CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
The mechanism of anticoagulant effect of DOACs is fundamentally different from that of vitamin K antagonists and is more similar to heparin-like anticoagulants. VKA anticoagulants work by diminishing the levels of functional vitamin K-dependent factors: II, VII, IX, X, protein C, and protein S. Heparin-like anticoagulants (for example, unfractionated, low-molecular-weight, pentasaccharide) accelerate the action of circulating antithrombin to inhibit serine proteases (activated factors, for example, such as IXa, Xa, and thrombin). Depending on the drug, DOACs act through direct inhibition of either thrombin or activated factor X (FXa). Inhibition of either target ultimately functions to limit thrombin generation. The endpoint of the APTT and PT reactions, fibrin formation, requires only about three to five percent of the total thrombin generated, and thus neither the APTT nor the PT are an accurate measure of overall thrombin generation. A plausible explanation why DOACs can function clinically as an anticoagulant yet may have minimal to no effect on the APTT and PT may reflect the limited measure of total thrombin generation of these screening assays. In a similar fashion, low-molecular-weight heparin and fondaparinux, when administered in typical therapeutic doses, have little to no impact on the APTT and PT.
As VKAs diminish the synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X, this leads to reduced activity that limits fibrin generation, causing prolongation of the PT. Prolongation of the PT in seconds correlates with the level of VKA anticoagulation. The PT result is reported with the international normalized ratio, a value calculated from the PT that is based on the international sensitivity index, a determination of the vitamin K-dependent factor responsiveness of a PT reagent. The INR allows clinicians to determine a patient’s level of warfarin anticoagulation regardless of which PT reagent was used. The INR is specific for warfarin anticoagulation and is not valid as a means to measure the level of DOAC anticoagulation. Patients therapeutic on apixaban, for example, may have a normal INR.
The take-home message is that the APTT and PT/INR do not serve as global measures of the level of anticoagulation for all anticoagulant therapies. A normal APTT and/or PT/INR cannot ensure that a patient on a DOAC has a normal functioning hemostatic system. Patients with therapeutic plasma DOAC concentrations may have a normal APTT and/or PT depending on the DOAC administered and the reagent used. Laboratory scientists should proactively and endlessly educate our clinical associates, stressing that for patients who are or may be on treatment with DOACs, the APTT and PT can no longer be used as a general gauge of a patient’s level of anticoagulation and associated bleeding risk. This potential patient safety issue is of particular concern in a patient who requires emergent therapy and whose medication history is unknown. Instead, the laboratory must provide an alternative recommendation for clinicians who seek our counsel on these anticoagulated patients. The laboratory should have a strategy in place to assure clinicians that significant levels of DOACs are not present in those patients who require an intervention, in order to reduce an otherwise potentially significant bleeding risk.
Dr. Adcock is chief medical officer of LabCorp Diagnostics, Burlington, NC.