Timing of INR reversal using fresh-frozen plasma in warfarin-associated intracerebral hemorrhage

  • Murtaza Akhter
  • Andrea Morotti
  • Abigail Sara Cohen
  • Yuchiao Chang
  • Alison M. Ayres
  • Kristin Schwab
  • Anand Viswanathan
  • Mahmut Edip Gurol
  • Christopher David Anderson
  • Steven Mark Greenberg
  • Jonathan Rosand
  • Joshua Norkin Goldstein


Rapid reversal of coagulopathy is recommended in warfarin-associated intracerebral hemorrhage (WAICH). However, rapid correction of the INR has not yet been proven to improve clinical outcomes, and the rate of correction with fresh-frozen plasma (FFP) can be variable. We sought to determine whether faster INR reversal with FFP is associated with decreased hematoma expansion and improved outcome. We performed a retrospective analysis of a prospectively collected cohort of consecutive patients with WAICH presenting to an urban tertiary care hospital from 2000 to 2013. Patients with baseline INR > 1.4 treated with FFP and vitamin K were included. The primary outcomes are occurrence of hematoma expansion, discharge modified Rankin Scale (mRS), and 30-day mortality. The association between timing of INR reversal, ICH expansion, and outcome was investigated with logistic regression analysis. 120 subjects met inclusion criteria (mean age 76.9, 57.5% males). Median presenting INR was 2.8 (IQR 2.3–3.4). Hematoma expansion is not associated with slower INR reversal [median time to INR reversal 9 (IQR 5–14) h vs. 10 (IQR 7–16) h, p = 0.61]. Patients with ultimately poor outcome received more rapid INR reversal than those with favorable outcome [9 (IQR 6–14) h vs. 12 (8–19) h, p = 0.064). We find no evidence of an association between faster INR reversal and either reduced hematoma expansion or better outcome.


