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Prothrombin Complex Concentrates for Oral Anticoagulant Therapy-Related Intracranial Hemorrhage: A Review of the Literature

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Abstract

Warfarin-related intracranial hemorrhage carries a high mortality and poor neurological outcome. Rapid reversal of coagulopathy is a cornerstone of medical therapy to halt bleeding progression; however the optimal approach remains undefined. Prothrombin complex concentrates have promising features that may rapidly reverse coagulopathy, but remain relatively unstudied. We aim to review the literature regarding the use of prothrombin complex concentrates in patients with warfarin-related intracranial hemorrhage. A comprehensive review of the literature was conducted using PUBMED and Google Scholar databases to identify the use of PCC in patients with warfarin-related intracranial hemorrhage. The characteristics abstracted included the type of PCC, dosing, study design, type of intracranial hemorrhage, changes in the INR, and adverse effects. Prothrombin complex concentrates are heterogenous in regards to factor concentration. PCC consistently reversed the INR in patients with intracranial hemorrhage. There is some evidence that PCC may reverse the INR more rapidly compared to fresh frozen plasma. Serious adverse effects were uncommon and included mainly thromboembolism. PCC has features which make it a promising therapy for patients with warfarin-related intracranial hemorrhage, and deserves more rigorous study in prospective-randomized controlled trials.

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References

  1. Mohr JP, Thompson JL, Lazar RM, Levin B, Sacco RL, Furie KL, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med. 2001;345(20):1444–51.

    Article  CAS  PubMed  Google Scholar 

  2. Hart RG, Boop BS, Anderson DC. Oral anticoagulants and intracranial hemorrhage. Facts and hypotheses. Stroke. 1995;26(8):1471–7.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med. 1994;120(11):897–902.

    CAS  PubMed  Google Scholar 

  5. Francis CW, Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement G, et al. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med. 2003;349(18):1703–12.

    Article  CAS  PubMed  Google Scholar 

  6. Lavoie A, Ratte S, Clas D, Demers J, Moore L, Martin M, et al. Preinjury warfarin use among elderly patients with closed head injuries in a trauma center. J Trauma. 2004;56(4):802–7.

    Article  PubMed  Google Scholar 

  7. Mina AA, Bair HA, Howells GA, Bendick PJ. Complications of preinjury warfarin use in the trauma patient. J Trauma. 2003;54(5):842–7.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Franke CL, de Jonge J, van Swieten JC, Op de Coul AA, van Gijn J. Intracerebral hematomas during anticoagulant treatment. Stroke. 1990;21(5):726–30.

    CAS  PubMed  Google Scholar 

  10. Radberg JA, Olsson JE, Radberg CT. Prognostic parameters in spontaneous intracerebral hematomas with special reference to anticoagulant treatment. Stroke. 1991;22(5):571–6.

    CAS  PubMed  Google Scholar 

  11. Steiner T, Rosand J, Diringer M. Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions. Stroke. 2006;37(1):256–62.

    Article  CAS  PubMed  Google Scholar 

  12. Flibotte JJ, Hagan N, O’Donnell J, Greenberg SM, Rosand J. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology. 2004;63(6):1059–64.

    CAS  PubMed  Google Scholar 

  13. Rosand J, Eckman MH, Knudsen KA, Singer DE, Greenberg SM. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med. 2004;164(8):880–4.

    Article  CAS  PubMed  Google Scholar 

  14. Bershad EM, Farhadi S, Suri MF, Feen ES, Hernandez OH, Selman WR, et al. Coagulopathy and inhospital deaths in patients with acute subdural hematoma. J Neurosurg. 2008;109(4):664–9.

    Article  PubMed  Google Scholar 

  15. Makris M, Greaves M, Phillips WS, Kitchen S, Rosendaal FR, Preston EF. 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(3):477–80.

    CAS  PubMed  Google Scholar 

  16. Baglin T. Management of warfarin (coumarin) overdose. Blood Rev. 1998;12(2):91–8.

    Article  CAS  PubMed  Google Scholar 

  17. Taberner DA, Thomson JM, Poller L. Comparison of prothrombin complex concentrate and vitamin K1 in oral anticoagulant reversal. Br Med J. 1976;2(6027):83–5.

    Article  CAS  PubMed  Google Scholar 

  18. Leissinger CA, Blatt PM, Hoots WK, Ewenstein B. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol. 2008;83(2):137–43.

    Article  CAS  PubMed  Google Scholar 

  19. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 8th edition. Chest. 2008;133(6 Suppl):160S–98S.

    Article  CAS  PubMed  Google Scholar 

  20. Nee R, Doppenschmidt D, Donovan DJ, Andrews TC. Intravenous versus subcutaneous vitamin K1 in reversing excessive oral anticoagulation. Am J Cardiol. 1999, 83(2):286–288 (A286–287).

    Google Scholar 

  21. Lubetsky A, Yonath H, Olchovsky D, Loebstein R, Halkin H, Ezra D. Comparison of oral vs intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study. Arch Intern Med. 2003;163(20):2469–73.

    Article  CAS  PubMed  Google Scholar 

  22. Pereira SP, Rowbotham D, Fitt S, Shearer MJ, Wendon J, Williams R. Pharmacokinetics and efficacy of oral versus intravenous mixed-micellar phylloquinone (vitamin K1) in severe acute liver disease. J Hepatol. 2005;42(3):365–70.

    Article  CAS  PubMed  Google Scholar 

  23. Baglin TP, Keeling DM, Watson HG. Guidelines on oral anticoagulation (warfarin): 3rd edition—2005 update. Br J Haematol. 2006;132(3):277–85.

    Article  CAS  PubMed  Google Scholar 

  24. Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2008;358(20):2127–37.

