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Efficacy and safety of prothrombin complex concentrate for vitamin K antagonist-associated intracranial hemorrhage: a systematic review and meta-analysis



Prothrombin complex concentrate (PCC) is the treatment of choice in vitamin K antagonist-associated intracranial hemorrhage (VKA-ICH). However, the efficiency and safety associated with their use remain unclear.


This study aimed to assess the current evidence of the clinical outcomes in patients with VKA-ICH treated with or without PCC.

Summary of review

A meta-analysis was conducted. Two randomized controlled trials and 19 observational studies were included. PCC use demonstrated a significant increased likelihood of international normalized ratio (INR) normalization (OR = 3.76; 95% CI 1.74–8.12), shortened time to INR correction (MD = − 1.30; 95% CI − 2.08 to − 0.53) and reduction of hematoma expansion (HE) rate (OR = 0.37; 95% CI 0.23–0.60). Although PCC use revealed a statistical reduction at 30-day mortality (OR = 0.62; 95% CI 0.50–0.78), the result was inconsistent with mortality at discharge (OR = 1.03; 95% CI 0.68–1.57) and 90-day follow-up (OR = 0.50; 95% CI 0.24–1.07), both of which yielded no significant difference. When subgroup analyses were performed focus on PCC only treatment with FFP, no statistically significant difference was observed in 30-day mortality (OR = 0.43; 95% CI 0.11–1.71) as well. Besides, significant difference was not found in neurologic improvement at discharge (OR = 1.85; 95% CI 0.32–10.75), 30-day follow-up (OR = 3.00; 95% CI 0.93–9.70), or 90-day follow-up (OR = 1.55; 95% CI 0.84–2.86). No statistically significant difference was noted in the risk of thromboembolism following PCC administration (OR = 0.61; 95% CI 0.23–1.63).


PCC use for VKA-ICH reversal was associated with a significant reduction in INR and HE rate, without an increased risk of thromboembolic events. However, this reduction was not associated with improvement in neurologic deficits or overall survival. Well-designed randomized trials with special considerations to the aspect are necessary.

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  1. Lip GY, Andreotti F, Fauchier L et al (2011) Bleeding risk assessment and management in atrial fibrillation patients: a position document from the European Heart Rhythm Association, endorsed by the European Society of Cardiology Working Group on Thrombosis. Europace 13:723–746

    Article  PubMed  Google Scholar 

  2. Cavallini A, Fanucchi S, Persico A (2008) Warfarin-associated intracerebral hemorrhage. Neurol Sci 29(SUPPL 2):266–S268

    Article  Google Scholar 

  3. Neau JP, Couderq C, Ingrand P, Blanchon P, Gil R, VGP Study Group (2001) Intracranial hemorrhage and oral anticoagulant treatment. Cerebrovasc Dis 11:195–200

    Article  CAS  PubMed  Google Scholar 

  4. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G (2012) Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141:e44S–e88S

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Keeling D, Baglin T, Tait C, Watson H, Perry D, Baglin C, Kitchen S, Makris M, British Committee for Standards in Haematology (2011) Guidelines on oral anticoagulation with warfarin—fourth edition. Br J Haematol 154:311–324

    Article  PubMed  Google Scholar 

  6. Coimbra R, Hoyt DB, Anjaria DJ, Potenza BM, Fortlage D, Hollingsworth-Fridlund P (2005) Reversal of anticoagulation in trauma: a North-American survey on clinical practices among trauma surgeons. J Trauma 59:375–382

    Article  PubMed  Google Scholar 

  7. Chai-Adisaksopha C, Hillis C, Siegal DM, Movilla R, Heddle N, Iorio A, Crowther M (2016) Prothrombin complex concentrates versus fresh frozen plasma for warfarin reversal. A systematic review and meta-analysis. Thromb Haemost 116:879–890

    Article  PubMed  Google Scholar 

  8. Dentali F, Marchesi C, Giorgi PM et al (2011) Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost 106:429–438

    Article  CAS  PubMed  Google Scholar 

  9. Steiner T, Al-Shahi SR, Beer R et al (2014) European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage. Int J Stroke 9:840–855

    Article  PubMed  Google Scholar 

  10. Hemphill JR, Greenberg SM, Anderson CS et al (2015) Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 46:2032–2060

    Article  PubMed  Google Scholar 

  11. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA 283:2008–2012

    Article  CAS  PubMed  Google Scholar 

  12. Steiner T, Poli S, Griebe M, Hüsing J, Hajda J, Freiberger A, Bendszus M, Bösel J, Christensen H, Dohmen C, Hennerici M, Kollmer J, Stetefeld H, Wartenberg KE, Weimar C, Hacke W, Veltkamp R (2016) Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurol 15:566–573

    Article  CAS  PubMed  Google Scholar 

  13. Boulis NM, Bobek MP, Schmaier A, Hoff JT (1999) Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery 45:1113–1118

    Article  CAS  PubMed  Google Scholar 

  14. Alonso DLM, Huertas N, Egido JA et al (2013) Questionable reversal of anticoagulation in the therapeutic management of cerebral haemorrhage associated with vitamin K antagonists. Thromb Haemost 110:1145–1151

