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Oral anticoagulant-associated intracerebral hemorrhage

Journal of Neurology volume 259, pages 212–224 (2012)Cite this article

Abstract

The incidence of oral anticoagulation-associated intracerebral hemorrhage (OAC-ICH) is growing due to the increasing use of warfarin and the older age of treated patients. Recent population studies reveal that OAC-ICH currently occurs at a frequency comparable to that of subarachnoid hemorrhage. Most frequently, OAC-ICH are located in deep or lobar regions of the brain, although it may also occur in the brainstem. These hemorrhages are larger than spontaneous hematomas and may be fatal in at least 50% of cases. The primary cause of brain injury in patients with OAC-ICH is the direct mechanical disruption of the brain tissue but secondary damage may occur through the intervention of matrix metalloproteinases, glutamate, cytokines, heme, iron, and the chemical toxicity of products such as thrombin, which are released from the clot. The pathogenesis of OAC-ICH also includes the effects of aging, the level of anticoagulation, genetic factors, and a high prevalence of concurrent cerebrovascular conditions, such as cerebral amyloid angiopathy, leukoaraiosis or previous strokes. The treatment of OAC-ICH is challenging and involves rapid reversal of anticoagulation with hemostatic drug therapies such as vitamin K, fresh frozen plasma, prothrombin complex concentrates or recombinant factor VIIa. These therapies may not always be sufficient to stabilize the patient’s clinical condition and lacking randomized controlled trials, the best hematological approach to reverse oral anticoagulation is debated. Other difficult decisions reviewed in this article are whether anticoagulation should be restarted after OAC-ICH, and when anticoagulant treatment should be resumed. The newer oral anticoagulants, which are increasingly being introduced for thromboembolism prevention, may confer a lower risk of intracranial bleeding than warfarin, although they do not have an antidote and their anticoagulant effect is difficult to monitor.

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References

  1. Whitlon DS, Sadowski JA, Suttie JW (1978) Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition. Biochemistry 17(8):1371–1377

    Article  PubMed  CAS  Google Scholar 

  2. Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P (2008) Antithrombotic and thrombolytic therapy for ischemic stroke: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 133(6 Suppl):630S–669S

    Article  PubMed  CAS  Google Scholar 

  3. Schulman S, Beyth RJ, Kearon C, Levine MN (2008) Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 133(6 Suppl):257S–298S

    Article  PubMed  CAS  Google Scholar 

  4. Schurgers LJ, Aebert H, Vermeer C, Bultmann B, Janzen J (2004) Oral anticoagulant treatment: friend or foe in cardiovascular disease? Blood 104(10):3231–3232

    Article  PubMed  CAS  Google Scholar 

  5. Hart RG, Tonarelli SB, Pearce LA (2005) Avoiding central nervous system bleeding during antithrombotic therapy: recent data and ideas. Stroke 36(7):1588–1593

    Article  PubMed  Google Scholar 

  6. Hart RG, Boop BS, Anderson DC (1995) Oral anticoagulants and intracranial hemorrhage. Facts and hypotheses. Stroke 26(8):1471–1477

    Article  PubMed  CAS  Google Scholar 

  7. Flaherty ML, Kissela B, Woo D, Kleindorfer D, Alwell K, Sekar P, Moomaw CJ, Haverbusch M, Broderick JP (2007) The increasing incidence of anticoagulant-associated intracerebral hemorrhage. Neurology 68(2):116–121

    Article  PubMed  CAS  Google Scholar 

  8. Levine MN, Raskob G, Beyth RJ, Kearon C, Schulman S (2004) Hemorrhagic complications of anticoagulant treatment: the Seventh ACCP Conference on antithrombotic and thrombolytic therapy. Chest 126(3 Suppl):287S–310S

    Article  PubMed  CAS  Google Scholar 

  9. (1994) Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 154 (13):1449–1457

  10. Steiner T, Rosand J, Diringer M (2006) Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions. Stroke 37(1):256–262

    Article  PubMed  CAS  Google Scholar 

  11. Smith NL, Psaty BM, Furberg CD, White R, Lima JA, Newman AB, Manolio TA (1999) Temporal trends in the use of anticoagulants among older adults with atrial fibrillation. Arch Intern Med 159(14):1574–1578

