DOAC-Remove abolishes the effect of direct oral anticoagulants on activated protein C resistance testing in real-life venous thromboembolism patients

Abstract

BackgroundDirect oral anticoagulants (DOACs) may cause false results of activated protein C resistance (APC-R) ratio. DOAC-Remove, a new reagent based on activated carbon, has been designed to eliminate the interference of DOACs on coagulation assays. The aim of the study was to investigate whether the use of DOAC-Remove enables to determine APC-R in patients treated with DOACs.MethodsWe assessed 74 venous thromboembolism (VTE) patients, including 25 on rivaroxaban, 25 on apixaban and 24 taking dabigatran. APC-R was determined using the Russell Viper Venom Time (RVVT)-based clotting test. APC-R and DOAC concentrations were tested at baseline and following DOAC-Remove. Thrombophilia, including factor V Leiden (FVL) mutation was tested.ResultsFVL mutation was found in 20 (27%) patients. The APC-R ratio at baseline was measurable in 43 patients (58.1%), including 20 (80%) on rivaroxaban, 19 (76%) on apixaban and four (16.7%) on dabigatran. In patients with measurable APC-R at baseline, the ratio >2.9 was found in 23 patients (53.5%). In 16 (37.2%) subjects APC-R ratio <1.8 suggested FVL mutation which was genetically confirmed. Four (9.3%) FVL carriers on dabigatran showed negative/equivocal APC-R results. In 11 (14.9%) patients taking rivaroxaban or apixaban, in whom blood was collected 2–5 h since the last dose, we observed unmeasurable APC-R. DOAC-Remove almost completely eliminated all plasma DOACs. After addition of DOAC-Remove all APC-R ratios were measurable. In four FVL carriers on dabigatran with false negative APC-R, DOAC-Remove resulted in APC-R ratios <1.8.ConclusionsDOAC-Remove effectively reduces DOACs concentration in plasma, which enables FVL testing using APC-R.

The effect of DOACs on laboratory tests and their removal by activated carbon to limit interference in functional assays

“…A particular version in mini‐tablet form was developed for more convenient application to 1ml volumes of test plasmas (DOAC Stop™, Haematex). Several studies have now been published which confirm that it and similar products (DOAC Remove) may be useful in blood coagulation testing labs to eliminate the in vitro effect of DOACs 6‐16 ; especially in testing for lupus anticoagulant.…”

“…APC resistance tests in which test plasmas are mixed with APC and then tested for residual anticoagulant effect, can mostly be based on aPTT or dRVVT methods. Since the dRVVT is more prolonged by DOACs than the aPTT, this method can give excessively long results with APC present 16 . APC resistance appears to be reduced by DOACs (ratio is increased) and their presence could yield false negative results.…”

“…Kopytek et al 16 used DOAC Remove™ on 74 patients on DOACs for venous thromboembolism and investigated APC resistance. They used a RVV‐based APCR method and found 31 unmeasurably‐long results initially.…”

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

“…38 Alternatively, in vitro removal of DOAC compounds from plasma prior to coagulation testing has been reported and may be more suitable. [39][40][41][42][43][44][45][46][47] DOAC-Stop (adsorbing agent, Hematex Research, Hornsby, Australia) and DOAC-Remove (activated carbon, 5-Diagnostics, Basel, Switzerland), both reportedly able to neutralize all DOACs with minimal effect on haemostasis tests, have been recently commercialized. [39][40][41][42][43][44][45][46][47] However, care should be taken, especially in LA testing, since in the reported studies, complete reversal did not occur in every sample and reversal varies among the different DOACs.…”

Limitations of a calibrated, quantitative APC‐R assay under routine conditions

“…Therefore, we also evaluated the DOAC‐Remove procedure, a simple method to overcome the effects of DOACS on coagulation tests. This has already published for APC‐R testing with a Russell viper venom time–based functional clotting assay 17 . The DOAC‐Remove procedure avoided misclassifications in the quantitative assay.…”