    Article  CAS  Google Scholar 

  15. Frontera JA, Gordon E, Zach V, Jovine M, Uchino K, Hussain MS, Aledort L (2014) Reversal of coagulopathy using prothrombin complex concentrates is associated with improved outcome compared to fresh frozen plasma in warfarin-associated intracranial hemorrhage. Neurocrit Care 21:397–406

    Article  CAS  PubMed  Google Scholar 

  16. Parry-Jones AR, Di Napoli M, Goldstein JN et al (2015) Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage. Ann Neurol 78:54–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Fong WC, Lo WT, Ng YW, Cheung YF, Wong GC, Ho HF, Chan JH, Li PC (2014) The benefit of prothrombin complex concentrate in decreasing neurological deterioration in patients with warfarin-associated intracerebral haemorrhage. Hong Kong Med J 20:486–494

    CAS  PubMed  Google Scholar 

  18. Majeed A, Meijer K, Larrazabal R, Arnberg F, Luijckx GJ, Roberts RS, Schulman S (2014) Mortality in vitamin K antagonist-related intracerebral bleeding treated with plasma or 4-factor prothrombin complex concentrate. Thromb Haemost 111:233–239

    Article  CAS  PubMed  Google Scholar 

  19. Edavettal M, Rogers A, Rogers F, Horst M, Leng W (2014) Prothrombin complex concentrate accelerates international normalized ratio reversal and diminishes the extension of intracranial hemorrhage in geriatric trauma patients. Am Surg 80:372–376

    PubMed  Google Scholar 

  20. Wong JK, Chen PC, Falvey J et al (2016) Anticoagulation reversal strategies for left ventricular assist device patients presenting with acute intracranial hemorrhage. ASAIO J 62:552–557

    Article  CAS  PubMed  Google Scholar 

  21. Kuwashiro T, Yasaka M, Itabashi R, Nakagaki H, Miyashita F, Naritomi H, Minematsu K (2011) Effect of prothrombin complex concentrate on hematoma enlargement and clinical outcome in patients with anticoagulant-associated intracerebral hemorrhage. Cerebrovasc Dis 31:170–176

    Article  CAS  PubMed  Google Scholar 

  22. Woo CH, Patel N, Conell C, Rao VA, Faigeles BS, Patel MC, Pombra J, Akins PT, Axelrod YK, Ge IY, Sheridan WF, Flint AC (2014) Rapid warfarin reversal in the setting of intracranial hemorrhage: a comparison of plasma, recombinant activated factor VII, and prothrombin complex concentrate. World Neurosurg 81:110–115

    Article  PubMed  Google Scholar 

  23. Yasaka M, Sakata T, Minematsu K, Naritomi H (2002) Correction of INR by prothrombin complex concentrate and vitamin K in patients with warfarin related hemorrhagic complication. Thromb Res 108:25–30

    Article  PubMed  Google Scholar 

  24. Siddiq F, Jalil A, McDaniel C, Brock DG, Pineda CC, Bell RD, Lee K (2008) Effectiveness of factor IX complex concentrate in reversing warfarin associated coagulopathy for intracerebral hemorrhage. Neurocrit Care 8:36–41

    Article  CAS  PubMed  Google Scholar 

  25. Fredriksson K, Norrving B, Strömblad LG (1992) Emergency reversal of anticoagulation after intracerebral hemorrhage. Stroke 23:972–977

    Article  CAS  PubMed  Google Scholar 

  26. Kuramatsu JB, Gerner ST, Schellinger PD, Glahn J, Endres M, Sobesky J, Flechsenhar J, Neugebauer H, Jüttler E, Grau A, Palm F, Röther J, Michels P, Hamann GF, Hüwel J, Hagemann G, Barber B, Terborg C, Trostdorf F, Bäzner H, Roth A, Wöhrle J, Keller M, Schwarz M, Reimann G, Volkmann J, Müllges W, Kraft P, Classen J, Hobohm C, Horn M, Milewski A, Reichmann H, Schneider H, Schimmel E, Fink GR, Dohmen C, Stetefeld H, Witte O, Günther A, Neumann-Haefelin T, Racs AE, Nueckel M, Erbguth F, Kloska SP, Dörfler A, Köhrmann M, Schwab S, Huttner HB (2015) Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage. JAMA 313:824–836

    Article  CAS  PubMed  Google Scholar 

  27. Rowe AS, Mahbubani PS, Bucklin MH, Clark CT, Hamilton LA (2016) Activated prothrombin complex concentrate versus plasma for reversal of warfarin-associated hemorrhage. Pharmacotherapy 36:1132–1137

