Intracranial Bleeding



The non-vitamin K antagonist oral anticoagulants (NOACs), dabigatran, rivaroxaban, apixaban, and edoxaban, are associated with a much lower incidence of intracranial hemorrhage than warfarin. This may be due to the fact that NOACs do not affect plasma concentrations of factor VII or the complexes of tissue factor and factor VIIa that are essential for the first reaction in the coagulation cascade, whereas warfarin suppresses factor VII production even within the therapeutic range of prothrombin time-international normalized ratios (PT-INRs). Another explanation may be that there are fewer coagulation inhibition points in the coagulation cascade with NOAC treatment than with warfarin treatment, and NOACs have a trough phase, while warfarin does not. There may be differences in the sites preventing intracranial hemorrhage between thrombin inhibitors and Xa inhibitors. Data have indicated that thrombin inhibitors and Xa inhibitors more strongly suppress brain hemorrhage and subdural hematoma, respectively, than warfarin. Analysis of the results obtained for East Asians in Phase III trials showed that, though the warfarin dose was maintained at a lower level for East Asians, the incidence of intracranial hemorrhage was higher among East Asians than non-East Asians. However, when an NOAC is used instead of warfarin, there is greater reduction of the incidence of intracranial hemorrhage in East Asians than in non-East Asians. Nonsurgical measures for intracranial hemorrhage during NOAC treatment are general measures, including systolic blood pressure control to less than 140 mmHg, charcoal administration, and application of hemodialysis to remove dabigatran, and specific measures, such as coagulation factor therapy including four-factor prothrombin complex concentrate, recombinant activated factor VII, and several antidotes including idarucizumab, andexanet alfa, and ciraparantag (arapazine).


Non-vitamin K antagonist oral anticoagulants (NOACs) Intracranial hemorrhage Antidote East Asia Coagulation cascade 