    Article  PubMed  CAS  Google Scholar 

  12. Xi G, Keep RF, Hoff JT (2006) Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol 5(1):53–63

    Article  PubMed  Google Scholar 

  13. Rosenberg GA, Navratil M (1997) Metalloproteinase inhibition blocks edema in intracerebral hemorrhage in the rat. Neurology 48(4):921–926

    PubMed  CAS  Google Scholar 

  14. Castillo J, Davalos A, Alvarez-Sabin J, Pumar JM, Leira R, Silva Y, Montaner J, Kase CS (2002) Molecular signatures of brain injury after intracerebral hemorrhage. Neurology 58(4):624–629

    PubMed  CAS  Google Scholar 

  15. Wang J, Dore S (2007) Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab 27(5):894–908

    PubMed  CAS  Google Scholar 

  16. Figueiredo RT, Fernandez PL, Mourao-Sa DS, Porto BN, Dutra FF, Alves LS, Oliveira MF, Oliveira PL, Graca-Souza AV, Bozza MT (2007) Characterization of heme as activator of Toll-like receptor 4. J Biol Chem 282(28):20221–20229

    Article  PubMed  CAS  Google Scholar 

  17. Kruman I, Bruce-Keller AJ, Bredesen D, Waeg G, Mattson MP (1997) Evidence that 4-hydroxynonenal mediates oxidative stress-induced neuronal apoptosis. J Neurosci 17(13):5089–5100

    PubMed  CAS  Google Scholar 

  18. Zazulia AR, Diringer MN, Videen TO, Adams RE, Yundt K, Aiyagari V, Grubb RL Jr, Powers WJ (2001) Hypoperfusion without ischemia surrounding acute intracerebral hemorrhage. J Cereb Blood Flow Metab 21(7):804–810

    Article  PubMed  CAS  Google Scholar 

  19. Mayer SA, Lignelli A, Fink ME, Kessler DB, Thomas CE, Swarup R, Van Heertum RL (1998) Perilesional blood flow and edema formation in acute intracerebral hemorrhage: a SPECT study. Stroke 29(9):1791–1798

    Article  PubMed  CAS  Google Scholar 

  20. Ropper AH, Zervas NT (1982) Cerebral blood flow after experimental basal ganglia hemorrhage. Ann Neurol 11(3):266–271

    Article  PubMed  CAS  Google Scholar 

  21. Suzuki J, Ebina T (1980) Sequential changes in tissue surrounding ICH. In: Pia HWLC, Zierski J (eds) Spontaneous intracerebral hematomas. Springer, Berlin, pp 121–128

    Google Scholar 

  22. 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(20):2127–2137

    Article  PubMed  CAS  Google Scholar 

  23. Katayama Y, Becker DP, Tamura T, Ikezaki K (1990) Early cellular swelling in experimental traumatic brain injury: a phenomenon mediated by excitatory amino acids. Acta Neurochir 51:271–273

    CAS  Google Scholar 

  24. Yang GY, Betz AL, Chenevert TL, Brunberg JA, Hoff JT (1994) Experimental intracerebral hemorrhage: relationship between brain edema, blood flow, and blood-brain barrier permeability in rats. J Neurosurg 81(1):93–102

    Article  PubMed  CAS  Google Scholar 

  25. Wagner KR, Xi G, Hua Y, Kleinholz M, de Courten-Myers GM, Myers RE, Broderick JP, Brott TG (1996) Lobar intracerebral hemorrhage model in pigs: rapid edema development in perihematomal white matter. Stroke 27(3):490–497

    Article  PubMed  CAS  Google Scholar 

  26. Brott T, Broderick J, Barsan W, Kothari R, Tomsick T, Spilker J, Huster G (1992) Hyper-acute clot retraction in spontaneous intracerebral hemorrhage. Stroke 23:141

    Article  Google Scholar 

  27. Gebel JM, Brott TG, Sila CA, Tomsick TA, Jauch E, Salisbury S, Khoury J, Miller R, Pancioli A, Duldner JE, Topol EJ, Broderick JP (2000) Decreased perihematomal edema in thrombolysis-related intracerebral hemorrhage compared with spontaneous intracerebral hemorrhage. Stroke 31(3):596–600