Intracerebral hemorrhage Warfarin Stroke Cerebral hemorrhage Anticoagulants 


  1. 1.
    Ferro JM (2006) Update on intracerebral haemorrhage. J Neurol 253:985–999. doi:10.1007/s00415-006-0201-4 CrossRefPubMedGoogle Scholar
  2. 2.
    Qureshi AI, Mendelow AD, Hanley DF (2009) Intracerebral haemorrhage. Lancet 373:1632–1644. doi:10.1016/S0140-6736(09)60371-8 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Flibotte JJ, Hagan N, O’Donnell J, Greenberg SM, Rosand J (2004) Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology 63:1059–1064CrossRefPubMedGoogle Scholar
  4. 4.
    Rosand J, Eckman MH, Knudsen KA, Singer DE, Greenberg SM (2004) The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med 164:880–884. doi:10.1001/archinte.164.8.880 CrossRefPubMedGoogle Scholar
  5. 5.
    Kuwashiro T, Yasaka M, Itabashi R, Nakagaki H, Miyashita F, Naritomi H, Minematsu K (2010) Enlargement of acute intracerebral hematomas in patients on long-term warfarin treatment. Cerebrovasc Dis 29:446–453. doi:10.1159/000289348 CrossRefPubMedGoogle Scholar
  6. 6.
    Cucchiara B, Messe S, Sansing L, Kasner S, Lyden P (2008) Hematoma growth in oral anticoagulant related intracerebral hemorrhage. Stroke 39:2993–2996. doi:10.1161/STROKEAHA.108.520668 CrossRefPubMedGoogle Scholar
  7. 7.
    Brouwers HB, Chang Y, Falcone G, Cai X, Ayres A, Battey TW, Vashkevich A, Mcnamara K, Valant V, Schwab K, Orzell S, Bresette L, Feske S, Rost N, Romero J, Viswanathan A, Chou SH-Y, Greenberg S, Rosand J, Goldstein J (2014) Predicting hematoma expansion after primary intracerebral hemorrhage. JAMA Neurol 71:158–164. doi:10.1001/jamaneurol.2013.5433 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Morgenstern LB, Hemphill JC, Anderson C, Becker K, Broderick JP, Connolly ES, Greenberg SM, Huang JN, MacDonald RL, Messé SR, Mitchell PH, Selim M, Tamargo RJ (2010) Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 41:2108–2129. doi:10.1161/STR.0b013e3181ec611b CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G (2008) Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133:160S–198S. doi:10.1378/chest.08-0670 CrossRefPubMedGoogle Scholar
  10. 10.
    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. doi:10.1182/blood-2009-11-253492 CrossRefPubMedGoogle Scholar
  11. 11.
    Goldstein JN, Thomas SH, Frontiero V, Joseph A, Engel C, Snider R, Smith EE, Greenberg SM, Rosand J (2006) Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke 37:151–155. doi:10.1161/01.STR.0000195047.21562.23 CrossRefPubMedGoogle Scholar
  12. 12.
    Zubkov AY, Mandrekar JN, Claassen DO, Manno EM, Wijdicks EFM, Rabinstein AA (2008) Predictors of outcome in warfarin-related intracerebral hemorrhage. Arch Neurol 65:1320–1325. doi:10.1001/archneur.65.10.1320 CrossRefPubMedGoogle Scholar
  13. 13.
    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 80:372–376PubMedGoogle Scholar
  14. 14.
    Nishijima DK, Dager WE, Schrot RJ, Holmes JF (2010) The efficacy of factor VIIa in emergency department patients with warfarin use and traumatic intracranial hemorrhage. Acad Emerg Med 17:244–251. doi:10.1111/j.1553-2712.2010.00666.x CrossRefPubMedGoogle Scholar
  15. 15.
    Menzin J, Hoesche J, Friedman M, Nichols C, Bergman GE, Crowther M, Garcia D, Jones C (2012) Failure to correct international normalized ratio and mortality among patients with warfarin-related major bleeding: an analysis of electronic health records. J Thromb Haemost 10:596–605. doi:10.1111/j.1538-7836.2012.04636.x CrossRefPubMedGoogle Scholar
  16. 16.
    Sarode R, Milling TJ, Refaai MA, Mangione A, Schneider A, Durn BL, Goldstein JN (2013) Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 128:1234–1243. doi:10.1161/CIRCULATIONAHA.113.002283 PubMedGoogle Scholar
  17. 17.
    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. doi:10.1001/jama.2015.0846 CrossRefPubMedGoogle Scholar
  18. 18.
    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. doi:10.1016/S1474-4422(16)00110-1 CrossRefPubMedGoogle Scholar
