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

Abstract

In 2018, the International Council for Standardization in Hematology (ICSH) published a consensus document providing guidance for laboratories on measuring direct oral anticoagulants (DOACs). Since that publication, several significant changes related to DOACs have occurred, including the approval of a new DOAC by the Food and Drug Administration, betrixaban, and a specific DOAC reversal agent intended for use when the reversal of anticoagulation with apixaban or rivaroxaban is needed due to life-threatening or uncontrolled bleeding, andexanet alpha. In addition, this ICSH Working Party recognized areas where additional information was warranted, including patient population considerations and updates in point-of-care testing. The information in this manuscript supplements our previous ICSH DOAC laboratory guidance document. The recommendations provided are based on (1) information from peer-reviewed publications about laboratory measurement of DOACs, (2) contributing author’s personal experience/expert opinion and (3) good laboratory practice.

Detection of Direct Oral Anticoagulants in Patient Urine Samples by Prototype and Commercial Test Strips for DOACs – A Systematic Review and Meta-analysis

“…Thromboelastographic methods, 23 global coagulation assays 24 , specific coagulation POCT testing methods using ecarin reagent for determination of dabigatran 25 , a dielectric microsensor after recalcification of a small amount whole blood sample 26 and others. 27 The performance of the urine based DOAC Dipstick to identify DOACs on the studied populations was at least as high as those obtained obtained with specific testing from patients' plasma and whole blood samples using chromogenic assays for DXI or tests based on ecarin reagent for dabigatran measurements.…”

“…The results of this meta-analysis confirm these high sensitivity and specificity of the prototype and commercial test strips and thereby increases the confidence in the results of the DOAC Dipstick test- supporting their use in emergency care medicine and other medical conditions where rapid medical decision-making processes are required. 11 27 Importantly, test results need to be interpreted only in connection with the patient's clinical situation. Examples for clinical indications are patients with acute ischemic stroke to help in thrombolysis or mechanical decision-making, acute or haemorrhagic for deciding to use an antidote, before an acute major urgent surgical intervention, before epidural anesthesia, to confirm stopping of a DOAC before a required temporary interruption or to check adherence to therapy.…”

Can direct oral anticoagulants be used in kidney transplant recipients?

“…Determining trough DOAC concentrations would help to identify drug accumulation in renal impairment and determine the impact of drug interactions and extremes of bodyweight. The ICSH produced recommendations for laboratory monitoring of DOAC levels and within this document are references for peak and trough DOAC levels based on clinical studies 18 …”

“…The primary outcome was whether trough and peak DOAC levels were within the expected ranges documented in the International Council for Standardisation in Haematology (ICSH) recommendations or published literature 18,19 . The secondary outcomes include new‐onset or recurrent VTE, new‐onset stroke during anticoagulant therapy, major bleeding as defined by the International Society of Thrombosis and Haemostasis (ISTH), 20 which includes bleeding leading to a decrease in hemoglobin (Hgb)≥2 g/dL at any time point, transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular, or retroperitoneal bleed) or clinically relevant non‐major bleeding (CRNMB), which is any sign of bleeding that does not fit the ISTH definition of major bleeding but requires medical intervention, leads to hospitalisation or requires a face to face review 21 …”

Direct oral anticoagulant (DOAC) interference in hemostasis assays

“…One par tic u larly chal leng ing area where direct Xa inhib i tor inter fer ence can limit ther a peu tic mon i tor ing of another drug is the spe cial case of patients switching from a direct Xa inhib i tor to ther apy with UFH or low molec u lar weight hep a rin (LMWH). 17 Early reports of effi cacy of DOACStop (DS; Haematex Research) for remov ing the mea sur able antiXa activ ity effect of rivaroxaban and apixaban but not hep a rins raise the pos si bil ity that plas mas in patients transitioning between a direct Xa inhib i tor and UFH or LMWH could be treated with DS prior mea sure ment with a UFH or LMWHcalibrated antiXa activ ity assay or aPTT for ther a peu tic mon i tor ing. [17][18][19] It is impor tant to note that the degree to which acti vated car bon adsorbs LMWH is incom pletely under stood, and fur ther study in this area is needed before rou tinely using DOACneu tral iz ing com pounds in sam ples also containing LMWH.…”