    Article  PubMed  CAS  Google Scholar 

  28. Hua Y, Keep RF, Hoff JT, Xi G (2007) Brain injury after intracerebral hemorrhage: the role of thrombin and iron. Stroke 38(2 Suppl):759–762

    Article  PubMed  CAS  Google Scholar 

  29. Xi G, Reiser G, Keep RF (2003) The role of thrombin and thrombin receptors in ischemic, hemorrhagic and traumatic brain injury: deleterious or protective? J Neurochem 84(1):3–9

    Article  PubMed  CAS  Google Scholar 

  30. Lee KR, Colon GP, Betz AL, Keep RF, Kim S, Hoff JT (1996) Edema from intracerebral hemorrhage: the role of thrombin. J Neurosurg 84(1):91–96

    Article  PubMed  CAS  Google Scholar 

  31. Lee KR, Betz AL, Keep RF, Chenevert TL, Kim S, Hoff JT (1995) Intracerebral infusion of thrombin as a cause of brain edema. J Neurosurg 83(6):1045–1050

    Article  PubMed  CAS  Google Scholar 

  32. Kitaoka T, Hua Y, Xi G, Hoff JT, Keep RF (2002) Delayed argatroban treatment reduces edema in a rat model of intracerebral hemorrhage. Stroke 33(12):3012–3018

    Article  PubMed  CAS  Google Scholar 

  33. Brodin E, Seljeflot I, Arnesen H, Hurlen M, Appelbom H, Hansen JB (2009) Endogenous thrombin potential (ETP) in plasma from patients with AMI during antithrombotic treatment. Thromb Res 123(4):573–579

    Article  PubMed  CAS  Google Scholar 

  34. Holbrook AM, Pereira JA, Labiris R, McDonald H, Douketis JD, Crowther M, Wells PS (2005) Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 165(10):1095–1106

    Article  PubMed  CAS  Google Scholar 

  35. Gasse C, Hollowell J, Meier CR, Haefeli WE (2005) Drug interactions and risk of acute bleeding leading to hospitalisation or death in patients with chronic atrial fibrillation treated with warfarin. Thromb Haemost 94(3):537–543

    PubMed  CAS  Google Scholar 

  36. Jonsson AK, Spigset O, Jacobsson I, Hagg S (2007) Cerebral haemorrhage induced by warfarin: the influence of drug–drug interactions. Pharmacoepidemiol Drug Saf 16(3):309–315

    Article  PubMed  CAS  Google Scholar 

  37. Hirsh J, Fuster V, Ansell J, Halperin JL (2003) American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation 107(12):1692–1711

    Article  PubMed  Google Scholar 

  38. Battistella M, Mamdami MM, Juurlink DN, Rabeneck L, Laupacis A (2005) Risk of upper gastrointestinal hemorrhage in warfarin users treated with nonselective NSAIDs or COX-2 inhibitors. Arch Intern Med 165(2):189–192

    Article  PubMed  CAS  Google Scholar 

  39. Lee GH, Kwon SU, Kang DW (2008) Warfarin-induced intracerebral hemorrhage associated with microbleeds. J Clin Neurol (Seoul, Korea) 4(3):131–133

    Article  Google Scholar 

  40. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group (1997) A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Ann Neurol 42(6):857–865

    Article  Google Scholar 

  41. Smith EE, Rosand J, Knudsen KA, Hylek EM, Greenberg SM (2002) Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke. Neurology 59(2):193–197

    PubMed  CAS  Google Scholar 

  42. Tanaka A, Ueno Y, Nakayama Y, Takano K, Takebayashi S (1999) Small chronic hemorrhages and ischemic lesions in association with spontaneous intracerebral hematomas. Stroke 30(8):1637–1642

    Article  PubMed  CAS  Google Scholar 

  43. Fazekas F, Kleinert R, Roob G, Kleinert G, Kapeller P, Schmidt R, Hartung HP (1999) Histopathologic analysis of foci of signal loss on gradient-echo T2*-weighted MR images in patients with spontaneous intracerebral hemorrhage: evidence of microangiopathy-related microbleeds. AJNR 20(4):637–642

