Skip to main content
SpringerLink
Log in

Rivaroxaban-Associated Intraparenchymal Hemorrhage Managed with 4-Factor Prothrombin Complex Concentrate

  • Thrombosis (D Slattery, Section Editor)
  • Published:
Current Emergency and Hospital Medicine Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Background: Rivaroxaban is a Xa inhibitor and one of the direct acting oral anticoagulants (DOAC) that currently does not have evidence-based guidelines for its reversal. Prothrombin complex concentrate (PCC) has been recommended as a potential reversal agent for life-threatening bleeds. With no direct antidote and its widespread usage, the attempt to manage life-threatening hemorrhages with procoagulant drugs will continue to rise.

Recent Findings

Case report :A 55-year-old male on rivaroxaban and clopidogrel presented to another facility with ataxia, confusion, and lateralizing weakness. Computed tomography (CT) scan of the brain showed a large intraparenchymal hemorrhage. He was intubated, given mannitol and nicardipine, and transferred to our tertiary care facility. His coagulation studies upon arrival were normal. He was given 50 units/kg of PCC in an attempt to reverse rivaroxaban and one unit of platelets for clopidogrel reversal. A repeat CT 18 h later showed extension of the bleed. Neurosurgical intervention was not done, and 4 days into his stay, a right cephalic vein thrombosis was found. During his hospital stay, the patient developed encephalopathy and required a tracheostomy tube and gastrostomy tube. A CT on day 36 showed stabilization of the bleeds, and on day 42, he was transferred to a skilled nursing facility.

Summary

Why should an emergency physician be aware of this? Novel oral anticoagulants are becoming ever popular due to their ease in management and lack of required monitoring when compared to conventional therapy. But, they are still associated with hemorrhages, which is their most common complication. Due to the lack of antidotes and reversal agents for DOACs, prothrombotic agents are being frequently utilized in the setting of life-threatening hemorrhages. While various case reports have been published on the usage of varying dosages of PCC to treat rivaroxaban-associated bleeds, no strong evidence exists to its clinical efficacy. Our case adds to the growing body of evidence showing a lack of clinical efficacy in the reversal of the anticoagulation effects of oral factor Xa inhibitors in addition to a complication in utilizing this potential reversal agent (J Crit Care 33:252–6, 2016; J Thromb Heamost 12:1428–1436, 2014; World Neurosurg 84(6)1956–1961, 2015)

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. Janssen Pharmaceuticals, Inc. XARELTO® (rivaroxaban) package insert. Titusville, NJ: Bayer Healthcare AG; August 2014.

  2. Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358:2765–75.

    Article  CAS  PubMed  Google Scholar 

  3. Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomized controlled trial. Lancet. 2008;372:31–9.

    Article  CAS  PubMed  Google Scholar 

  4. Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358:2776–86.

    Article  CAS  PubMed  Google Scholar 

  5. Romualdi E, Donadini MP, Ageno W. Oral rivaroxaban after symptomatic venous thromboembolism: the continued treatment study (EINSTEIN-extension study). Expert Rev Cardiovasc Ther. 2011;9:841–4.

    Article  CAS  PubMed  Google Scholar 

  6. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N 302 Engl J Med. 2011;365:883–91.

    Article  CAS  Google Scholar 

  7. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499–510.

    Article  Google Scholar 

  8. The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287–97.

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Granger CB, Alexander JH, McMurray J, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–92.

    Article  CAS  PubMed  Google Scholar 

  11. Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, et al. Treatment of acute venous thromboembolism with dabigatran. Circulation. 2014;129:764–72.

    Article  CAS  PubMed  Google Scholar 

  12. EINSTEIN Investigators. Oral rivaroxaban for sympotomatic venous thromboembolism. N Engl J Med. 2010;363:2499–510.

    Article  Google Scholar 

  13. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799–808.

    Article  CAS  PubMed  Google Scholar 

  14. Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406–15.

    Article  Google Scholar 

  15. Mueck W, Stampfuss J, Kubitza D, Becka M. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet. 2014;53(1):1–16.

    Article  CAS  PubMed  Google Scholar 

  16. Mangram A, Oguntodu O, Dzandu J, et al. Is there a difference in efficacy, safety and cost-effectiveness between 3-factor and 4-factor prothrombin complex concentrates among trauma patients on oral anticoagulants? J Crit Care. 2016;33:252–6.

