Why is International Normalized Ratio (INR) falsely elevated on Argatroban (Argatroban is a direct thrombin inhibitor)?

From the Guidelines

Argatroban causes a falsely elevated INR because it interferes with the laboratory test used to measure INR, as evidenced by the fact that 21% of patients with an INR > 3.0 while receiving argatroban and warfarin cotherapy had a subtherapeutic INR 4 h after discontinuation of argatroban 1. This is due to argatroban's mechanism of action as a direct thrombin inhibitor, which prevents thrombin from converting fibrinogen to fibrin, a crucial step in the clotting cascade that INR measures. When argatroban is present in a blood sample, it continues to inhibit thrombin during the laboratory test, artificially prolonging the clotting time and resulting in an elevated INR reading that doesn't accurately reflect the patient's true coagulation status. Some key points to consider when managing anticoagulation with argatroban include:

• The INR should not be interpreted as an indicator of the effect of warfarin alone when administered with argatroban 1.
• Alternative methods such as chromogenic factor X assays or specialized nomograms that account for the combined effects of argatroban and warfarin should be used to manage anticoagulation during the transition period 1.
• Argatroban also prolongs routine coagulation tests such as the prothrombin time (PT) and aPTT, which can be used as a first-line treatment-monitoring assay, but it must be measured before treatment is started to check its “normality” 1. The most recent and highest quality study, from 2020, highlights the importance of careful monitoring and management of anticoagulation when using argatroban, particularly when transitioning to warfarin therapy 1.

From the FDA Drug Label

Because argatroban is a direct thrombin inhibitor, co-administration of argatroban and warfarin produces a combined effect on the laboratory measurement of the INR However, concurrent therapy, compared to warfarin monotherapy, exerts no additional effect on vitamin K–dependent factor Xa activity. The relationship between INR on co-therapy and warfarin alone is dependent on both the dose of argatroban and the thromboplastin reagent used. This relationship is influenced by the International Sensitivity Index (ISI) of the thromboplastin.

The INR is falsely elevated on argatroban because argatroban is a direct thrombin inhibitor and its co-administration with warfarin produces a combined effect on the laboratory measurement of the INR. The elevation of INR is dependent on the dose of argatroban and the thromboplastin reagent used, and is influenced by the International Sensitivity Index (ISI) of the thromboplastin 2.

• Key points:
  • Argatroban is a direct thrombin inhibitor
  • Co-administration with warfarin affects INR measurement
  • Relationship between INR on co-therapy and warfarin alone depends on argatroban dose and thromboplastin reagent used
  • International Sensitivity Index (ISI) of the thromboplastin influences the relationship between INR on co-therapy and warfarin alone

From the Research

INR Elevation on Argatroban

• The International Normalized Ratio (INR) can be falsely elevated in patients receiving argatroban, a direct thrombin inhibitor, due to its effect on the coagulation pathway 3, 4, 5.
• Studies have shown that argatroban can increase INR values, even at therapeutic doses, without a corresponding increase in the risk of bleeding 3, 4, 5.
• The effect of argatroban on INR values is dose-dependent and can be influenced by the type of thromboplastin used in the laboratory assay 5.
• In patients with heparin-induced thrombocytopenia (HIT), the use of argatroban can result in elevated INR values, which may not accurately reflect the patient's coagulation status 3, 4.

Mechanism of INR Elevation

• Argatroban inhibits thrombin directly, which can affect the coagulation cascade and lead to an increase in INR values 5, 6.
• The effect of argatroban on INR values is thought to be due to its ability to inhibit the conversion of prothrombin to thrombin, which is a critical step in the coagulation pathway 6.
• The use of argatroban can also affect the results of other coagulation tests, such as the activated partial thromboplastin time (aPTT) 3, 4, 7.

Clinical Implications

• The false elevation of INR values in patients receiving argatroban can lead to confusion and potentially inappropriate management decisions 3, 4.
• Clinicians should be aware of the potential for argatroban to affect INR values and use caution when interpreting these results in patients receiving this medication 3, 4, 5.
• Alternative coagulation tests, such as the ecarin clotting time or thrombin inhibition time, may be useful in monitoring the anticoagulant effect of argatroban in certain patient populations 7.