    PubMed  CAS  Google Scholar 

  44. Fan YH, Zhang L, Lam WW, Mok VC, Wong KS (2003) Cerebral microbleeds as a risk factor for subsequent intracerebral hemorrhages among patients with acute ischemic stroke. Stroke 34(10):2459–2462

    Article  PubMed  Google Scholar 

  45. Naka H, Nomura E, Takahashi T, Wakabayashi S, Mimori Y, Kajikawa H, Kohriyama T, Matsumoto M (2006) Combinations of the presence or absence of cerebral microbleeds and advanced white matter hyperintensity as predictors of subsequent stroke types. AJNR 27(4):830–835

    PubMed  CAS  Google Scholar 

  46. Lee SH, Ryu WS, Roh JK (2009) Cerebral microbleeds are a risk factor for warfarin-related intracerebral hemorrhage. Neurology 72(2):171–176

    Article  PubMed  CAS  Google Scholar 

  47. Beyth RJ, Quinn LM, Landefeld CS (1998) Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med 105(2):91–99

    Article  PubMed  CAS  Google Scholar 

  48. Kuijer PM, Hutten BA, Prins MH, Buller HR (1999) Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med 159(5):457–460

    Article  PubMed  CAS  Google Scholar 

  49. Shireman TI, Mahnken JD, Howard PA, Kresowik TF, Hou Q, Ellerbeck EF (2006) Development of a contemporary bleeding risk model for elderly warfarin recipients. Chest 130(5):1390–1396

    Article  PubMed  Google Scholar 

  50. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH (2010) Guidelines for the management of atrial fibrillation: the task force for the management of atrial fibrillation of the European Society of Cardiology (ESC). Eur Heart J 31(19):2369–2429

    Article  PubMed  Google Scholar 

  51. Woo D, Sauerbeck LR, Kissela BM, Khoury JC, Szaflarski JP, Gebel J, Shukla R, Pancioli AM, Jauch EC, Menon AG, Deka R, Carrozzella JA, Moomaw CJ, Fontaine RN, Broderick JP (2002) Genetic and environmental risk factors for intracerebral hemorrhage: preliminary results of a population-based study. Stroke 33(5):1190–1195

    Article  PubMed  Google Scholar 

  52. Eckman MH, Wong LK, Soo YO, Lam W, Yang SR, Greenberg SM, Rosand J (2008) Patient-specific decision-making for warfarin therapy in nonvalvular atrial fibrillation: how will screening with genetics and imaging help? Stroke 39(12):3308–3315

    Article  PubMed  Google Scholar 

  53. Loebstein R, Yonath H, Peleg D, Almog S, Rotenberg M, Lubetsky A, Roitelman J, Harats D, Halkin H, Ezra D (2001) Interindividual variability in sensitivity to warfarin—Nature or nurture? Clin Pharmacol Ther 70(2):159–164

    Article  PubMed  CAS  Google Scholar 

  54. Aithal GP, Day CP, Kesteven PJ, Daly AK (1999) Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 353(9154):717–719

    Article  PubMed  CAS  Google Scholar 

  55. Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, Blough DK, Thummel KE, Veenstra DL, Rettie AE (2005) Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 352(22):2285–2293

    Article  PubMed  CAS  Google Scholar 

  56. Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, Limdi NA, Page D, Roden DM, Wagner MJ, Caldwell MD, Johnson JA (2009) Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 360(8):753–764

    Article  PubMed  Google Scholar 

  57. Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW (2004) Identification of the gene for vitamin K epoxide reductase. Nature 427(6974):541–544

    Article  PubMed  CAS  Google Scholar 

  58. Wadelius M, Chen LY, Downes K, Ghori J, Hunt S, Eriksson N, Wallerman O, Melhus H, Wadelius C, Bentley D, Deloukas P (2005) Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J 5(4):262–270

    Article  PubMed  CAS  Google Scholar 

  59. Schwarz UI, Ritchie MD, Bradford Y, Li C, Dudek SM, Frye-Anderson A, Kim RB, Roden DM, Stein CM (2008) Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med 358(10):999–1008

