Bleeding on Anti-Xa Drugs: “Does All Bleeding Really Stop?

  • Colin G. KaideEmail author
  • Kelsey Kauffman


Anticoagulation for many different indications is common. Atrial fibrillation, valvular heart disease, congestive heart failure, pulmonary embolism, and deep venous thrombosis top the list. While traditionally warfarin played a significant role in anticoagulation, newer agents that require little to no monitoring and are easier to manage are beginning to take over the scene. While some agents target factor II, the largest degree of growth in the world of anticoagulation is represented by anti-Xa inhibitors. Reversal of this class of drugs has been limited to replenishing of additional coagulation factors in a nonspecific attempt to overwhelm the circulating anti-Xa agent. While this strategy has been largely adopted in the face of no specific antidotes, its effectiveness has been questioned. Now a novel antidote is available, which is very effective in restoring coagulation and reducing anti-Xa levels to almost normal. Despite this, we are still faced with the question of reversal agents improving survival in patients anticoagulated on anti-Xa agents who suffer a bleeding event. The benefits must be weighed along with the high cost of andexanet. Further, the high degree of thrombosis after reversal with this agent needs to be understood in terms of the general reversal of hypercoagulable patients versus some here-to-for unknown prothrombotic properties of andexanet.


Anti Xa inhibitor Rivaroxaban Apixaban Edoxaban Betrixaban Andexanet Kcentra Four-factor PCC Prothrombin complex concentrate FEIBA Thrombosis 


Disclosure Statement

Kelsey Kauffman has no disclosures to report.

Colin Kaide reports affiliation with Callibra inc. No relevance to this chapter.

Also Colin Kaide provides Lecturing for Portola pharmaceuticals. All possible biases were explored by both authors and every attempt to provide unbiased information was made, including final editing by Kelsey Kauffman who has no Portola connections.


  1. 1.
    Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91.CrossRefGoogle Scholar
  2. 2.
    Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–92.Google Scholar
  3. 3.
    Piccini JP, Garg J, Patel MR, et al; ROCKET AF Investigators. Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. Eur Heart J. 2014;35(28):1873–80.Google Scholar
  4. 4.
    Sangkuhla K, Shuldinerc AR, Kleina TE, Altmana RB. Platelet aggregation pathway. Pharmacogenet Genomics. 2011;21(8):516–21.CrossRefGoogle Scholar
  5. 5.
    Furie B, Furie BC. Thrombus formation in vivo. J Clin Invest. 2005;115(12):3355–62.CrossRefGoogle Scholar
  6. 6.
    Roehrig S, Straub A, Pohlmann J, et al. Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor. J Med Chem. 2005;48(19):5900–8.CrossRefGoogle Scholar
  7. 7.
    Blommel ML, Blommel AL. Dabigatran etexilate: a novel oral direct thrombin inhibitor. Am J Health Syst Pharm. 2011;68(16):1506–19.CrossRefGoogle Scholar
  8. 8.
    Frumkin K. Rapid reversal of warfarin-associated hemorrhage in the emergency department by prothrombin complex concentrates. Ann Emerg Med. 2013;62(6):616–26. e8CrossRefGoogle Scholar
  9. 9.
    Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3. Suppl):188S–203S.CrossRefGoogle Scholar
  10. 10.
    Weitz JI. Low-molecular-weight heparins. N Engl J Med. 1997;337(10):688–98.CrossRefGoogle Scholar
  11. 11.
    Weitz JI, Hirsh J. New anticoagulant drugs. Chest. 2001;119(1 Suppl):95S–107S.CrossRefGoogle Scholar
  12. 12.
    Cuker A, Siegal DM, Crowther MA, Garcia DA. Laboratory measurement of the anticoagulant activity of the nonvitamin K oral anticoagulants. J Am Coll Cardiol. 2014;64(11):1128–39.CrossRefGoogle Scholar
  13. 13.
    Cuker A, Husseinzadeh H. Laboratory measurement of the anticoagulant activity of edoxaban: a systemic review. J Thromb Thrombolysis. 2015;39(3):288–94.CrossRefGoogle Scholar
  14. 14.
    van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103(6):1116–27.CrossRefGoogle Scholar
  15. 15.
    Nowak G. The ecarin clotting time, a universal method to quantify direct thrombin inhibitors. Pathophysiol Haemost Thromb. 2003;33(4):173–18.CrossRefGoogle Scholar
  16. 16.
    da Luz LT, Nascimento B, Rizoli S. Thrombelastography (TEG®): practical considerations on its clinical use in trauma resuscitation. Scand J Trauma Resusc Emerg Med. 2013;21:29.CrossRefGoogle Scholar
  17. 17.
    Levi M, Moore KT, Castillejos CF, et al. Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost. 2014;12(9):1428–36.CrossRefGoogle Scholar
  18. 18.
    Mao G, King L, Young S, et al. Factor Eight Inhibitor Bypassing Agent (FEIBA) for reversal of target-specific oral anticoagulants in life-threatening intracranial bleeding. J Emerg Med. 2017;52(5):731–7.CrossRefGoogle Scholar
  19. 19.
    Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124(14):1573–9.CrossRefGoogle Scholar
  20. 20.
    Song Y, Wang Z, Perlstein I, et al. Reversal of apixaban anticoagulation by four-factor prothrombin complex concentrates in healthy subjects: a randomized three-period crossover study. J Thromb Haemost. 2017;15(11):2125–37.CrossRefGoogle Scholar
  21. 21.
    Brown KS, Wickremasingha P, Parasrampuria DA, et al. The impact of a three-factor prothrombin complex concentrate on the anticoagulatory effects of the factor Xa inhibitor edoxaban. Thromb Res. 2015;136(4):825–31.CrossRefGoogle Scholar
  22. 22.
    Zahir H, Brown KS, Vandell AG, et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation. 2015;131(1):82–90.CrossRefGoogle Scholar
  23. 23.
    Gerner ST, Kuramatsu JB, Sembill JA, et al. Association of prothrombin complex concentrate administration and hematoma enlargement in non-vitamin K antagonist oral anticoagulant-related intracerebral hemorrhage. Ann Neurol. 2018;83(1):186–96.CrossRefGoogle Scholar
  24. 24.
    Kaatz S, Kouides PA, Garcia DA, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol. 2012;87(Suppl 1):S141–5.CrossRefGoogle Scholar
  25. 25.
    Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(24):3042–67.CrossRefGoogle Scholar
  26. 26.
    Connolly SJ, Crowther M, Eikelboom JW, et al; ANNEXA-4 Investigators. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. 2019. Scholar
  27. 27.
    Andexanet alfa (Andexxa) [package insert]. South San Francisco: Portola Pharmaceuticals, Inc; 2018.Google Scholar
  28. 28.
    Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373(25):2413–24.CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of Emergency Medicine, Wexner Medical Center at The Ohio State UniversityColumbusUSA

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