Skip to main content

Advertisement

SpringerLink
Log in

Emergency Reversal of Anticoagulation: Novel Agents

  • Critical Care (SA Mayer, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Historically, oral anticoagulation involved the administration of vitamin K antagonists, such as warfarin. However, because of the need for frequent monitoring and the desire for safer anticoagulants, several novel oral anticoagulants have been developed. These newer agents include the factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban), along with the direct thrombin inhibitors (eg, dabigatran). This manuscript provides a brief overview of their uses and mechanisms of action, along with a review of currently available evidence for reversal strategies when life-threatening bleeding occurs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. De Caterina R, Husted S, Wallentin L, et al. General mechanisms of coagulation and targets of anticoagulants (section I). Position paper of the ESC working group on thrombosis-task force on anticoagulants in heart disease Thromb Haemost. 2013;109:569–79.

    Google Scholar 

  2. Dahlback B. Blood coagulation Lancet. 2000;355:1627–32.

    CAS  Google Scholar 

  3. Wheeler AP, Rice TW. Coagulopathy in critically ill patients: Part 2 – soluble clotting factors and hemostatic testing. Chest. 2010;137:185–94.

    Article  CAS  PubMed  Google Scholar 

  4. Vine AK. Recent advances in haemostasis and thrombosis. Retina. 2009;29:1–7.

    Article  PubMed  Google Scholar 

  5. Mackman N. The role of tissue factor and factor VIIa in hemostasis. Anesth Analg. 2009;108:1147–52.

    Article  Google Scholar 

  6. Mackman N, Tilley RE, Key NS. Role of the extrinsic pathway and blood coagulation in hemostasis and thrombosis. Arterioscler Thromb Vasc Biol. 2007;27:1687–93.

    Article  CAS  PubMed  Google Scholar 

  7. Davi G, Patrono C. Platelet activation and thrombosis. N Engl J Med. 2007;357:2482–94.

    Article  CAS  PubMed  Google Scholar 

  8. Hirsh J, Dalen JE, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 2001;119(1Suppl):8S–21S.

    Article  CAS  PubMed  Google Scholar 

  9. Li T, Chang CY, Jin DY, et al. Identification of the gene for vitamin K epoxide reductase. Nature. 2004;247:541–4.

    Article  Google Scholar 

  10. Garcia D, Barrett YC, Ramacciotti E, et al. Laboratory assessment of the anticoagulant effects of the next generation of oral anticoagulants. J Thromb Haemost. 2013;11:242–52.

    Article  Google Scholar 

  11. Yee DL, O’Brien SH, Young G. The pharmacokinetics and pharmacodynamics of anticoagulants in paediatric patients. Clin Pharmacokinet. 2013;52:967–80. This review by Yee et al. provides an in-depth review of the pharmacologic properties of several of the newer anticoagulants.

    Article  CAS  PubMed  Google Scholar 

  12. Ageno W, Gallus AS, Wittkowsky A, et al. Antithrombotic therapy and prevention of thrombosis, 9th edition. American College of Chest Physicians evidence-based clinical practice guidelines Chest. 2012;141(Suppl):e44S–88S.

    CAS  Google Scholar 

  13. Lee CJ, Ansell JE. Direct thrombin inhibitors. Br J Clin Pharmacol. 2011;72:581–92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Prescribing information. Boehringer Ingelheim Pharmaceuticals. Pradaxa. Available at: http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf. Accessed 7 April 2014.

  15. Hankey GJ, Eikelboom JW. Dabigatran etexilate: a new oral thrombin inhibitor. Circulation. 2011;123:1436–50.

    Article  PubMed  Google Scholar 

  16. Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with two doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial. 2011;123:2363–72.

    CAS  Google Scholar 

  17. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51.

    Article  CAS  PubMed  Google Scholar 

  18. Ganetsky M, Babu KM, Salhanick SD, et al. Dabigatran: review of pharmacology and management of bleeding complications of this novel oral anticoagulant. J Med Toxicol. 2011;7:281–7. Ganetsky and colleagues provide an in-depth review of dabigatran, and review strategies that are and are not likely to be effective in reversal of the anticoagulation effects of dabigatran.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Hapgood G, Butler J, Malan E, et al. The effect of dabigatran on the activated partial thromboplastin time and thrombin time as determined by the Hemoclot thrombin inhibitor assay in patient plasma samples. Thromb Haemost. 2013;110:308–15.

    Article  CAS  PubMed  Google Scholar 

  20. Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis. 2012;23:138–43.

    Article  CAS  PubMed  Google Scholar 

  21. 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;103:1116–27.

    Article  PubMed  Google Scholar 

  22. Bowry R, Fraser S, Archeval-Lao JM, et al. Thromboelastography detects the anticoagulant effect of rivaroxaban in patients with stroke. Stroke. 2014;45:880–3.

    Article  CAS  PubMed  Google Scholar 

  23. Kawano-Castillo J, Ward E, Elliott A, et al. Thromboelastography detects possible coagulation disturbance in patients with intracerebral hemorrhage with hematoma enlargement. Stroke. 2014;45:683–8.

    Article  PubMed  Google Scholar 

  24. Anonymous. Bleeding with dabigatran, rivaroxaban, apixaban. No antidote, and little clinical experience. Prescrire Int. 2013;22:155–9.