    Article  CAS  PubMed  Google Scholar 

  17. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;2(Suppl):e445–885.

    Google Scholar 

  18. Pollack CV. Managing bleeding in anticoagulated patients in the emergency care setting. J Emerg Med. 2013;45:467–77.

    Article  PubMed  Google Scholar 

  19. Siegal DM, Crowther MA. Acute management of bleeding in patients on novel oral anticoagulants. Eur 313 Heart J. 2013;34:489–500.

    Article  CAS  Google Scholar 

  20. Miller MP, Trujillo TC, Nordenholz KE. Practical considerations in emergency management of bleeding in the setting of target-specific oral anticoagulants. Am J Emerg Med. 2014;32:375–82.

    Article  PubMed  Google Scholar 

  21. Kaatz S, Kouides PA, Garcia DA, et al. Guidance on the emergent reversal of oral thrombin and factor 317 Xa inhibitors. Am J Hematol. 2012;89:S414–145.

    Google Scholar 

  22. Pernod G, Albaladejo P, Godier A, Samama CM, Susen S, Gruel Y, et al. Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor Xa 320 inhibitors: proposals of the Working Group on Perioperative Haemostasis (GIHP) – March 2013. Arch Cardiovasc Dis. 2013;106:382–93.

    Article  PubMed  Google Scholar 

  23. Kalus JS. Pharmacologic interventions for reversing the effects of oral anticoagulants. Am J Health-Syst Pharm. 2013;70:S12–21.

    Article  CAS  PubMed  Google Scholar 

  24. Fawole A, Daw HA, Crowther MA. Practical management of bleeding due to the anticoagulants dabigatran, rivaroxaban, and apixaban. Cleve Clin J Med. 2103;80:443–51.

    Article  Google Scholar 

  25. 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.

    Article  CAS  PubMed  Google Scholar 

  26. Thigen JL, Limdi NA. Reversal of oral anticoagulation. Pharmacotherapy. 2013;33:1199–213.

    Article  Google Scholar 

  27. Akwaa F, Spyropoulos AC. Treatment of bleeding complications when using oral anticoagulants for 332 prevention of strokes. Curr Treat Options Cardiovasc Med. 2013;15:288–98.

    Article  PubMed  Google Scholar 

  28. Knepper J, Horne D, Obi A, Wakefield TW. A systemic update on the state of novel anticoagulants a primer on reversal and bridging. J Vasc Surg: Venous and Lym Dis. 2013;1:418–26.

    Google Scholar 

  29. Grandhi R, Newman C, Zhang X, et al. Administration of 4-factor prothrombin complex concentrate as in antidote for intracranial bleeding in patients taking direct factor Xa inhibitors. World Neurosurg. 2015;84(6):1956–61.

    Article  PubMed  Google Scholar 

  30. Balla S, Koerber S, Flaker G. Management of bleeding in patients receiving non-vitamin K antagonists. Postgrad Med J. 2017;93(1098):221–5.

    Article  PubMed  Google Scholar 

  31. Cuker A, Siegal D, Crowther M, et al. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol. 2014;64:1128–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. •• Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by 337 prothrombin complex concentrate. A randomized, placebo-controlled, crossover study in healthy 338 subjects. Circulation. 2011;124:1573–9. This study reports a complete reversal of elevated prothrombin time (PT) and normalization of endogenous thrombin potential (ETP) following administration of 4-factor PCC in humans given rivaroxaban. In summary, this study provides evidence for successful reversal of rivaroxaban with 4-factor PCC via markers of PT and ETP.

    Article  CAS  PubMed  Google Scholar 

  33. Dinkelaar J, Molenaar PJ, Ninivaggi M, de Laat B, Brinkman HJM, Leyte A. In vitro assessment using thrombin generation of the applicability of prothrombin complex concentrate as an antidote for rivaroxaban. J Thromb Haemost 341. 2013;11:1111–8.

    Article  CAS  Google Scholar 

  34. Marlu R, Hodaj E, Paris A, Albaladejo P, Crackowski J, Pernod G. Effect of non-specific agents on anticoagulant activity of dabigatran and rivaroxaban. Thromb Haemost. 2012;108:217–24.

