‐MS to determine DOAC values accurately. Thus, in patients treated with DOAC who develop LA of medium and higher titers, the authors do not recommend checking DOAC levels with functional tests |
| DOAC‐Remove | ||
| Cox‐Morton et al 2019 44 | DOAC‐Remove did not interfere with coagulation testing in normal plasma or in patients on DOAC with a known LA in 1566 routine patient samples tested. DOAC‐Remove prevented 5% of patients having a false LA detected. DOAC did not significantly affect the LA aPTT ratio, protein S antigen, or protein C activity | Authors concluded DOAC‐Remove reversed DOAC effects on hemostasis assays and aids diagnostic accuracy |
| Jourdi et al 2019 46 | Authors evaluated DOAC‐Remove in dRVVT testing in patient samples: 49 apixaban, 48 rivaroxaban, 24 dabigatran, and 30 none. DOAC‐Remove did not affect dRVVT results in non‐DOAC patients, whereas it resulted in DOAC concentrations <20 ng/ml in 82%, 98%, and 100% of apixaban, rivaroxaban, and dabigatran samples, respectively. DOAC‐Remove corrected DOAC interference with dRVVT assays in 76%, 85%, and 95% of the patients, respectively | Authors recommend the use of DOAC‐Remove for every rivaroxaban sample, whereas it might only be used in positive apixaban and dabigatran samples. A residual DOAC interference cannot be ruled out in case of persisting dRVVT positive results after treatment with DOAC‐Remove |
| Favre et al 2021 48 | 61 referred patients on anticoagulant treatment receiving either DOACs (n = 47: n = 27 rivaroxaban, n = 18 apixaban, n = 2 dabigatran), unfractionated heparin (UFH; n = 7) or LMWH (n = 7); plus 9 patients without anticoagulant treatment | No significant differences between PT, aPTT, fibrinogen, aPTT‐LA, dRVVT, protein C, or protein S before and after the addition of DOAC‐Remove for patients not taking DOACs. Treatment caused aPTT‐LA and dRVVT screen tests falsely positive to became negative |
| Skaugen et al 2021 49 | Study aimed to establish performance characteristics of DOAC‐Remove for neutralization of the effects of rivaroxaban and apixaban in LA testing using samples spiked with rivaroxaban or apixaban and testing by dRVVT, aPTT, and dPT. DOAC‐Remove neutralized rivaroxaban and apixaban concentrations as high as 415 and 333 ng/ml, respectively | Authors concluded that DOAC‐Remove has acceptable performance characteristics for neutralizing effects of rivaroxaban and apixaban for LA testing in the dRVVT and aPTT methods but not in the dPT method |
| Al‐Qawzai et al 2021 50 | 20 samples each from: a control group of non‐anticoagulated patients negative for LA; patients receiving direct factor‐Xa inhibitors (rivaroxaban, apixaban, edoxaban); patients receiving LMWH, dabigatran or argatroban; and patients on warfarin with INR ≥1.5. Testing for PT, aPTT, and TT performed with and without DOAC‐Remove | DOAC‐Remove normalized DOAC and argatroban containing samples |
| DOAC‐Filter | ||
| Farkh et al 2021 51 | Authors evaluated DOAC Filter in 38 rivaroxaban, 41 apixaban, and 68 none patient samples. LA testing was performed using dRVVT and SCT | Authors concluded that DOAC Filter was an easy‐to‐use device allowing FXa inhibitor removal, and thus limiting their interference with LA testing in treated patients |
| Sevenet et al 2020 52 | Study aimed to confirm that DOAC Filter efficiently removes DOACs and to ascertain that coagulation assays are not impacted by filtration. Normal pool plasma (NPP) spiked with DOACs up to 300 ng/ml, with dabigatran etexilate (n = 27), rivaroxaban (n = 35), apixaban (n = 33), and edoxaban (n = 27) or 120 ng/ml for betrixaban (n = 4), and 18 plasma samples from DOAC‐treated patients | Authors conclude that DOAC Filter efficiently removes DOACs from plasma and achieves concentrations below DOAC‐specific assays LoD, except in the case of one apixaban sample. The integrity of plasma is respected, and the cartridge seems not to affect LA diagnosis (NB: Study was from the manufacturer of DOAC Filter) |
| “Activated charcoal” (AC) | ||
| Frans et al 2019 55 | Study evaluated whether AC can be used to resolve DOAC interference on hemostasis tests (anti‐FXa, DTI, PT, aPTT, SCT, dRVVT) using samples from patients receiving DOACs (n = 29), LMWH (n = 10), and VKA (n = 10) | Authors concluded that AC selectively removes DOAC interference on PT, aPTT, and LA assays |
Text includes modifications to promote clarity and brevity. The authors apologize if this causes any misinterpretation of the original material. Additional descriptive text is available in Table S2. See original references reporting data on DOAC neutralization for extended information. Also refer to LA guidelines, 5 , 16 , 18 noting the potential utility of these agents, as well as important caveats (Table 2 and Table S1).
Abbreviations: APCR, activated protein C resistance; aPTT, activated partial thromboplastin time; DOACs, direct oral anticoagulants; dPT, dilute prothrombin time; DTIs, direct thrombin inhibitors; dRVVT, dilute Russell's viper venom time; DTT, diluted thrombin time; INR, international normalized ratio; LA, lupus anticoagulant; LoD, limit of detection; LM‐MS, liquid chromatography coupled with mass spectrometry; LMWH, low molecular weight heparin; PT, prothrombin time; SCT, silica clotting time; TT, thrombin time; UFH, unfractionated heparin; VKAs, vitamin K antagonists; VTE, venous thromboembolism.