  1. 1.
    Yasaka M, Minematsu K, Naritomi H, Sakata T, Yamaguchi T. Predisposing factors for enlargement of intracerebral hemorrhage in patients treated with warfarin. Thromb Haemost. 2003;89:2782–3.Google Scholar
  2. 2.
    Itabashi R, Yasaka M, Kuwashiro T, Nakagaki H, Miyashita F, Naritomi H, et al. Location of acute brain hemorrhage in patients undergoing antithrombotic therapy. J Neurol Sci. 2009;280:87–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Toyoda K, Yasaka M, Nagata K, Nagao T, Gotoh J, Sakamoto T, et al. Antithrombotic therapy influences location, enlargement, and mortality from intracerebral hemorrhage. The Bleeding with Antithrombotic Therapy (BAT) Retrospective Study. Cerebrovasc Dis. 2009;27:151–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Kuwashiro T, Yasaka M, Itabashi R, Nakagaki H, Miyashita F, Naritomi H, et al. Enlargement of acute intracerebral hematomas in patients on long-term warfarin treatment. Cerebrovasc Dis. 2010;29:446–53.CrossRefPubMedGoogle Scholar
  5. 5.
    Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. RE-LY Steering Committee and Investigators: dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51 and Erratum in: N Engl J Med. 2010; 363:1877.CrossRefPubMedGoogle Scholar
  6. 6.
    Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, The ROCKET AF Investigators, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–91.CrossRefPubMedGoogle Scholar
  7. 7.
    Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, ARISTOTLE Committees and Investigators, et al. . Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–92.CrossRefPubMedGoogle Scholar
  8. 8.
    Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093–104.CrossRefPubMedGoogle Scholar
  9. 9.
    Hori M, Matsumoto M, Tanahashi N, Momomura S, Uchiyama S, Goto S, et al. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation – the J-ROCKET AF study –. Circ J. 2012;76:2104–11.CrossRefPubMedGoogle Scholar
  10. 10.
    Hart RG, Diener HC, Yang S, Connolly SJ, Wallentin L, Reilly PA, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: The RE-LY trial. Stroke. 2012;43:1511–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Graham DJ, Reichman ME, Wernecke M, Zhang R, Southworth MR, Levenson M, et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for non-valvular atrial fibrillation. Circulation. 2015;131:157–64.CrossRefPubMedGoogle Scholar
  12. 12.
    Hagii J, Tomita H, Metoki N, Saito S, Shiroto H, Hitomi H, et al. Characteristics of intracerebral hemorrhage during rivaroxaban treatment: comparison with those during warfarin. Stroke. 2014;45:2805–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Komori M, Yasaka M, Kokuba K, Matsuoka H, Fujimoto S, Yoshida M, et al. Intracranial hemorrhage during dabigatran treatment. Circ J. 2014;78:1335–41.CrossRefPubMedGoogle Scholar
  14. 14.
    Hylek EM, Held C, Alexander JH, Lopes RD, De Caterina R, et al. Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: the ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): predictors, characteristics, and clinical outcomes. J Am Coll Cardiol. 2014;63:2141–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Yasaka M. J-ROCKET AF trial increased expectation of lower-dose rivaroxaban made for Japan. Circ J. 2012;76:2086–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Wong KS, Hu D, Oomman A, Tan RS, Patel M, Singer D, et al. Rivaroxaban for stroke prevention in East Asia patients from the ROCKET AF trial. Stroke. 2014;45:1739–49.CrossRefPubMedGoogle Scholar
  17. 17.
    Yasaka M, Lip GY. Stroke prevention in Asian patients with atrial fibrillation. Stroke. 2014;45:1608–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Ohmura T, Ikegami K, Hori K, Encinas J, Maruyama I. Effect of anticoagulant drug dabigatran etexilate on thrombus formation and bleeding in an AV shunted model and effect of vitamin K on the antithrombotic action. Pharma Medica. 2011;29:137–42.Google Scholar
  19. 19.
    Yasaka M. New insights into nonvitamin K antagonist oral anticoagulants’ reversal of intracerebral hemorrhage. Front Neurol Neurosci. 2015;37:93–106.CrossRefPubMedGoogle Scholar
  20. 20.
    Saji N, Kimura K, Aoki J, Uemura J, Sakamoto Y. Intracranial hemorrhage caused by Non-Vitamin K Antagonist Oral Anticoagulants (NOACs). Multicenter retrospective cohort study in Japan. Circ J. 2015;79:1018–23.CrossRefPubMedGoogle Scholar
  21. 21.
    Connolly BJ, Pearce LA, Hart RG. Vitamin K antagonists and risk of subdural hematoma: meta-analysis of randomized clinical trials. Stroke. 2014;45:1672–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Hirano T. New era of oral anticoagulation for Japanese non-valvular atrial fibrillation patients. Circ J. 2014;78:1317–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Won SY, Schlunk F, Dinkel J, Karatas H, Leung W, Hayakawa K, et al. Imaging of contrast medium extravasation in anticoagulation-associated intracerebral hemorrhage with dual-energy computed tomography. Stroke. 2013;44:2883–90.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Lauer A, Cianchetti FA, Van Cott EM, Schlunk F, Schulz E, Pfeilschifter W, et al. Anticoagulation with the oral direct thrombin inhibitor dabigatran does not enlarge hematoma volume in experimental intracerebral hemorrhage. Circulation. 2011;124:1654–62.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Wong KS, Hu DY, Oomman A, Tan RS, Patel MR, Singer DE, et al. Rivaroxaban for stroke prevention in East Asia patients from the ROCKET AF trial. Stroke. 2014;45:1739–47.CrossRefPubMedGoogle Scholar