    Article  PubMed  CAS  Google Scholar 

  60. Genes for Cerebral Hemorrhage on Anticoagulation (GOCHA) Collaborative Group (2009) Exploiting common genetic variation to make anticoagulation safer. Stroke 40(3 Suppl):S64–S66

    Google Scholar 

  61. Flaherty ML, Haverbusch M, Sekar P, Kissela B, Kleindorfer D, Moomaw CJ, Sauerbeck L, Schneider A, Broderick JP, Woo D (2006) Long-term mortality after intracerebral hemorrhage. Neurology 66(8):1182–1186

    Article  PubMed  CAS  Google Scholar 

  62. Foulkes MA, Wolf PA, Price TR, Mohr JP, Hier DB (1988) The Stroke Data Bank: design, methods, and baseline characteristics. Stroke 19(5):547–554

    Article  PubMed  CAS  Google Scholar 

  63. Andersen KK, Olsen TS, Dehlendorff C, Kammersgaard LP (2009) Hemorrhagic and ischemic strokes compared: stroke severity, mortality, and risk factors. Stroke 40(6):2068–2072

    Article  PubMed  Google Scholar 

  64. Leira R, Davalos A, Silva Y, Gil-Peralta A, Tejada J, Garcia M, Castillo J (2004) Early neurologic deterioration in intracerebral hemorrhage: predictors and associated factors. Neurology 63(3):461–467

    PubMed  CAS  Google Scholar 

  65. Cucchiara B, Messe S, Sansing L, Kasner S, Lyden P (2008) Hematoma growth in oral anticoagulant related intracerebral hemorrhage. Stroke 39(11):2993–2996

    Article  PubMed  CAS  Google Scholar 

  66. Franke CL, de Jonge J, van Swieten JC, Op de Coul AA, van Gijn J (1990) Intracerebral hematomas during anticoagulant treatment. Stroke 21(5):726–730

    Article  PubMed  CAS  Google Scholar 

  67. 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(8):880–884

    Article  PubMed  CAS  Google Scholar 

  68. Kawamata T, Takeshita M, Kubo O, Izawa M, Kagawa M, Takakura K (1995) Management of intracranial hemorrhage associated with anticoagulant therapy. Surg Neurol 44(5):438–442 (discussion 443)

    Article  PubMed  CAS  Google Scholar 

  69. Kase CS, Robinson RK, Stein RW, DeWitt LD, Hier DB, Harp DL, Williams JP, Caplan LR, Mohr JP (1985) Anticoagulant-related intracerebral hemorrhage. Neurology 35(7):943–948

    PubMed  CAS  Google Scholar 

  70. Flaherty ML, Haverbusch M, Sekar P, Kissela BM, Kleindorfer D, Moomaw CJ, Broderick JP, Woo D (2006) Location and outcome of anticoagulant-associated intracerebral hemorrhage. Neurocrit Care 5(3):197–201

    Article  PubMed  Google Scholar 

  71. Hart RG (2000) What causes intracerebral hemorrhage during warfarin therapy? Neurology 55(7):907–908

    PubMed  CAS  Google Scholar 

  72. Flaherty ML, Tao H, Haverbusch M, Sekar P, Kleindorfer D, Kissela B, Khatri P, Stettler B, Adeoye O, Moomaw CJ, Broderick JP, Woo D (2008) Warfarin use leads to larger intracerebral hematomas. Neurology 71(14):1084–1089

    Article  PubMed  CAS  Google Scholar 

  73. Flibotte JJ, Hagan N, O’Donnell J, Greenberg SM, Rosand J (2004) Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology 63(6):1059–1064

    PubMed  CAS  Google Scholar 

  74. Zubkov AY, Mandrekar JN, Claassen DO, Manno EM, Wijdicks EF, Rabinstein AA (2008) Predictors of outcome in warfarin-related intracerebral hemorrhage. Arch Neurol 65(10):1320–1325

