Jerrold H Levy MD FAHA FCCM Professor of Anesthesiology ; Associate Professor of Surgery ; CoDirector , Cardiothoracic ICU Duke University Medical Center , North Carolina , USA

The current novel direct oral anticoagulants ( DOACs ) are increasingly used for preventing stroke in patients with non-valvular atrial fibrillation , but also for treating venous thromboembolic events based on their individual approvals in different countries . The currently available agents are dabigatran , a direct thrombin inhibitor , and rivaroxaban , apixaban and edoxaban , direct factor Xa inhibitors . ¹ As with any anticoagulation agent , bleeding can occur and therapeutic strategies for managing patients when this happens are important . Despite frequently described potential concerns about the availability of reversal strategies for the novel agents , there are other extensively used anticoagulation agents in clinical practice that do not have reversal agents , including low molecular weight heparin and the P2Y12 receptor antagonist platelet inhibitors , clopidogrel , prasugrel and ticagrelor . Despite these concerns , the risk of bleeding and adverse events for the DOACs in their clinical development studies was lower than with warfarin . ^{2 – 5} Nonetheless , therapeutic approaches for managing lifethreatening bleeding in patients on any anticoagulant needs to be considered . Furthermore , in cases of trauma or emergency surgery , emergency reversal of anticoagulation may be required .

Dabigatran , the only direct thrombin inhibitor of the DOACs , has several unique considerations . A specific

monoclonal Fab fragment reversal agent , idarucizumab , has been approved for use in the United States and other countries for urgent dabigatran reversal . ^{6 , 7} However , alternative reversal agents are also available , such as prothrombin complex concentrates ( PCCs ), including activated PCCs ( aPCCs ). In this discussion , the specific role of PCCs will be considered . Preclinical studies , in vitro / ex vivo reports , human volunteer data , and case reports show that PCCs have therapeutic applications to reverse DOACs in a dose-dependent manner . Although the focus of this discussion will be the potential applications of PCCs for the Xa inhibitors , they also have potential use in patients with lifethreatening haemorrhage for dabigatran bleeding management if idarucizumab is not available . ⁸

Managing DOAC-related bleeding As mentioned , despite the ability of DOACs to reduce bleeding risk relative to warfarin , managing acute bleeding is still a concern with any anticoagulation agent . The DOACs have half-lives that are approximately 5 – 17 hours depending on the specific agent and renal function , and shorter than warfarin and other vitamin K antagonists . ¹ Although stopping the DOACs results in restoration of normal haemostatic function within 24 – 48 hours , this may not be sufficiently rapid for emergency management of bleeding patients , patients requiring emergency surgery or procedural interventions , and / or following traumatic injury . ¹ No reversal agent is approved for rapid reversal of anti-FXa anticoagulation , although andexanet and cirapantag are currently under investigation . ⁹ Therefore , the focus of this discussion on managing bleeding

and reversing the effects of DOACs will review strategies specifically for factor Xa inhibitors , and will focus on human data for anticoagulation reversal including PCCs as therapeutic strategies .

When bleeding occurs in DOAC treatment , especially following moderate or severe bleeding , an overview of management strategies for any haemorrhagic patient is important to consider . For minor bleeding , either stopping the agent or other basic strategies should be followed , especially with the relatively shorter half-lives of these novel agents . However , with moderate to severe bleeding , strategies should focus on haemodynamic and haemostatic support in addition to discontinuing any anticoagulant . ^{1 , 10} Haemodynamic support includes intravenous volume administration with hypovolaemia in addition to vasoconstrictive therapy with catecholamines to restore blood pressure . ¹ In the haemorrhagic patient , along with appropriate laboratory testing , additional volume resuscitative therapy may be required , including red blood cells , plasma / fresh frozen plasma , platelets , and fibrinogen repletion with cryoprecipitate or fibrinogen concentrates depending upon the availability in the particular country . ¹ Of note is that recommendations from the European Heart Rhythm Association suggest PCCs should be administered with life-threatening DOAC-related bleeding rather than plasma / fresh frozen plasma and will be considered in more detail . ¹⁰

PCCs PCCs are factor concentrates that contain varying amounts of vitamin K-dependent clotting factors in addition to vitamin

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