Hemostasis testing: What is the impact of direct oral anticoagulants?

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Tests used to screen and confirm the presence of a lupus anticoagulant that are based on the aPTT or Russell’s viper venom may be variably affected by the presence of any DOAC, leading to falsely elevated or false-positive lupus anticoagulant results. aPTT-based screening and phospholipid neutralization methods are generally affected more commonly by dabigatran than by direct FXa inhibitors, while both classes of DOACs impact RVV-based phospholipid neutralization and screening assays. DOAC therapy therefore can cause false-positive lupus anticoagulant results, and this can greatly impact therapy as lupus anticoagulants are generally treated using long-term anticoagulation with VKA and not DOACs.

Thrombophilia testing may be affected by the presence of DOACs depending on the underlying test methodology. Chromogenic antithrombin activity assays that are based on FXa generation are overestimated in the presence of direct FXa inhibitor drugs, and assays based on FIIa generation are overestimated by dabigatran. Clot-based protein C and S assays are falsely overestimated by all DOACs. A deficiency of antithrombin or protein C or S could potentially be missed in DOAC-treated patients. In this population, chromogenic protein C and free protein S antigen assays are recommended due to their lack of DOAC interference. Assays for activated protein C resistance (APCr) are typically overestimated in the presence of any DOAC masking protein C resistance. However, with certain methodologies, such as a prothrombinase-based APCr assay, the levels of dabigatran typically evident when treated with a standard dose can elevate results to the extent that an abnormal APCr result is falsely extended into the normal range (Gessoni G, et al. Blood Transfus. 2017;15​[6]:562–567).

All DOAC-affected thrombophilia and lupus anticoagulant assays may be impacted by even trough levels of DOACs, depending on the specific assay and the specific DOAC present (Gosselin RC, et al. Int J Lab Hematol. 2019;41[suppl 1]:33–39). To obtain accurate results, hemostasis testing should be performed four to five days after DOAC therapy is discontinued. When anticoagulant therapy cannot or should not be discontinued and testing must be completed, other options must be entertained. Testing may be sent to a laboratory that offers methods not interfered with by DOACs (for example, a chromogenic antithrombin based on FXa rather than FIIa inactivation for a patient on dabigatran or a free protein S antigen rather than a clot-based protein S activity). Another consideration is to switch anticoagulant therapy from DOAC to low-molecular-weight heparin for a transient period. Although not FDA approved, adsorbent agents (primarily using activated charcoal) have been developed, often in the form of tablets, that can be added to plasma and following centrifugation remove DOACs from the plasma sample. These tablets tend to remove even high concentrations of DOACs, but there appears to be a modest increase in thrombin generation noted in post-treatment of normal plasma (DOAC naive) samples (Kopatz WF, et al. Thromb Res. 2018;170:97–101).

Anticoagulation using DOACs in preference to warfarin is increasing in popularity. These anticoagulants can significantly affect many hemostasis assays, often causing results to be spurious. In general, DOACs may cause the results of factor activity assays to be spuriously reduced, factor inhibitor assays to be spuriously positive, lupus anticoagulant assays to be spuriously positive, and thrombophilia testing to be spuriously normal. Such factitious results may have a negative impact on patient care. Laboratorians can play an important role in helping clinicians order appropriate testing in patients on DOACs as well as in assisting in the proper interpretation of results.

Dr. Adcock is chief medical officer and senior vice president, LabCorp of America, Burlington, NC.