    Article  PubMed  Google Scholar 

  75. Sjoblom L, Hardemark HG, Lindgren A, Norrving B, Fahlen M, Samuelsson M, Stigendal L, Stockelberg D, Taghavi A, Wallrup L, Wallvik J (2001) Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study. Stroke 32(11):2567–2574

    Article  PubMed  CAS  Google Scholar 

  76. Huttner HB, Schellinger PD, Hartmann M, Kohrmann 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(6):1465–1470

    Article  PubMed  CAS  Google Scholar 

  77. Oden A, Fahlen M (2002) Oral anticoagulation and risk of death: a medical record linkage study. BMJ (Clinical research ed) 325(7372):1073–1075

    Article  Google Scholar 

  78. Koo S, Kucher N, Nguyen PL, Fanikos J, Marks PW, Goldhaber SZ (2004) The effect of excessive anticoagulation on mortality and morbidity in hospitalized patients with anticoagulant-related major hemorrhage. Arch Intern Med 164(14):1557–1560

    Article  PubMed  Google Scholar 

  79. Aguilar MI, Hart RG, Kase CS, Freeman WD, Hoeben BJ, Garcia RC, Ansell JE, Mayer SA, Norrving B, Rosand J, Steiner T, Wijdicks EF, Yamaguchi T, Yasaka M (2007) Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. Mayo Clin Proc 82(1):82–92

    PubMed  CAS  Google Scholar 

  80. Fredriksson K, Norrving B, Stromblad LG (1992) Emergency reversal of anticoagulation after intracerebral hemorrhage. Stroke 23(7):972–977

    Article  PubMed  CAS  Google Scholar 

  81. Phan TG, Koh M, Wijdicks EF (2000) Safety of discontinuation of anticoagulation in patients with intracranial hemorrhage at high thromboembolic risk. Arch Neurol 57(12):1710–1713

    Article  PubMed  CAS  Google Scholar 

  82. Wijdicks EF, Schievink WI, Brown RD, Mullany CJ (1998) The dilemma of discontinuation of anticoagulation therapy for patients with intracranial hemorrhage and mechanical heart valves. Neurosurgery 42(4):769–773

    Article  PubMed  CAS  Google Scholar 

  83. Dentali F, Ageno W, Crowther M (2006) Treatment of coumarin-associated coagulopathy: a systematic review and proposed treatment algorithms. J Thromb Haemost 4(9):1853–1863

    Article  PubMed  CAS  Google Scholar 

  84. 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(1):151–155

    Article  PubMed  Google Scholar 

  85. Warkentin TE, Crowther MA (2002) Reversing anticoagulants both old and new. Can J Anaesth 49(6):S11–S25

    PubMed  Google Scholar 

  86. Leissinger CA, Blatt PM, Hoots WK, Ewenstein B (2008) Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol 83(2):137–143

    Article  PubMed  CAS  Google Scholar 

  87. Preston FE, Laidlaw ST, Sampson B, Kitchen S (2002) Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients. Br J Haematol 116(3):619–624

    Article  PubMed  CAS  Google Scholar 

  88. van Aart L, Eijkhout HW, Kamphuis JS, Dam M, Schattenkerk ME, Schouten TJ, Ploeger B, Strengers PF (2006) Individualized dosing regimen for prothrombin complex concentrate more effective than standard treatment in the reversal of oral anticoagulant therapy: an open, prospective randomized controlled trial. Thromb Res 118(3):313–320

    Article  PubMed  CAS  Google Scholar 

  89. 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(2):170–176

    Article  PubMed  CAS  Google Scholar 

  90. Freeman WD, Brott TG, Barrett KM, Castillo PR, Deen HG Jr, Czervionke LF, Meschia JF (2004) Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clin Proc 79(12):1495–1500

    Article  PubMed  CAS  Google Scholar 

  91. Lin J, Hanigan WC, Tarantino M, Wang J (2003) The use of recombinant activated factor VII to reverse warfarin-induced anticoagulation in patients with hemorrhages in the central nervous system: preliminary findings. J Neurosurg 98(4):737–740

    Article  PubMed  CAS  Google Scholar 

  92. Brody DL, Aiyagari V, Shackleford AM, Diringer MN (2005) Use of recombinant factor VIIa in patients with warfarin-associated intracranial hemorrhage. Neurocrit Care 2(3):263–267

