Indications and Methods of Anticoagulation Reversal Jeremy L. Holzmacher, MD, Babak Sarani, MD* KEYWORDS Anticoagulation reversal Direct oral anticoagulants Warfarin Prothrombin complex concentrate Protamine Idarucizumab Andexanet alfa Aripazine KEY POINTS Understanding the mechanisms of action and pharmacology of anticoagulant drugs is required to maximize the ability to reverse anticoagulation when needed. Reversing anticoagulation for invasive procedures should weigh the patient-related risks for thrombosis against the potential for bleeding. The approval of idarucizumab for dabigatran reversal and the impending development of specific and non-specific anti-factor Xa reversal agents now comprise a key strategy in the treatment of anticoagulant-associated hemorrhage and perioperative treatment. INTRODUCTION The use of anticoagulants within the United States is on the rise with specific direct oral anticoagulant (DOAC) medications gaining Food and Drug Administration (FDA) approval for the prevention of thromboembolic complications, including stroke pre- vention associated with atrial fibrillation and in the treatment of venous thromboembo- lism.1 Normal hemostasis is a tightly controlled and highly regulated process that uses enzyme activation and amplification along with endothelial and platelet interactions to activate thrombin and propagate fibrin formation and cross-linking (Fig. 1).2 Anticoag- ulant medications disrupt this process directly by inhibiting clotting factor activity, indi- rectly by depleting vitamin K–dependent clotting factors, or by amplifying native anticoagulant pathways through antithrombin III (ATIII).2 Historically, the most com- mon anticoagulant prescribed was warfarin, and standard reversal strategy was based on factor repletion using plasma and vitamin K.2–4 The advent of both oral Disclosure Statement: The authors have nothing to disclose. Center for Trauma and Critical Care, Department of Surgery, George Washington University Medical Center, 2150 Pennsylvania Avenue Northwest, Suite 6B, Washington, DC 20037, USA * Corresponding author. 2150 Pennsylvania Avenue Northwest, Suite 6B, Washington, DC 20037. E-mail address: [email protected] Surg Clin N Am 97 (2017) 1291–1305 http://dx.doi.org/10.1016/j.suc.2017.07.002 surgical.theclinics.com 0039-6109/17/ª 2017 Elsevier Inc. All rights reserved. 1292 Holzmacher & Sarani Fig. 1. Coagulation cascade and targets of oral and parenteral anticoagulant agents. (Data from Ferreira JL, Wipf JE. Pharmacologic therapies in anticoagulation. Med Clin North Am 2016;100(4):695–718.) and parenteral direct anti–factor Xa and thrombin (factor IIa) inhibitors, however, has required the development of alternative reversal methods. In 2010, the FDA approved dabigatran, a direct thrombin inhibitor, for the prevention of stroke in patients with nonvalvular atrial fibrillation. Shortly thereafter, 3 additional DOACs—rivaroxaban, apixaban, and edoxaban—were approved for similar indica- tions.2 The benefits of DOAC drugs were the immediacy of full anticoagulation without the need for routine blood monitoring and better overall bleeding profiles; however, DOAC-specific antidotes have been slow to development, have limited availability, and are expensive.5 As such, reversal strategies for these newer medications are either newly formed or still forming. Considering the evolving nature of anticoagulation and need for cogent and evi- denced based reversal strategies, this article reviews the mechanisms of action of the commonly used anticoagulants as well as the indications for and current method- ologies of anticoagulation reversal. Although many patients on full anticoagulation may also be taking antiplatelet medications, the methods for mitigating their effects on hemostasis are beyond the scope of this article. Similarly, postprocedural resump- tion of anticoagulation and periprocedural bridging are not discussed. REVERSAL STRATEGIES FOR ALL ANTICOAGULANTS Underlying any decision to reverse a patient’s anticoagulation status is the risk-benefit analysis weighing possible thrombosis against potential bleeding (Fig. 2). With this un- derstanding, anticoagulation reversal can be divided into 3 categories depending on the urgency needed to restore hemostasis: (1) emergent or urgent requiring reversal in less than an hour, (2) semiurgent requiring reversal within hours, or (3) nonurgent reversal that can typically happen over a matter of days. Regardless of the urgency, reversing any anticoagulant starts by withholding the offending agent. In emergent and semiurgent circumstances, considerations should be given toward administering Methods of Anticoagulation Reversal 1293 Fig. 2. Balancing risk of