Role of coagulation factor concentrates for reversing dabigatran-related anticoagulation.

1316 June 2014 T novel oral anticoagulation agents (NOACs) include dabigatran, a direct thrombin inhibitor, and rivaroxaban, apixaban, and edoxaban, direct Factor Xa inhibitors, indicated for either stroke prevention with nonvalvular atrial fibrillation or thromboprophylaxis.1,2 The NOACs are administered orally, have predictable onsets within 2 to 4 h, and an offset more rapid than warfarin. Although monitoring is not required, dabigatran’s effects can be assessed using standard coagulation assays such as thrombin times and partial thromboplastin times (PTTs), whereas Xa inhibitors require more specialized antifactor-Xa assays. However, managing any anticoagulated critically ill patient is problematic, because all anticoagulation agents can cause bleeding, and patients were anticoagulated for a specific prothrombotic issue. Despite concerns about the NOACs, warfarin and other commonly used anticoagulants including low-molecular-weight heparin are not completely reversible with standard therapies. For acute warfarin reversal, despite the extensive use of plasma, four-component prothrombin complex concentrates (PCCs) are recommended in recent guidelines, and now available in the United States.3,4 Unlike warfarin, NOACs’ anticoagulation effects normalize in approximately 24 to 48 h after discontinuing the drug with normal renal function. However, after trauma, emergency surgery, or major bleeding, acute therapeutic considerations are needed. Current information to help clinicians make decisions about managing bleeding in patients receiving NOACs is based on indirect information derived from multiple sources including in vitro data using human blood, animal models, and from volunteers anticoagulated with NOACs.2 In this month’s ANESTHESIOlOgy, van Ryn et al.5 evaluated different coagulation factor concentrates (CFCs) to reverse bleeding induced by dabigatran etexilate using a rat tail bleeding model. CFCs available in most countries were compared including three-factor and four-factor PCCs, an activated PCC (factor VIII inhibitor bypassing activity [FEIBA]), and recombinant factor VIIa.4 They used multiple coagulation tests to evaluate anticoagulation and reversal including PTT, thrombin times, ecarin clotting time, and prothrombin time. They also evaluated thrombin generation using a sensitive fluorometric assay with human plasma spiked with dabigatran at therapeutic and supratherapeutic values. Dabigatran increased bleeding times in the animal model approximately 2.7-fold with supratherapeutic dabigatran levels, and all the CFCs studied significantly reversed this prolonged bleeding time, usually returning to baseline within 5 min. However, the recombinant factor VIIa dose required was 500 μg/ kg, a dose approximately fiveto six-fold higher than that used for hemophilia with inhibitors, lower doses were ineffective in the model. The standard coagulation tests were prolonged threeto eight-fold over baseline dosing, and despite reducing bleeding, there were minimal changes in coagulation tests, and the assays were not predictive of bleeding reversal. In human blood samples, restoration of thrombin generation was dependent on the dabigatran concentration. Dabigatran reversal occurred at concentrations seen with therapeutic levels, but not at supratherapeutic levels. In summary, in the animal model, CFCs reversed dabigatran-induced bleeding, but routine coagulation assays did not predict this reversal, but there was variability based on the level of anticoagulation.5 Novel to clinicians in the United States is the application of PCCs as a therapeutic approach to bleeding. In the current study, higher doses of one four-component PCC (Beriplex/KCENTRA; CSl Behring, Marburg, germany/King of Role of Coagulation Factor Concentrates for Reversing Dabigatran-related Anticoagulation