  26. 26.
    Goto S, Zhu J, Liu L, Oh BH, Wojdyla DM, Aylward P, et al. Efficacy and safety of apixaban compared with warfarin for stroke prevention in patients with atrial fibrillation from East Asia: a sub-analysis of the 50 literature cited apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation(ARISTOTLE) trial. AHJ. 2014;168:303–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Yamashita T, Koretsune Y, Yang Y, Chen SA, Chung N, Shimada YJ, et al. Edoxaban vs. warfarin in East Asian patients with atrial fibrillation: an ENGAGE AF-TIMI 48 subanalysis. Circ J. 2016;80:860–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Toyoda K. Problems concerning antithrombotic therapy for Japanese patients: lessons from the Bleeding with Antithrombotic Therapy (BAT) study. J Jpn Soc Thromb Hemost. 2009;20:594–601.CrossRefGoogle Scholar
  29. 29.
    van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 2010;9:167–76.CrossRefPubMedGoogle Scholar
  30. 30.
    Shen AY, Yao JF, Brar SS, Jorgensen MB, Chen W. Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation. J Am Coll Cardiol. 2007;50:309–15.CrossRefPubMedGoogle Scholar
  31. 31.
    Benavente OR, Coffey CS, Conwit R, Hart RG, McClure LA, Pearce LA, et al. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet. 2013;382:507–15.CrossRefPubMedGoogle Scholar
  32. 32.
    Toyoda K, Yasaka M, Uchiyama S, Nagao T, Gotoh J, Nagata K, et al. Blood pressure levels and bleeding events during antithrombotic therapy: the Bleeding with Antithrombotic Therapy (BAT) Study. Stroke. 2010;41:1440–4.CrossRefPubMedGoogle Scholar
  33. 33.
    Shoji A, Satoh K, Nakano Y, Sumitomo H, Niki H, et al. Dabigatran related intracranial hemorrhage, five cases report. Jpn J Stroke. 2014;36:186–90 (Abstract with English).CrossRefGoogle Scholar
  34. 34.
    Debata A, Tateishi Y, Hamabe J, Horie N, Izumo T, Hayashi K, et al. Three cases of spontaneous intracerebral hemorrhage under rivaroxaban. Jpn J Stroke. 2015; in press (Abstract with English).Google Scholar
  35. 35.
    Singh T, Maw TT, Henry BL, Pastor-Soler NM, Unruh ML, Hallows KR, et al. Extracorporeal therapy for dabigatran removal in the treatment of acute bleeding: a single center experience. Clin J Am Soc Nephurol. 2013;8:1533–9.CrossRefGoogle Scholar
  36. 36.
    Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol. 2012;87(Suppl 1):S141–5.CrossRefPubMedGoogle Scholar
  37. 37.
    Hankey GJ. Unanswered questions and research priorities to optimise stroke prevention in atrial fibrillation with the new oral anticoagulants. Thromb Haemost. 2014;111:808–16.CrossRefPubMedGoogle Scholar
  38. 38.
    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.CrossRefPubMedGoogle Scholar
  39. 39.
    Anderson CS, Huang Y, Wang JG, Arima H, Neal B, Peng B, et al. Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet Neurol. 2008;7:391–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate. a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124:1573–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Perlstein I, Wang Z, Yan Song Y, et al.: Reversal of apixaban anticoagulation by 4-factor prothrombin complex concentrates in healthy subjects. 56th Americal Society of Hematology Annual Meeting and Exposition, San Francisco, December, 2014Google Scholar
  42. 42.
    Zahir H1, Brown KS2, Vandell AG2, Desai M2, Maa JF2, Dishy V, et al.: Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation. 2015; 131:82-90Google Scholar
  43. 43.
    Hamada H, Wasa S, Mima Y, Yasaka M, Kuwashiro T, Okada Y. A case of thalamic hemorrhage which occurred during anticoagulant therapy with Xa inhibitor and expanded even after the administration of ptorhrombin complex concentrate. Jpn Stroke J. 2016; in press.Google Scholar
  44. 44.
    Vanden Daelen S, Peetermans M, Vanassche T, Verhamme P, Vandermeulen E. Monitoring and reversal strategies for new oral anticoagulants. Expert Rev Cardiovasc Ther. 2015;13:95–103.CrossRefPubMedGoogle Scholar
  45. 45.
    Costin J, Ansell J, Laulicht B, Bakhru S, Steiner S. Reversal agents in development for the new oral anticoagulants. Postgrad Med. 2014;126:19–24.CrossRefPubMedGoogle Scholar
  46. 46.
    Pollack Jr CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373:511–20.CrossRefPubMedGoogle Scholar
  47. 47.
    Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19:446–51.CrossRefPubMedGoogle Scholar
  48. 48.
    Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373:2413–24.CrossRefPubMedGoogle Scholar
  49. 49.
    Ansell JE1, Bakhru SH, Laulicht BE, Steiner SS, Grosso M, Brown K, et al.: Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014;371:2141-2142.Google Scholar

Copyright information

© Springer Science+Business Media Singapore 2017

Authors and Affiliations

  1. 1.Department of Cerebrovascular Medicine and NeurologyNational Hospital Organization, Kyushu Medical CenterFukuokaJapan

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