Reversal of anticoagulation in warfarin-associated intracerebral hemorrhage
- W David Freeman, MD
W David Freeman, MD
- Professor of Neurology
- Mayo Clinic
- Maria I Aguilar, MD
Maria I Aguilar, MD
- Associate Professor of Neurology
- Mayo Clinic Arizona
- Jeffrey Weitz, MD
Jeffrey Weitz, MD
- Professor of Medicine and Biochemistry
- McMaster University
- Section Editors
- Lawrence LK Leung, MD
Lawrence LK Leung, MD
- Editor-in-Chief — Hematology
- Section Editor — Disorders of Hemostasis and Coagulation
- Professor of Medicine
- Stanford University School of Medicine
- Scott E Kasner, MD
Scott E Kasner, MD
- Section Editor — Stroke
- Professor of Neurology
- University of Pennsylvania School of Medicine
Warfarin-associated intracerebral hemorrhage (ICH) is the most devastating complication of warfarin therapy, accounting for 90 percent of warfarin-related deaths and most of the remaining permanent disability . In terms of absolute risk, the rate of spontaneous intracerebral hemorrhage (ICH) among 70-year-old subjects averages 0.15 percent/year. In those treated with warfarin to an INR of 2.0 to 3.0, the rate of ICH is increased to 0.3 to 0.8 percent/year [2,3].
Reversal of anticoagulation in patients with warfarin-associated ICH is a medical emergency, as anticoagulation is associated with hematoma growth, neurologic deterioration, and increased risk of death and major disability [4,5].
This topic discusses the reversal of anticoagulation in patients with warfarin-associated ICH. Other aspects of the diagnosis and management of intracerebral hemorrhage are presented separately. The risk of intracerebral hemorrhage in patients taking warfarin therapy, management issues regarding resumption of anticoagulation in patients with prior ICH, and reversal of anticoagulation in other settings are also discussed separately. (See "Spontaneous intracerebral hemorrhage: Treatment and prognosis" and "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Risk of intracerebral bleeding in patients treated with anticoagulants" and "The use of antithrombotic therapy in patients with an acute or prior intracerebral hemorrhage" and "Correcting excess anticoagulation after warfarin".)
Anticoagulation therapy is both a risk factor for hematoma enlargement and for worse outcomes after ICH. Hematoma growth, particularly within the first 24 hours after ICH, is an independent predictor of mortality and poor outcome. (See "Spontaneous intracerebral hemorrhage: Treatment and prognosis", section on 'Preceding antithrombotic use' and "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Hemorrhage enlargement'.)
The degree of INR prolongation at the time of warfarin-associated ICH correlates with initial hematoma size, progressive hematoma enlargement after admission, functional outcome, and mortality [6-11]. One-half of patients with warfarin-associated ICH die within 30 days of the onset of this complication [6,10,12-16]. In one study, warfarin-associated ICH was fatal in two-thirds of patients whose INRs were >3.0 on presentation . Most episodes of warfarin-associated ICH occur in patients with a therapeutic level of anticoagulation (INR 2.0 to 3.5) [6,12-14,17,18].
- Fang MC, Go AS, Chang Y, et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med 2007; 120:700.
- Hart RG, Tonarelli SB, Pearce LA. Avoiding central nervous system bleeding during antithrombotic therapy: recent data and ideas. Stroke 2005; 36:1588.
- García-Rodríguez LA, Gaist D, Morton J, et al. Antithrombotic drugs and risk of hemorrhagic stroke in the general population. Neurology 2013; 81:566.
- Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. Mayo Clin Proc 2007; 82:82.
- Goodnough LT, Shander A. How I treat warfarin-associated coagulopathy in patients with intracerebral hemorrhage. Blood 2011; 117:6091.
- Rosand J, Eckman MH, Knudsen KA, et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med 2004; 164:880.
- Flaherty ML, Tao H, Haverbusch M, et al. Warfarin use leads to larger intracerebral hematomas. Neurology 2008; 71:1084.
- Berwaerts J, Dijkhuizen RS, Robb OJ, Webster J. Prediction of functional outcome and in-hospital mortality after admission with oral anticoagulant-related intracerebral hemorrhage. Stroke 2000; 31:2558.
- Yasaka M, Minematsu K, Naritomi H, et al. Predisposing factors for enlargement of intracerebral hemorrhage in patients treated with warfarin. Thromb Haemost 2003; 89:278.
- Cucchiara B, Messe S, Sansing L, et al. Hematoma growth in oral anticoagulant related intracerebral hemorrhage. Stroke 2008; 39:2993.
- Flibotte JJ, Hagan N, O'Donnell J, et al. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology 2004; 63:1059.
- Punthakee X, Doobay J, Anand SS. Oral-anticoagulant-related intracerebral hemorrhage. Thromb Res 2002; 108:31.
- Sjöblom L, Hårdemark HG, Lindgren A, et al. Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study. Stroke 2001; 32:2567.
- Neau JP, Couderq C, Ingrand P, et al. Intracranial hemorrhage and oral anticoagulant treatment. Cerebrovasc Dis 2001; 11:195.
- Hart RG, Boop BS, Anderson DC. Oral anticoagulants and intracranial hemorrhage. Facts and hypotheses. Stroke 1995; 26:1471.
- Claassen DO, Kazemi N, Zubkov AY, et al. Restarting anticoagulation therapy after warfarin-associated intracerebral hemorrhage. Arch Neurol 2008; 65:1313.
- Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003; 349:1019.