bleeding against risk of thrombosis. ICH, intracranial hemorrhage; TE, thromboembolism. (Data from Doherty JU, Gluckman TJ, Hucker WJ, et al. 2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation. J Am Coll Cardiol 2017;69(7):871–98; and Re- chenmacher SJ, Fang JC. Bridging anticoagulation. J Am Coll Cardiol 2015;66(12):1392–403.) agent-specific antidotes if available or concentrated factor depending on the expedi- ency of effect. It is also important to take into context the need for anticoagulation reversal. For instance, bleeding wounds or traumatic injuries may be amenable to local measures, including topical hemostatic agents, manual pressure, or tourniquets. Appropriate laboratory testing should be done to establish degree of coagulopathy on presentation and monitor the efficacy of reversal methods if possible. Unfortu- nately, there is currently no commercially available, reliable means to measure the de- gree of coagulopathy from DOAC use. Nonetheless, this point is especially relevant because some interventions have a shorter duration of effect (eg, plasma) compared with the anticoagulant used resulting in potential rebound of the anticoagulant effect over time. Lastly, it is important to remember that in emergent or urgent cases, therapy can and often should be initiated prior to laboratory results becoming available. PARENTERAL ANTICOAGULANTS Parenteral anticoagulants can be divided into 2 categories depending on the mecha- nism of action: (1) indirect anticoagulants, which act as cofactors with ATIII to inacti- vate factor Xa and/or thrombin, and (2) direct anticoagulants, which specifically target and inactivate thrombin.2 The former are comprised of unfractionated heparin (UFH) and the low-molecular-weight heparins (LMWHs), including enoxaparin and fondapar- inux, whereas the latter represent argatroban and bivalirudin. UNFRACTIONATED HEPARIN Mechanism of Action and Pharmacology UFH acts as an indirect anticoagulant by amplifying the activity of ATIII to inactivate fac- tors Xa and thrombin and thereby hinder thrombus formation (Table 1). Routes of de- livery vary between subcutaneous injection and intravenous (IV) infusion with variable dosing depending on the indication of use and the route of administration.2 Typical pro- phylactic dosages are given as 5000 U to 7500 U subcutaneous injections in 8-hour or 12-hour intervals whereas therapeutic dosing is weight based and titrated to an acti- vated partial thromboplastin time (aPTT) 1.5 times to 2.0 times of control.2,6 Some 1294 Holzmacher & Sarani Table 1 Parenteral anticoagulants —mechanism of action, pharmacology, and reversal Agent Mechanism Pharmacology Reversal Method UFH Cofactor with Elimination: Nonurgent: ATIII, inactivates Hepatic Hold infusion for 4–6 h factors Xa and Dose dependent results in near-complete thrombin Half-life: 60–90 min reversal Monitor: aPPT (1.5–2.0 Emergent/urgent: times control) Protamine sulfate 1 mg/80–100 U UFH if within 15 min of UFH infusion 0.5 mg/80–100 U within 60 min or 0.25 mg/80–100 U within 2 h Maximum 50 mg dose Enoxaparin Cofactor to ATIII, Elimination: renal Nonurgent: inactivates Half-life: w4–8 h Time dependent, w24 h factor Xa and Monitor: Anti- Xa levels Emergent/urgent: thrombin (0.5 IU/mL constitutes PCC at 20 U/kg therapeutic) Partial reversal with protamine, but degree unclear If dosed 8h: 1 mg/1 mg enoxaparin If dosed >8 h: 0.5 mg/1 mg enoxaparin Fondaparinux Cofactor to ATIII, Elimination: renal Nonurgent inactivates Half-life w17–21 h Time dependent: w24 h factor Xa, Monitor: anti- Xa levels Emergent/urgent: less activity (0.5 IU/mL constitutes PCC at 20 U/kg toward factor IIa therapeutic) Protamine has not been shown to be effective Argatroban Direct thrombin Elimination: hepatic Nonurgent: inhibitor Half-life: w30–60 min Time dependent: full Monitor: aPTT reversal in w4–6 h INR can be falsely Emergent/urgent: elevated No effective means of reversal has been established Data from Baglin T, Barrowcliffe TW, Cohen A, et al, the British Committee for Standards in Haema- tology. Guidelines on the use and monitoring of heparin. Br J Haematol 2006;133(1):19–34; and Di Nisio M, Middeldorp S, Bu¨ ller HR. Direct thrombin inhibitors. N Engl J Med 2005;353(10):1028–40. institutions, however, monitor anti–factor Xa levels with therapeutic anticoagulation defined as greater than or equal to 0.5 IU/kg.2,6 UFH is metabolized by the liver and un- dergoes dose-dependent elimination with a half-life of approximately 60 minutes to 90 minutes.3 Bioavailability differs depending on the route of delivery, with subcutane- ous administration having a bioavailability of 50% or less whereas IV use confers 100% bioavailability.6 Therefore, although no