An 87-year-old man with atrial fibrillation (CHA2DS2-VASc score of 5) on dabigatran presented with cough, weakness and recent falls. He was seen by his primary care physician one week earlier where his doses of verapamil and metoprolol were increased for a heart rate of 120 bpm. On admission to the emergency room he was found to be bradycardic with a heart rate in the 30's and a chest x-ray revealed a right lower lobe pneumonia. Initial labs showed a serum creatinine of 3.05 mg/dL, elevated from a baseline of 1.20 mg/dL, PTT of 100.6 seconds, INR of 6.0, ALT of 546 U/L and AST of 422 U/L. There were no clinical or radiographic signs of active bleeding, but it was felt the patient might require central venous access due to his critical condition and potential need for urgent dialysis. He was given 2 units of FFP and 5 mg of oral vitamin K. Seven hours after admission his INR was 9.4, PTT 115.3 and thrombin time >150. He was given an additional two units of FFP, 10 mg of IV vitamin K and 5,020 international units of inactivated prothrombin complex concentrates. Twenty-four hours after admission creatinine was 2.68, INR 5.5, PTT 84.6 and diluted thrombin time 125 seconds.
Which of the following statements about monitoring the anti-coagulant activity of dabigatran is most accurate:
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The correct answer is: 3. The diluted thrombin time exhibits a linear relationship with dabigatran levels that is maintained at high concentrations.
As one of the major advantages of novel oral anticoagulants such as dabigatran is the lack of the need for routine monitoring, less is known about their effect on coagulation parameters as compared to heparin or warfarin. This suboptimal ability to monitor dabigatran activity can pose a challenge in patients who experience bleeding while on the medication or, as in the case above, patients with acute kidney failure. As Dabigatran is renally cleared, patients presenting with a decline in glomerular filtration rate are at risk for developing a severe coagulopathy. This coagulopathy can lead to life threatening hemorrhage or complicate the ability to undergo urgent procedures.
The best way to measure dabigatran activity in cases of suspected toxicity is still under investigation. Dabigatran is a direct thrombin inhibitor making the thrombin time an ideal assay to measure the drug's anticoagulant effect. The thrombin time exhibits a linear relationship with dabigatran levels but high concentrations generally exceed the limit of measurement. The diluted thrombin time combines the patient's plasma with normal control plasma allowing for a similar linear relationship with the ability to discriminate anticoagulant effect at higher dabigatran concentrations. The PTT, a more available assay, exhibits a curvilinear relationship with dabigatran at low to normal concentrations, but quickly plateaus as the concentration exits the therapeutic range. The PT/INR has shown inconsistent associations with dabigatran levels and, in general, is not recommended as a monitoring tool.1-3
The best method of dabigatran reversal is not known and, as in the case above, many agents have been tried empirically to reverse drug-induced anticoagulation. Activated prothrombin complex concentrates and activated factor VII have shown promise in preclinical studies and specific antidotes are currently under investigation.4-7 In addition, dialysis has been reported as an effective means of dabigatran removal.8
References
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Baglin T, Keeling D, Kitchen S. Effects on routine coagulation screens and assessment of anticoagulation intensity in patients taking oral dabigatran or rivaroxaban: guidance from the British committee for standards in haematology. Br J Haematol 2012;159:427-9.
Ganetsky M, Babu KM, Salhanick SD, Brown RS, Boyer EW. Dabigatran: review of pharmacology and management of bleeding complications of this novel oral anticoagulant. J Med Toxicol 2011;7:281-7.
Wolzt M, Levi M, Sarich TC, et al. Effect of recombinant factor VIIa on melagatran-induced inhibition of thrombin generation and platelet activation in healthy volunteers. Thromb Haemost 2004;91:1090-6.
Davis PK, Musunuru H, Walsh H, Mitra R, Ploplis V, Castellino FJ. The ex vivo reversibility of dabigatran-induced whole-blood coagulopathy as monitored by thromboelastography: mechanistic implications for clinical medicine. Thromb Haemost 2012;108:586-8.
Van Ryn J, Litzenburger T, Waterman A, et al. Dabigatran anticoagulant activity is neutralized by an antibody selective to dabigatran in in vitro and in vivo models. J AM Coll Cardiol 2011;57(Suppl 1):E1130.
Lu G, Luan P, Hollenbach SJ, et al. Reconstructed recombinant factor Xa as an antidote to reverse anticoagulation by factor Xa inhibitors. J Thromb Haemost 2009;5(Suppl 2): Abstract OC-TH-107.
Obeng-Gyasi S, Loor MM, Samotowka MA, Moorman ML. Management of dabigatran-inducted anticoagulation in trauma and acute care surgery patients. J Trauma Acute Care Surg 2012;73:1064-9.
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