- Yasaka M, Sakata T, Minematsu K, Naritomi H. Correction of INR by prothrombin complex concentrate and vitamin K in patients with warfarin related hemorrhagic complication. Thromb Res 2002; 108:25.
- Huttner HB, Schellinger PD, Hartmann M, et al. 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 2006; 37:1465.
- Fredriksson K, Norrving B, Strömblad LG. Emergency reversal of anticoagulation after intracerebral hemorrhage. Stroke 1992; 23:972.
- Steiner T, Rosand J, Diringer M. Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions. Stroke 2006; 37:256.
- Lee SB, Manno EM, Layton KF, Wijdicks EF. Progression of warfarin-associated intracerebral hemorrhage after INR normalization with FFP. Neurology 2006; 67:1272.
- Bershad EM, Suarez JI. Prothrombin complex concentrates for oral anticoagulant therapy-related intracranial hemorrhage: a review of the literature. Neurocrit Care 2010; 12:403.
- Makris M, Greaves M, Phillips WS, et al. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost 1997; 77:477.
- Cartmill M, Dolan G, Byrne JL, Byrne PO. Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies. Br J Neurosurg 2000; 14:458.
- Pabinger I, Brenner B, Kalina U, et al. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost 2008; 6:622.
- Khorsand N, Veeger NJ, van Hest RM, et al. An observational, prospective, two-cohort comparison of a fixed versus variable dosing strategy of prothrombin complex concentrate to counteract vitamin K antagonists in 240 bleeding emergencies. Haematologica 2012; 97:1501.
- Boulis NM, Bobek MP, Schmaier A, Hoff JT. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery 1999; 45:1113.
- Hanger HC, Geddes JA, Wilkinson TJ, et al. Warfarin-related intracerebral haemorrhage: better outcomes when reversal includes prothrombin complex concentrates. Intern Med J 2013; 43:308.
- Dowlatshahi D, Butcher KS, Asdaghi N, et al. Poor prognosis in warfarin-associated intracranial hemorrhage despite anticoagulation reversal. Stroke 2012; 43:1812.
- Hellstern P, Halbmayer WM, Köhler M, et al. Prothrombin complex concentrates: indications, contraindications, and risks: a task force summary. Thromb Res 1999; 95:S3.
- Hellstern P. Production and composition of prothrombin complex concentrates: correlation between composition and therapeutic efficiency. Thromb Res 1999; 95:S7.
- Toth P, van Veen JJ, Robinson K, et al. Real world usage of PCC to "rapidly" correct warfarin induced coagulopathy. Blood Transfus 2013; 11:500.
- Cabral KP, Fraser GL, Duprey J, et al. Prothrombin complex concentrates to reverse warfarin-induced coagulopathy in patients with intracranial bleeding. Clin Neurol Neurosurg 2013; 115:770.
- Bertram M, Bonsanto M, Hacke W, Schwab S. Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation. J Neurol 2000; 247:209.
- http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm350026.htm (Accessed on May 07, 2013).
- Evans SJ, Biss TT, Wells RH, Hanley JP. Emergency warfarin reversal with prothrombin complex concentrates: UK wide study. Br J Haematol 2008; 141:268.
- Holland L, Warkentin TE, Refaai M, et al. Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion 2009; 49:1171.
- Rizos T, Jenetzky E, Herweh C, et al. Point-of-care reversal treatment in phenprocoumon-related intracerebral hemorrhage. Ann Neurol 2010; 67:788.
- Voils SA, Baird B. Systematic review: 3-factor versus 4-factor prothrombin complex concentrate for warfarin reversal: does it matter? Thromb Res 2012; 130:833.
- Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2008; 358:2127.
- Sørensen B, Johansen P, Nielsen GL, et al. Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects. Blood Coagul Fibrinolysis 2003; 14:469.
- Freeman WD, Brott TG, Barrett KM, et al. Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clin Proc 2004; 79:1495.
- Robinson MT, Rabinstein AA, Meschia JF, Freeman WD. Safety of recombinant activated factor VII in patients with warfarin-associated hemorrhages of the central nervous system. Stroke 2010; 41:1459.
- Goldstein JN, Thomas SH, Frontiero V, et al. Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke 2006; 37:151.
- Morgenstern LB, Hemphill JC 3rd, Anderson C, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2010; 41:2108.
- Goldstein JN, Rosand J, Schwamm LH. Warfarin reversal in anticoagulant-associated intracerebral hemorrhage. Neurocrit Care 2008; 9:277.
- Aiyagari V, Testai FD. Correction of coagulopathy in warfarin associated cerebral hemorrhage. Curr Opin Crit Care 2009; 15:87.
- 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; 141:e44S.
- Hanley JP. Warfarin reversal. J Clin Pathol 2004; 57:1132.
- Baker RI, Coughlin PB, Gallus AS, et al. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust 2004; 181:492.
- Degos V, Westbroek EM, Lawton MT, et al. Perioperative management of coagulation in nontraumatic intracerebral hemorrhage. Anesthesiology 2013; 119:218.
- Keeling D, Baglin T, Tait C, et al. Guidelines on oral anticoagulation with warfarin - fourth edition. Br J Haematol 2011; 154:311.
- Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:160S.
- REVERSAL AGENTS
- Intravenous vitamin K
- Fresh frozen plasma
- Unactivated prothrombin-complex concentrates
- - Common features
- - Three versus four-factor PCCs
- - Supplements to three-factor PCC
- Recombinant factor VIIa
- Initial treatment
- Treatment goals and monitoring
- Resumption of anticoagulation
- SUMMARY AND RECOMMENDATIONS