    Article  PubMed  Google Scholar 

  93. Lee SB, Manno EM, Layton KF, Wijdicks EF (2006) Progression of warfarin-associated intracerebral hemorrhage after INR normalization with FFP. Neurology 67(7):1272–1274

    Article  PubMed  CAS  Google Scholar 

  94. 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(1):25–30

    Article  PubMed  Google Scholar 

  95. Illanes S, Zhou W, Schwarting S, Heiland S, Veltkamp R (2011) Comparative effectiveness of hemostatic therapy in experimental warfarin-associated intracerebral hemorrhage. Stroke 42(1):191–195

    Article  PubMed  CAS  Google Scholar 

  96. Hanley JP (2004) Warfarin reversal. J Clin Pathol 57(11):1132–1139

    Article  PubMed  CAS  Google Scholar 

  97. Bertram M, Bonsanto M, Hacke W, Schwab S (2000) Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation. J Neurol 247(3):209–214

    Article  PubMed  CAS  Google Scholar 

  98. Lieberman A, Hass WK, Pinto R, Isom WO, Kupersmith M, Bear G, Chase R (1978) Intracranial hemorrhage and infarction in anticoagulated patients with prosthetic heart valves. Stroke 9(1):18–24

    Article  PubMed  CAS  Google Scholar 

  99. Butler AC, Tait RC (1998) Management of oral anticoagulant-induced intracranial haemorrhage. Blood Rev 12(1):35–44

    Article  PubMed  CAS  Google Scholar 

  100. Leker RR, Abramsky O (1998) Early anticoagulation in patients with prosthetic heart valves and intracerebral hematoma. Neurology 50(5):1489–1491

    PubMed  CAS  Google Scholar 

  101. Nakagawa T, Kubota T, Handa Y, Kawano H, Sato K (1995) Intracranial hemorrhage due to long-term anticoagulant therapy in patients with prosthetic heart valves–four case reports. Neurol Med Chir 35(3):156–159

    Article  CAS  Google Scholar 

  102. Tinker JH, Tarhan S (1978) Discontinuing anticoagulant therapy in surgical patients with cardiac valve prostheses. Observations in 180 operations. JAMA 239(8):738–739

    Article  PubMed  CAS  Google Scholar 

  103. Chamorro A, Busse O, Obach V, Toni D, Sandercock P, Reverter JC, Cervera A, Torres F, Davalos A (2005) The rapid anticoagulation prevents ischemic damage study in acute stroke—final results from the writing committee. Cerebrovasc Dis 19(6):402–404. doi:10.1159/000086100

    Article  PubMed  CAS  Google Scholar 

  104. Pessin MS, Estol CJ, Lafranchise F, Caplan LR (1993) Safety of anticoagulation after hemorrhagic infarction. Neurology 43(7):1298–1303

    PubMed  CAS  Google Scholar 

  105. Chamorro A, Vila N, Saiz A, Alday M, Tolosa E (1995) Early anticoagulation after large cerebral embolic infarction: a safety study. Neurology 45(5):861–865

    PubMed  CAS  Google Scholar 

  106. Einhaupl KM, Villringer A, Meister W, Mehraein S, Garner C, Pellkofer M, Haberl RL, Pfister HW, Schmiedek P (1991) Heparin treatment in sinus venous thrombosis. Lancet 338(8767):597–600

    Article  PubMed  CAS  Google Scholar 

  107. Stam J, De Bruijn SF, DeVeber G (2002) Anticoagulation for cerebral sinus thrombosis. Cochrane database of systematic reviews (Online) 4:CD002005

    Google Scholar 

  108. Chamorro A (2001) Immediate anticoagulation in acute focal brain ischemia revisited: gathering the evidence. Stroke 32(2):577–578

    Article  PubMed  CAS  Google Scholar 

  109. Knudsen KA, Rosand J, Karluk D, Greenberg SM (2001) Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria. Neurology 56(4):537–539