    Google Scholar 

  25. Battinelli EM. Reversal of new oral anticoagulants. Circulation. 2011;124:1508–10.

    Article  PubMed  Google Scholar 

  26. Young G, Yonekawa KE, Nakagawa PA, et al. Recombinant activated factor VII effectively reverses the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin ex vivo as measured using thromboelastography.

  27. Pragst I, Zeitler SH, Doerr B, et al. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. J Thromb Heaemost. 2012;10:1841–8.

    Article  CAS  Google Scholar 

  28. Schiele F, Van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;18:3554–62.

    Article  Google Scholar 

  29. Zhou W, Schwarting S, Illanes S, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke. 2011;42:3594–9.

    Article  PubMed  Google Scholar 

  30. 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;124:1573–9.

    Article  CAS  PubMed  Google Scholar 

  31. Marlu R, Hodaj E, Paris A, et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomized crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012;108:217–24.

    Article  CAS  PubMed  Google Scholar 

  32. Dinkelaar J, Molenaar PJ, Ninivaggi M, et al. In vitro assessment, using thrombin generation, of the applicability of prothrombin complex concentrate as an antidote for rivaroxaban. J Thromb Haemost. 2013;11:1118–8.

    Article  Google Scholar 

  33. Wann LS, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. J Am Col Cardiol. 2011;57:1330–7. This guideline is from a widely respected group that examines the evidence base for the management and reversal of dabigatran.

    Article  Google Scholar 

  34. Kaatz S, Kouides PA, Garcia DA, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Haematol. 2012;87 Suppl 1:S141–5. This paper discusses important reversal strategies of both the oral direct thrombin inhibitors, as well as the factor Xa inhibitors.

    Article  CAS  Google Scholar 

  35. Steiner T, Bohm M, Dichgans M, et al. Recommendations for the emergency management of complications associated with the new direct oral anticoagulants (DOACs) apixaban, dabigatran, and rivaroxaban. Clin Res Cardiol. 2013;102:399–412. This paper discusses important reversal strategies of both the oral direct thrombin inhibitors, as well as the factor Xa inhibitors.

    Article  CAS  PubMed  Google Scholar 

  36. Rybinnik I, Mullen MT, Messe S, et al. Treatment of acute stroke in patients on dabigatran: a survey of US stroke specialists. J Stroke Cerebrovasc Dis. 2013;22:1312–6. This paper demonstrates the wide variety of practice strategies being used in current clinical care.

    Article  PubMed  Google Scholar 

  37. Baumann Kreuziger LM, Reding MT. Management of bleeding associated with dabigatran and rivaroxaban: a survey of current practices. Thromb Res. 2013;132:e161–3.

    Article  CAS  PubMed  Google Scholar 

  38. Kubitza D, Becka M, Roth A, et al. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin. 2008;24:2757–65.

    Article  CAS  PubMed  Google Scholar 

  39. Yeh CH, Fredenburgh JC, Weitz JI. Oral direct factor Xa inhibitors. Circ Res. 2012;111:1069–78.

    Article  CAS  PubMed  Google Scholar 

  40. Rupprecht HJ, Blank R. Clinical pharmacology of direct and indirect factor Xa inhibitors. Drugs. 2010;70:2153–70.

    CAS  PubMed  Google Scholar 

  41. Prescribing information. Bristol-Myers Squibb Company. Eliquis. Available at: http://packageinserts.bms.com/pi/pi_eliquis.pdf. Accessed 7 April 2014.

  42. Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet. 2009;48:1–22.

    Article  CAS  PubMed  Google Scholar 

  43. Bhanwra S, Ahluwalia K. The new factor Xa inhibitor: apixaban. J Pharmacol Pharmacother. 2014;5:12–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Prescribing information. Janssen Pharmaceuticals. Xarelto. Available at: http://www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf#zoom=100. Accessed 7 April 2014.

  45. Gresham C, Levine M, Ruha AM. Case files of the Medical Toxicology Fellowship at Banner Good Samaritan Medical Center in Phoenix, AZ: a non-warfarin anticoagulant overdose. J Med Toxicol. 2009;5:242–9.

    Article  PubMed Central  PubMed  Google Scholar 

  46. Hillarp A, Baghaei F, Fagerberg Blixter I, et al. The effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost. 2011;9:133–9.

    Article  CAS  PubMed  Google Scholar 

  47. Martin AC, LeBonniec B, Fischer AM, et al. Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis. Int J Cardiol. 2013;168:4228–33.

    Article  PubMed  Google Scholar 

  48. Godier A, Miclot A, Le Bonniec B, et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology. 2012;116:94–102.

    Article  CAS  PubMed  Google Scholar 

  49. Fukuda T, Honda Y, Kamisato C, et al. Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents. Thromb Haemost. 2012;107:253–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Michael Levine declares that he has no conflict of interest. Joshua N. Goldstein has received consultancy fees from CSL Behring.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Department of Emergency Medicine, Section of Medical Toxicology, University of Southern California, 1200 North State Street, Room 1011, Los Angeles, CA, 90033, USA

    Michael Levine

  2. Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA

    Joshua N. Goldstein

Authors
  1. Michael Levine
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joshua N. Goldstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Levine.

Additional information

This article is part of the Topical Collection on Critical Care

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Levine, M., Goldstein, J.N. Emergency Reversal of Anticoagulation: Novel Agents. Curr Neurol Neurosci Rep 14, 471 (2014). https://doi.org/10.1007/s11910-014-0471-7

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11910-014-0471-7

Keywords

Search

Navigation