  19. 19.
    Goldstein JN, Refaai MA, Milling TJ, Lewis B, Goldberg-Alberts R, Hug BA, Sarode R (2015) Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet. doi:10.1016/S0140-6736(14)61685-8 PubMedCentralGoogle Scholar
  20. 20.
    Hemphill JC, Bonovich DC, Besmertis L, Manley GT, Johnston SC, Tuhrim S (2001) The ICH Score: a simple, reliable grading scale for intracerebral hemorrhage editorial comment: a simple, reliable grading scale for intracerebral hemorrhage. Stroke 32:891–897. doi:10.1161/01.STR.32.4.891 CrossRefPubMedGoogle Scholar
  21. 21.
    Rost NS, Smith EE, Chang Y, Snider RW, Chanderraj R, Schwab K, FitzMaurice E, Wendell L, Goldstein JN, Greenberg SM, Rosand J (2008) Prediction of functional outcome in patients with primary intracerebral hemorrhage the FUNC Score. Stroke 39(8):2304–2309. doi:10.1161/STROKEAHA.107.512202 CrossRefPubMedGoogle Scholar
  22. 22.
    Goldstein JN, Fazen LE, Snider R, Schwab K, Greenberg SM, Smith EE, Lev MH, Rosand J (2007) Contrast extravasation on CT angiography predicts hematoma expansion in intracerebral hemorrhage. Neurology 68:889–894. doi:10.1212/01.wnl.0000257087.22852.21 CrossRefPubMedGoogle Scholar
  23. 23.
    Delgado Almandoz JE, Yoo AJ, Stone MJ, Schaefer PW, Goldstein JN, Rosand J, Oleinik A, Lev MH, Gonzalez RG, Romero JM (2009) Systematic characterization of the computed tomography angiography spot sign in primary intracerebral hemorrhage identifies patients at highest risk for hematoma expansion: the spot sign score. Stroke 40:2994–3000. doi:10.1161/STROKEAHA.109.554667 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Brott T, Broderick J, Kothari R, Barsan W, Tomsick T, Sauerbeck L, Spilker J, Duldner J, Khoury J (1997) Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 28:1–5CrossRefPubMedGoogle Scholar
  25. 25.
    Brouwers HB, Biffi A, Ayres AM, Schwab K, Cortellini L, Romero JM, Rost NS, Viswanathan A, Greenberg SM, Rosand J, Goldstein JN (2012) Apolipoprotein E genotype predicts hematoma expansion in lobar intracerebral hemorrhage. Stroke 43:1490–1495. doi:10.1161/STROKEAHA.111.643262 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Demchuk AM, Dowlatshahi D, Rodriguez-Luna D, Molina CA, Blas YS, Dzialowski I, Kobayashi A, Boulanger J-M, Lum C, Gubitz G, Padma V, Roy J, Kase CS, Kosior J, Bhatia R, Tymchuk S, Subramaniam S, Gladstone DJ, Hill MD, Aviv RI (2012) Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective observational study. Lancet Neurol 11:307–314. doi:10.1016/S1474-4422(12)70038-8 CrossRefPubMedGoogle Scholar
  27. 27.
    Romero JM, Brouwers HB, Lu J, Delgado Almandoz JE, Kelly H, Heit J, Goldstein J, Rosand J, Gonzalez RG (2013) Prospective validation of the computed tomographic angiography spot sign score for intracerebral hemorrhage. Stroke 44:3097–3102. doi:10.1161/STROKEAHA.113.002752 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Dowlatshahi D, Butcher KS, Asdaghi N, Nahirniak S, Bernbaum ML, Giulivi A, Wasserman JK, Poon M-C, Coutts SB (2012) Poor prognosis in warfarin-associated intracranial hemorrhage despite anticoagulation reversal. Stroke 43:1812–1817. doi:10.1161/STROKEAHA.112.652065 CrossRefPubMedGoogle Scholar
  29. 29.
    Boulis NM, Bobek MP, Schmaier A, Hoff JT (1999) Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery 45:1113–1119CrossRefPubMedGoogle Scholar
  30. 30.
    Cartmill M, Dolan G, Byrne JL, Byrne PO (2000) Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies. Br J Neurosurg 14:458–461CrossRefPubMedGoogle Scholar
  31. 31.
    Makris M, Greaves M, Phillips WS, Kitchen S, Rosendaal FR, Preston EF (1997) Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost 77:477–480PubMedGoogle Scholar
  32. 32.
    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 108:25–30CrossRefPubMedGoogle Scholar
  33. 33.
    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. doi:10.1159/000321766 CrossRefPubMedGoogle Scholar