    PubMed  CAS  Google Scholar 

  110. PROGRESS Collaborative Group (2001) Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 358(9287):1033–1041

    Google Scholar 

  111. O’Donnell HC, Rosand J, Knudsen KA, Furie KL, Segal AZ, Chiu RI, Ikeda D, Greenberg SM (2000) Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage. N Engl J Med 342(4):240–245

    Article  PubMed  Google Scholar 

  112. Eckman MH, Rosand J, Knudsen KA, Singer DE, Greenberg SM (2003) Can patients be anticoagulated after intracerebral hemorrhage? A decision analysis. Stroke 34(7):1710–1716

    Article  PubMed  Google Scholar 

  113. Stangier J (2008) Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 47(5):285–295

    Article  PubMed  CAS  Google Scholar 

  114. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361(12):1139–1151

    Article  PubMed  CAS  Google Scholar 

  115. Gage BF (2009) Can we rely on RE-LY? N Engl J Med 361(12):1200–1202

    Article  PubMed  CAS  Google Scholar 

  116. van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, Clemens A (2010) Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 103(6):1116–1127

    Article  PubMed  Google Scholar 

  117. Hylek EM (2010) Therapeutic potential of oral factor Xa inhibitors. N Engl J Med 363(26):2559–2561

    Article  PubMed  CAS  Google Scholar 

  118. Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Van Mieghem W, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O’Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S (2011) Apixaban in patients with atrial fibrillation. N Engl J Med 364(9):806–817

    Article  PubMed  CAS  Google Scholar 

  119. Berwaerts J, Dijkhuizen RS, Robb OJ, Webster J (2000) Prediction of functional outcome and in-hospital mortality after admission with oral anticoagulant–related intracerebral hemorrhage. Stroke 31:2558–2562

    Google Scholar 

  120. Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood EM; Warfarin Reversal Consensus Group (2004) Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust 181(9):492–497

    Google Scholar 

  121. Baglin TP, Keeling DM, Watson HG; British Committee for Standards in Haematology (2006) Guidelines on oral anticoagulation (warfarin): third edition—2005 update. Br J Haematol 132(3):277–285

    Google Scholar 

  122. Steiner T, Kaste M, Forsting M, Mendelow D, Kwiecinski H, Szikora I, Juvela S, Marchel A, Chapot R, Cognard C, Unterberg A, Hacke W (2006) Recommendations for the management of intracranial haemorrhage—part I: spontaneous intracerebral haemorrhage. The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI Executive Committee. Cerebrovasc Dis 22(4):294–316

    Google Scholar 

  123. Broderick J, Connolly S, Feldmann E, Hanley D, Kase C, Krieger D, Mayberg M, Morgenstern L, Ogilvy CS, Vespa P, Zuccarello M; American Heart Association; American Stroke Association Stroke Council; High Blood Pressure Research Council; Quality of Care and Outcomes in Research Interdisciplinary Working Group (2007) Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Stroke 38(6):2001–2023

    Google Scholar 

  124. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G; American College of Chest Physicians (2008) Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133(6 Suppl):160S–198S

    Google Scholar 

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Acknowledgments

Search strategy and selection criteria

References for this Review were identified through searches of PubMed by use of the search terms “warfarin” or “oral anticoagulation” and “intracranial hemorrhage”, from December 1986 to February 2011. Only papers in English were reviewed in detail. Further references were obtained from the bibliographies of the papers identified through our searches. The final reference list was generated on the basis of relevance to the topic of this Review.

Conflict of interest

Á Chamorro has given lectures and received consultancy fees from Servier, Sanofi-Synthelabo, Takeda, Bristol-Myers Squibb and Boehringer Ingelheim. Á Cervera has received consultancy fees from Boehringer Ingelheim. S Amaro declares to have no conflict of interests.

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  1. Comprehensive Stroke Center, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 170 Villarroel, 08036, Barcelona, Spain

    Álvaro Cervera, Sergio Amaro & Ángel Chamorro

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  1. Álvaro Cervera
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Correspondence to Ángel Chamorro.

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Cervera, Á., Amaro, S. & Chamorro, Á. Oral anticoagulant-associated intracerebral hemorrhage. J Neurol 259, 212–224 (2012). https://doi.org/10.1007/s00415-011-6153-3

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