Clinicians increasingly prescribe direct oral anticoagulants (DOACs) for a variety of clinical indications, including venous thromboembolism (VTE) treatment in adults and children, VTE prevention after orthopedic surgery, and stroke prevention in patients with atrial fibrillation. In 2020, DOAC prescriptions outnumbered those for warfarin by nearly two to one.
The two main DOAC classes are direct thrombin inhibitors (DTIs), such as dabigatran, and direct factor Xa inhibitors (DXaIs), such as apixaban, rivaroxaban, and edoxaban. Like warfarin, these medications are small molecules for which oral administration enables anticoagulation in the ambulatory setting. Unlike warfarin, DOACs directly and reversibly inhibit their target procoagulant factor and do not require routine monitoring for dosage adjustments.
Because of their growing popularity, DOACs present many challenges for the clinical laboratory. One is that therapeutic DOAC concentrations may interfere with many routine coagulation assays. Clinicians often overlook the possible impact of these medications on test results, which can lead to errors in interpretation and patient management. Diagnostic errors due to DOAC interference are particularly concerning in the context of thrombophilia testing since these patients are at highest risk of receiving anticoagulation therapy at the time of testing. The scope of this problem is further compounded because different coagulation assay reagents exhibit varying sensitivities to interference from different DOACs. Laboratorians must take a personalized approach depending on which of their assays are affected and how.
Impact of DOACs on Common Coagulation Tests
To identify the impact of DOACs on routine coagulation tests, laboratory professionals should understand how the mechanism of these anticoagulants intersects with laboratory testing methodologies. Coagulation assays rely on clot-based, chromogenic, immunologic, or molecular principles (Table 1). Although immunologic and molecular assays are unaffected by DOACs, clot-based and chromogenic assays may be affected if the DOAC target is involved in the clotting or chromogenic reaction.
Since all clot-based tests require thrombin for clot formation, DTIs will prolong all clot-based tests except for fibrinogen. DXaIs have the potential to prolong all clot-based tests except for thrombin time and fibrinogen, but their effect on the very common prothrombin time (PT) and activated partial thromboplastin time (aPTT) assays is variable and dependent on the specific reagents implemented in the laboratory, the particular DOAC present, and its concentration in the specimen.
For example, the PT and aPTT reagents used in our laboratory are somewhat sensitive to rivaroxaban, but completely insensitive to apixaban, the most prescribed DOAC. We observe no correlation between measured apixaban or rivaroxaban concentration and PT or aPTT. Laboratories should know the sensitivity of their PT and aPTT reagents to the various DOACs, but in general, should not rely on these routine coagulation tests to rule in or out the presence of DXaIs.
Compared with clot-based assays, chromogenic assays are less affected by DOACs. However, chromogenic methods requiring activity of thrombin (e.g., antithrombin activity with thrombin substrate) or factor Xa (e.g., antithrombin activity with factor Xa substrate, heparin anti-Xa) will be falsely elevated by direct thrombin inhibitors or direct factor Xa inhibitors, respectively.
Strategies to Avoid Diagnostic Errors From DOAC Interference
Laboratories can implement strategies in all phases of testing to minimize the clinical impact of DOAC interference with coagulation assays.
One of the most important preanalytical interventions is to offer alternatives to tests impacted by DOACs. For example, prioritize antigen-based or chromogenic protein C and S measurements instead of clot-based assays as first-line testing for suspected protein C or S deficiency. And replace clot-based activated protein C resistance with molecular testing for the factor V Leiden mutation. Another preanalytical intervention is to circulate information about interference by DOACs to healthcare providers in various educational formats, such as in test catalogs and in the electronic medical record at the time susceptible tests are ordered.
In accordance with international guidelines, thrombophilia testing ideally should be performed in patients not receiving any anticoagulant treatment. When clinically feasible, DOAC therapy should be interrupted for at least 2 days prior to thrombophilia testing. It is worth noting that 2 days may not be long enough for DOAC elimination in certain patients, such as those with renal insufficiency.
In the analytical and post-analytical phases, it is essential for laboratories to know which anticoagulants are present in specimens sent for diagnostic testing. This information is necessary for appropriate handling of specimens, which may include rejection of anticoagulant-containing samples, specimen pretreatment with DOAC-neutralizing tablets or filters, or addition of interpretive comments to test results explaining potential interference. Two routine tests, thrombin time and anti-Xa activity, are sensitive screening tests for DTIs and DXaIs, respectively.
Our laboratory screens samples submitted for lupus anticoagulant testing for the presence of DOACs, and we estimate that approximately 5%–10% of these specimens contain a DXaI. We take this information into account when interpreting test results and specifically mention the possible impact of anticoagulants in the interpretive report for potentially affected specimens.
An alternative approach is to neutralize DOACs by treating the sample with an activated carbon product (e.g., DOAC-Stop) or an extractive filter (e.g., DOAC Filter) prior to testing. One challenge with these neutralization products is that they have not been FDA-approved and may affect coagulation testing in unknown ways, such as affecting an assay’s ability to recognize a lupus anticoagulant. Therefore, the performance of DOAC-neutralizing agents needs to be validated locally by the laboratory prior to implementation.
With the increasing use of DOACs, clinical laboratories must be equipped to deal with potential interference from these anticoagulants on coagulation assays. Laboratorians should know which of their tests are affected (or not) by which DOACs and actively communicate the nature of such interference (or lack thereof) to prevent diagnostic errors.
Julie Schmidt, BS, MT(ASCP), SH(ASCP)CM, is a medical laboratory scientist supervisor in the hematology laboratory at the University of Iowa Hospitals & Clinics in Iowa City, Iowa. +Email: [email protected]
Anna Merrill, PhD, DABCC, is a clinical assistant professor and associate director of clinical chemistry at the University of Iowa Hospitals & Clinics in Iowa City, Iowa. +Email: [email protected]
Recommended Reading
Chen A, Stecker E, A Warden B. Direct oral anticoagulant use: A practical guide to common clinical challenges. J Am Heart Assoc 2020; doi:10.1161/JAHA.120.017559.
Adcock DM. Hemostasis testing: What is the impact of direct oral anticoagulants? https://www.captodayonline.com/hemostasis-testing-what-is-the-impact-of-direct-oral-anticoagulants/ (Accessed July 2019).
Moser KA, Smock KJ. Direct oral anticoagulant (DOAC) interference in hemostasis assays. Hematology Am Soc Hematol Educ Program 2021; doi:10.1182/hematology.2021000241.
Gosselin R, Grant RP, Adcock DM. Comparison of the effect of the anti-Xa direct oral anticoagulants apixaban, edoxaban, and rivaroxaban on coagulation assays. Int J Lab Hematol 2016; doi:10.1111/ijlh.12528.
Siriez R, Dogné JM, Gosselin R, et al. Comprehensive review of the impact of direct oral anticoagulants on thrombophilia diagnostic tests: Practical recommendations for the laboratory. Int J Lab Hematol 2021; doi:10.1111/ijlh.13342.