    Article  CAS  PubMed  Google Scholar 

  28. Takahashi A, Kato TS, Oda N, Komamura K, Kanzaki H, Asakura M, Hashimura K, Niwaya K, Funatsu T, Nakatani T, Kobayashi J, Kitamura S, Shishido T, Miyata S, Takahashi JC, Iihara K, Kitakaze M (2010) Prothrombin complex concentrate for rapid reversal of warfarin-induced anticoagulation and intracerebral hemorrhage in patients supported by a left ventricular assist device. Int J Gerontol 4:143–147

    Article  Google Scholar 

  29. Huhtakangas J, Tetri S, Juvela S, Saloheimo P, Bode MK, Karttunen V, Käräjämäki A, Hillbom M (2015) Improved survival of patients with warfarin-associated intracerebral haemorrhage: a retrospective longitudinal population-based study. Int J Stroke 10:876–881

    Article  PubMed  Google Scholar 

  30. Yasaka M, Minematsu K, Naritomi H, Sakata T, Yamaguchi T (2003) Predisposing factors for enlargement of intracerebral hemorrhage in patients treated with warfarin. Thromb Haemost 89:278–283

    Article  CAS  PubMed  Google Scholar 

  31. DeLoughery EP, DeLoughery TG (2017) Use of three procoagulants in improving bleeding outcomes in the warfarin patient with intracranial hemorrhage. Blood Coagul Fibrinolysis 28:612–616

    Article  CAS  PubMed  Google Scholar 

  32. Lihai S, Feng Z (2010) Clinical treatment of intracranial hemorrhage due to oral warfarin therapy in 27 patients [in Chinese]. Chin J Neuromed 9:1262–1264

    Google Scholar 

  33. Cartmill M, Dolan G, Byrne JL et al (2000) Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies. Br J Neurosurg 14:458–461

    Article  CAS  PubMed  Google Scholar 

  34. Sacco S, Marini C, Carolei A (2004) Medical treatment of intracerebral hemorrhage. Neurol Sci 25(SUPPL 1):S6–S9

    Article  PubMed  Google Scholar 

  35. Diringer MN, Edwards DF (2001) Admission to a neurologic/neurosurgical intensive care unit is associated with reduced mortality rate after intracerebral hemorrhage. Crit Care Med 29:635–640

    Article  CAS  PubMed  Google Scholar 

  36. Mansouri B, Heidari K, Asadollahi S, Nazari M, Assarzadegan F, Amini A (2013) Mortality and functional disability after spontaneous intracranial hemorrhage: the predictive impact of overall admission factors. Neurol Sci 34:1933–1939

    Article  PubMed  Google Scholar 

  37. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC, Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, Popescu BA, Schotten U, van Putte B, Vardas P, Agewall S, Camm J, Baron Esquivias G, Budts W, Carerj S, Casselman F, Coca A, de Caterina R, Deftereos S, Dobrev D, Ferro JM, Filippatos G, Fitzsimons D, Gorenek B, Guenoun M, Hohnloser SH, Kolh P, Lip GYH, Manolis A, McMurray J, Ponikowski P, Rosenhek R, Ruschitzka F, Savelieva I, Sharma S, Suwalski P, Tamargo JL, Taylor CJ, van Gelder IC, Voors AA, Windecker S, Zamorano JL, Zeppenfeld K (2016) 2016 ESC Guidelines for the Management of Atrial Fibrillation Developed in Collaboration With EACTS. Eur Heart J 37:2893–2962

    Article  PubMed  Google Scholar 

  38. Skolnick BE, Mathews DR, Khutoryansky NM, Pusateri AE, Carr ME (2010) Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects. Blood 116:693–701

    Article  CAS  PubMed  Google Scholar 

  39. Ciccone A, Pozzi M, Motto C et al (2008) Epidemiological, clinical, and therapeutic aspects of primary intracerebral hemorrhage. Neurol Sci 29(SUPPL 2):S256–S257

    Article  PubMed  Google Scholar 

  40. Holland L, Warkentin TE, Refaai M, Crowther MA, Johnston MA, Sarode R (2009) Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion 49:1171–1177

    Article  CAS  PubMed  Google Scholar 

  41. Kohler M (1999) Thrombogenicity of prothrombin complex concentrates. Thromb Res 95:S13–S17

    Article  CAS  PubMed  Google Scholar 

  42. Witt DM, Delate T, Garcia DA, Clark NP, Hylek EM, Ageno W, Dentali F, Crowther MA (2012) Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption for gastrointestinal tract bleeding. Arch Intern Med 172:1484–1491

    Article  CAS  PubMed  Google Scholar 

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The work was supported by the National Key R&D Program of China (2017YFC1307500, 2017YFC1307504) and Science and Technology Project of Huizhou City (2017C0416032).

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Correspondence to Yamei Tang.

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Pan, R., Cheng, J., Lai, K. et al. Efficacy and safety of prothrombin complex concentrate for vitamin K antagonist-associated intracranial hemorrhage: a systematic review and meta-analysis. Neurol Sci 40, 813–827 (2019).

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  • Intracranial hemorrhage
  • Vitamin K antagonists
  • Prothrombin complex concentrate
  • Meta-analysis