International Council for Standardization in Haematology (ICSH) Recommendations for Laboratory Measurement of Direct Oral Anticoagulants

Abstract

This guidance document was prepared on behalf of the International Council for Standardization in Haematology (ICSH) for providing haemostasis-related guidance documents for clinical laboratories. This inaugural coagulation ICSH document was developed by an ad hoc committee, comprised of international clinical and laboratory direct acting oral anticoagulant (DOAC) experts. The committee developed consensus recommendations for laboratory measurement of DOACs (dabigatran, rivaroxaban, apixaban and edoxaban), which would be germane for laboratories assessing DOAC anticoagulation. This guidance document addresses all phases of laboratory DOAC measurements, including pre-analytical (e.g. preferred time sample collection, preferred sample type, sample stability), analytical (gold standard method, screening and quantifying methods) and post analytical (e.g. reporting units, quality assurance). The committee addressed the use and limitations of screening tests such as prothrombin time, activated partial thromboplastin time as well as viscoelastic measurements of clotting blood and point of care methods. Additionally, the committee provided recommendations for the proper validation or verification of performance of laboratory assays prior to implementation for clinical use, and external quality assurance to provide continuous assessment of testing and reporting method.

An update on laboratory assessment for direct oral anticoagulants (DOACs)

“…Direct oral anticoagulants function as anticoagulants by inhibiting activated serine proteases, specifically thrombin and activated factor X (FXa), and for this reason, these drugs affect commonly used global coagulation assays as well as select special coagulation assays . Different aPTT and PT reagents show varying responsiveness to each of these agents .…”

“…In general, direct thrombin inhibitors (dTI) tend to prolong the APTT more than the PT while direct FXa inhibitors (DXa) drugs prolong the PT to a greater extent than the aPTT. Likewise, one‐stage factor activity and inhibitor (ie, Bethesda) assays that are dependent on either the aPTT or PT are affected by DOAC presence and the degree of interference depends on reagent responsiveness, specific DOAC present, and DOAC concentration . DOAC‐affected one‐stage factor activity results spuriously underestimate factor activity which may or may not demonstrate nonparallelism.…”

Influence of DOAC Stop on coagulation assays in samples from patients on rivaroxaban or apixaban

“…Direct oral anticoagulants (DOACs) have predictable pharmacokinetics, requiring no laboratory monitoring and are increasingly used in clinical practice . However, they interfere with almost all clotting assays to a varying degree, depending on the DOAC, the assay principles and the reagents used …”

“…Some patients are investigated for haemostatic defects while on these drugs, but the interference in the assays can cause problems with interpretation and there is a significant risk that results can be misinterpreted . Of particular concern would be the potential for a misdiagnosis of acquired haemophilia A in patients with an apparent reduction in factor VIII activity and an apparent factor VIII inhibitor, or the potential for a misdiagnosis of antiphospholipid syndrome in patients with a falsely elevated lupus anticoagulant assay; this may effect patient treatment choices …”

“…The recommended method for measuring direct anti‐Xa anticoagulants is by LC‐MS/MS or a suitably calibrated anti‐Xa activity assay; although this will identify patients whose results may be affected by these DOACs, it does not aid interpretation of the results of those assays.…”