  34. 34.
    Huttner HB, Schellinger PD, Hartmann M, Köhrmann M, Juettler E, Wikner J, Mueller S, Meyding-Lamade U, Strobl R, Mansmann U, Schwab S, Steiner T (2006) Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke 37:1465–1470. doi:10.1161/01.STR.0000221786.81354.d6 CrossRefPubMedGoogle Scholar
  35. 35.
    Parry-Jones AR, Di Napoli M, Goldstein JN, Schreuder FHBM, Tetri S, Tatlisumak T, Yan B, van Nieuwenhuizen KM, Dequatre-Ponchelle N, Lee-Archer M, Horstmann S, Wilson D, Pomero F, Masotti L, Lerpiniere C, Godoy DA, Cohen AS, Houben R, Al-Shahi Salman R, Pennati P, Fenoglio L, Werring D, Veltkamp R, Wood E, Dewey HM, Cordonnier C, Klijn CJM, Meligeni F, Davis SM, Huhtakangas J, Staals J, Rosand J, Meretoja A (2015) Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage. Ann Neurol 78:54–62. doi:10.1002/ana.24416 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Hanger HC, Geddes JAA, Wilkinson TJ, Lee M, Baker AE (2013) Warfarin-related intracerebral haemorrhage: better outcomes when reversal includes prothrombin complex concentrates. Intern Med J 43:308–316. doi:10.1111/imj.12034 CrossRefPubMedGoogle Scholar
  37. 37.
    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. doi:10.1007/s12028-014-9972-0 CrossRefPubMedGoogle Scholar
  38. 38.
    Roitberg B, Emechebe-Kennedy O, Amin-Hanjani S, Mucksavage J, Tesoro E (2005) Human recombinant factor VII for emergency reversal of coagulopathy in neurosurgical patients: a retrospective comparative study. Neurosurgery 57:832-836CrossRefPubMedGoogle Scholar
  39. 39.
    Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, Skolnick BE, Steiner T (2008) Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 358:2127–2137. doi:10.1056/NEJMoa0707534 CrossRefPubMedGoogle Scholar
  40. 40.
    Yuan ZH, Jiang JK, Huang WD, Pan J, Zhu JY, Wang JZ (2010) A meta-analysis of the efficacy and safety of recombinant activated factor VII for patients with acute intracerebral hemorrhage without hemophilia. J Clin Neurosci 17:685–693. doi:10.1016/j.jocn.2009.11.020 CrossRefPubMedGoogle Scholar
  41. 41.
    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. doi:10.1111/j.1537-2995.2008.02080.x CrossRefPubMedGoogle Scholar
  42. 42.
    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. doi:10.1007/s12028-007-9011-5 CrossRefGoogle Scholar
  43. 43.
    Bershad EM, Farhadi S, Suri MFK, Feen ES, Hernandez OH, Selman WR, Suarez JI (2008) Coagulopathy and in hospital deaths in patients with acute subdural hematoma. J Neurosurg 109:664–669. doi:10.3171/JNS/2008/109/10/0664 CrossRefPubMedGoogle Scholar
  44. 44.
    Brody DL, Aiyagari V, Shackleford AM, Diringer MN (2005) Use of recombinant factor VIIa in patients with warfarin-associated intracranial hemorrhage. Neurocrit Care 2:263–267. doi:10.1385/NCC:2:3:263 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Wikkelsø A, Wetterslev J, Møller AM, Afshari A (2016) Thromboelastography (TEG) or thromboelastometry (ROTEM) to monitor haemostatic treatment versus usual care in adults or children with bleeding. Cochrane Database Syst Rev. doi:10.1002/14651858.CD007871.pub3 PubMedGoogle Scholar

Copyright information

© SIMI 2017

Authors and Affiliations

  • Murtaza Akhter
    • 1
    • 3
  • Andrea Morotti
    • 2
  • Abigail Sara Cohen
    • 2
  • Yuchiao Chang
    • 3
  • Alison M. Ayres
    • 2
  • Kristin Schwab
    • 2
  • Anand Viswanathan
    • 2
  • Mahmut Edip Gurol
    • 2
  • Christopher David Anderson
    • 2
  • Steven Mark Greenberg
    • 2
  • Jonathan Rosand
    • 2
  • Joshua Norkin Goldstein
    • 3
  1. 1.Department of Emergency MedicineUniversity of Arizona College of Medicine–Phoenix and Maricopa Integrated Health SystemPhoenixUSA
  2. 2.Department of Neurology, Massachusetts General HospitalHarvard Medical SchoolBostonUSA
  3. 3.Department of Emergency Medicine, Massachusetts General HospitalHarvard Medical SchoolBostonUSA

Personalised recommendations