    Article  CAS  PubMed  Google Scholar 

  35. Perzborn E, Heitmeier S, Laux V, Buchmüller A. Reversal of rivaroxaban-induced anticoagulation with prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant activated factor VII in vitro. Thromb Res. 2014;133:671681.

    Article  Google Scholar 

  36. Körber M, Langer E, Ziemer S, et al. Measurement and reversal of prophylactic and therapeutic peak levels of rivaroxaban: an in vitro study. Clin Appl Thromb Hemost. 2014;20:735–40.

    Article  PubMed  Google Scholar 

  37. Zhou W, Zorn M, Nawroth P, Butehorn U, Perzborn E, Heitmeier S, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban. Stroke. 2013;44:771–8.

    Article  CAS  PubMed  Google Scholar 

  38. Perzborn E, Gruber A, Tinel H, Marzec UM, Buetehorn U, Buchmueller A, et al. Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates. Thromb Haemost. 2013;110:162–72.

    Article  CAS  PubMed  Google Scholar 

  39. 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 

  40. • Levi M, Moore K, Castillejos C, 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 Heamost. 2014;12:1428–36. This study was unable to completely reverse the PT as described in the Eerenberg study. In addition, 4-factor PCC did not produce as robust of a reversal of ETP that 3-factor PCC did. Both 3-factor and 4-factor PCC did not have an effect on activated partial thromboplastin time (APTT). In summary, this study presents evidence for a more muted response to PCC as compared to the Eerenberg study.

    Article  CAS  Google Scholar 

  41. Purruckeer JC, Capper D, Behrens L, Veltkamp R. Secondary hematoma expansion in intracerebral hemorrhage during rivaroxaban therapy. Am J Emerg Med 2014;947e3947.e5.

  42. Gonzva J, Patricelli R, Lignac D. Spontaneous splenic rupture in a patient treated with rivaroxaban. Am J Emerg Med. 2014;32:950.e3.

    Article  PubMed  Google Scholar 

  43. Mao G, King L, Young S, Kaplan R. Factor eight inhibitor bypassing agent (FIEBA) for reversal of target specific oral anticoagulants in life-threatening intracranial bleeding. J EmergMed. 2017;52(5):731–7.

    Article  Google Scholar 

  44. • Riley T, Gauthier-Lewis M, Sanchez C, et al. Role of agents for reversing the effects of target-specific oral anticoagulants. Am J Health-Syst Pharm. 2017;74(2):54–61. This article looked at the various different mechanisms for reversing oral anticoagulants. It also reviewed the latest information on the new reversal agents that are still currently in early trials, but may show some promising effects for reversing oral anticoagulants, especially factor Xa inhibitors.

    Article  PubMed  Google Scholar 

  45. Lauw M, Coppens M, Eikelboom J. Recent advances in antidotes for direct oral anticoagulants: their arrival is imminent. Can J Cardiol 2014. Accepted manuscript pending publication.

  46. Siegal D, Curnutte J, Connolly S, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373:2413–24.

    Article  CAS  PubMed  Google Scholar 

  47. Connolly S, Milling T, Eikelboom J, et al. ANNEXA-4 investigators. Adenanet alfa for acute major bleeding associated with the factor XA inhibitors. N Engl Med. 2016;375:1131–41.

    Article  CAS  Google Scholar 

  48. Ansell J, Bakhru S, Laulicht B, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014;371:2141–2.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacy, University Medical Center of Southern Nevada, 1800 W. Charleston Blvd., Las Vegas, NV, 89102, USA

    Jayme S. K. Patel & Aryan J. Rahbar

  2. Department of Emergency Medicine, UNLV School of Medicine, 901 Rancho Lane, Suite 135, Las Vegas, NV, 89102, USA

    Ketan Patel & Tiffany W. Sigal

Authors
  1. Jayme S. K. Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aryan J. Rahbar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ketan Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tiffany W. Sigal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jayme S. K. Patel.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

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.

Additional information

This article is part of the Topical Collection on Thrombosis

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Patel, J.S.K., Rahbar, A.J., Patel, K. et al. Rivaroxaban-Associated Intraparenchymal Hemorrhage Managed with 4-Factor Prothrombin Complex Concentrate. Curr Emerg Hosp Med Rep 6, 62–68 (2018). https://doi.org/10.1007/s40138-018-0157-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40138-018-0157-6

Keywords

Search

Navigation