• Thromboembolic Disease
• Toxicology Thrombotic Disorders
• Critical Care

• Thromboembolic Disease
• Toxicology
• Emergency Medicine
• Thrombotic Disorders
• Critical Care

Colin G. Kaide, MD, Ohio State University, Columbus, Ohio, USA, discussed the treatment of acute bleeding in patients taking old and new anticoagulants. Warfarin reversal involves 2 phases: immediate reversal and sustained reversal. Options for immediate reversal include fresh-frozen plasma (FFP), prothrombin complex concentrate (PCC), and activated PCC (aPCC) factor VIII inhibitor bypassing activity (FEIBA; Table 1).

For sustained reversal of warfarin, vitamin K must be given. Vitamin K promotes generation of the active forms of factors II, VII, IX, and X; it can be administered orally or intravenously [Ansell J et al. Chest. 2008].

Unfractionated heparin (UFH) can be reversed with protamine, which binds to and inactivates heparin. Protamine is administered at 1 mg/100 U UFH to a maximum dose of 50 mg. Protamine is not fully effective against low-molecular-weight heparin (LMWH). For enoxaparin reversal, protamine should be administered at 1 mg/1 mg enoxaparin if LMWH was taken within the previous 8 hours or at 0.5 mg/1 mg enoxaparin if LMWH was taken within 8 to 12 hours, up to a maximum of 50mg. Dosing should be repeated if the bleeding has not stopped and antifactor Xa levels are elevated 2 to 4 hours after the last protamine dose [Hirsh J et al. Chest. 2001].

One study found the anticoagulant effect of the fondaparinux was shown to be reversible in healthy volunteers with the administration of rVIIa dosed at 90 μg/kg [Bijsterveld NR et al. Circulation. 2002]. Another study found that rVIIa did not significantly reverse markers of anticoagulation for fondaparinux, whereas markers were likely improved with administration of PCC and completely reversed with aPCC (Feiba) [Desmurs-Clavel H et al. Thromb Res. 2009].

Several new oral anticoagulants (NOACs) have been developed. Among them are the direct thrombin inhibitors, dabigatran, and the direct-factor Xa inhibitors, rivaroxaban and apixaban. Reversing the action of these agents is a challenge. Hemodialysis can stop the activity of dabigatran but not of rivaroxaban and apixaban (Table 2).

Specific reversal agents for the NOACs are under development. For dabigatran, a humanized monoclonal antibody fragment is currently being investigated in several animal and in vitro studies. Clinical trials are currently underway studying the recombinant factor Xa derivative, and adexanet alfa, as a specific reversal agent for rivaroxaban [NCT02220725] and apixaban [NCT02207725]. This agent is a factor Xa decoy that targets and sequesters direct and indirect factor Xa inhibitors in the blood. Once bound, the factor Xa inhibitors cannot bind and inhibit native factor Xa, allowing restoration of normal hemostasis.

Platelet inhibitors, including salicylates, clopidogrel, and factor IIb/IIIa inhibitors may be somewhat reversed by transfusion of platelets [Vilahur G et al. J Thromb Haemost. 2007] and desmopressin [Leithouser B et al. Clin Hemorheol. 2008], but there is no definitive proof. If reversal is attempted using platelets, 2 to 3 pools of platelets should be used. ε-Aminocaproic acid is an antifibrinolytic agent used for hemophiliacs that might reverse fibrinolytics, but there are no data supporting this use [Stief T. Clin Appl Thromb Hemost. 2008].

Dr Kaide concluded that anticoagulant reversal should be attempted in situations where “maximal harm is already in progress” and the risk of bleeding outweighs the risk of reversal of anticoagulation. New antidotes for the NOACs are under development and will be available in the near future.

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