    Article  CAS  PubMed  Google Scholar 

  25. Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2005;352(8):777–85.

    Article  CAS  PubMed  Google Scholar 

  26. rFVIIa in ICH in patients treated with anticoagulants or anti-platelets. www.clinicaltrials.gov.

  27. Appelboam R, Thomas EO. The headache over warfarin in British neurosurgical intensive care units: a national survey of current practice. Intensive Care Med. 2007;33(11):1946–53.

    Article  CAS  PubMed  Google Scholar 

  28. Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood EM. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust. 2004;181(9):492–7.

    PubMed  Google Scholar 

  29. Tullis JL, Melin M. Management of Christmas disease and Stuart-Prower deficiency with a prothrombin-complex concentrate (factors II, VII, IX, X). Bibl Haematol. 1968;29:1134–9.

    CAS  PubMed  Google Scholar 

  30. Sandler SG, Rath CE, Ruder A. Prothrombin complex concentrates in acquired hypoprothrombinemia. Ann Intern Med. 1973;79(4):485–91.

    CAS  PubMed  Google Scholar 

  31. Josic D, Hoffer L, Buchacher A, Schwinn H, Frenzel W, Biesert L, et al. Manufacturing of a prothrombin complex concentrate aiming at low thrombogenicity. Thromb Res. 2000;100(5):433–41.

    Article  CAS  PubMed  Google Scholar 

  32. Hellstern P. Production and composition of prothrombin complex concentrates: correlation between composition and therapeutic efficiency. Thromb Res. 1999;95(4 Suppl 1):S7–12.

    Article  CAS  PubMed  Google Scholar 

  33. McQuillan AM, Eikelboom JW, Hankey GJ, Baker R, Thom J, Staton J, et al. Protein Z in ischemic stroke and its etiologic subtypes. Stroke. 2003;34(10):2415–9.

    Article  PubMed  Google Scholar 

  34. Lubetsky A, Hoffman R, Zimlichman R, Eldor A, Zvi J, Kostenko V, et al. Efficacy and safety of a prothrombin complex concentrate (Octaplex) for rapid reversal of oral anticoagulation. Thromb Res. 2004;113(6):371–8.

    Article  CAS  PubMed  Google Scholar 

  35. Evans G, Luddington R, Baglin T. Beriplex P/N reverses severe warfarin-induced overanticoagulation immediately and completely in patients presenting with major bleeding. Br J Haematol. 2001;115(4):998–1001.

    Article  CAS  PubMed  Google Scholar 

  36. Ostermann H, Haertel S, Knaub S, Kalina U, Jung K, Pabinger I. Pharmacokinetics of Beriplex P/N prothrombin complex concentrate in healthy volunteers. Thromb Haemost. 2007;98(4):790–7.

    CAS  PubMed  Google Scholar 

  37. Boulis NM, Bobek MP, Schmaier A, Hoff JT. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery. 1999;45(5):1113–8. discussion 1118–1119.

    Article  CAS  PubMed  Google Scholar 

  38. Cartmill M, Dolan G, Byrne JL, Byrne PO. Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies. Br J Neurosurg. 2000;14(5):458–61.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  40. Lankiewicz MW, Hays J, Friedman KD, Tinkoff G, Blatt PM. Urgent reversal of warfarin with prothrombin complex concentrate. J Thromb Haemost. 2006;4(5):967–70.

    Article  CAS  PubMed  Google Scholar 

  41. Pabinger I, Brenner B, Kalina U, Knaub S, Nagy A, Ostermann H. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost. 2008;6(4):622–31.

    Article  CAS  PubMed  Google Scholar 

  42. Preston FE, Laidlaw ST, Sampson B, Kitchen S. Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients. Br J Haematol. 2002;116(3):619–24.

    Article  CAS  PubMed  Google Scholar 

  43. Vigue B, Ract C, Tremey B, Engrand N, Leblanc PE, Decaux A, et al. Ultra-rapid management of oral anticoagulant therapy-related surgical intracranial hemorrhage. Intensive Care Med. 2007;33(4):721–5.

    Article  CAS  PubMed  Google Scholar 

  44. Yasaka M, Oomura M, Ikeno K, Naritomi H, Minematsu K. Effect of prothrombin complex concentrate on INR and blood coagulation system in emergency patients treated with warfarin overdose. Ann Hematol. 2003;82(2):121–3.

    CAS  PubMed  Google Scholar 

  45. van Aart L, Eijkhout HW, Kamphuis JS, Dam M, Schattenkerk ME, Schouten TJ, et al. 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. 2006;118(3):313–20.

    Article  PubMed  Google Scholar 

  46. Bruce D, Nokes TJ. Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital. Crit Care. 2008;12(4):R105.

    Article  PubMed  Google Scholar 

  47. Yasaka M, Sakata T, Naritomi H, Minematsu K. Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation. Thromb Res. 2005;115(6):455–9.

    Article  CAS  PubMed  Google Scholar 

  48. Hellstern P, Halbmayer WM, Kohler M, Seitz R, Muller-Berghaus G. Prothrombin complex concentrates: indications, contraindications, and risks: a task force summary. Thromb Res. 1999;95(4 Suppl 1):S3–6.

    Article  CAS  PubMed  Google Scholar 

  49. Schulman S, Bijsterveld NR. Anticoagulants and their reversal. Transfus Med Rev. 2007;21(1):37–48.

    Article  PubMed  Google Scholar 

  50. Pindur G, Morsdorf S. The use of prothrombin complex concentrates in the treatment of hemorrhages induced by oral anticoagulation. Thromb Res. 1999;95(4 Suppl 1):S57–61.

    Article  CAS  PubMed  Google Scholar 

  51. Makris M, Watson HG. The management of coumarin-induced over-anticoagulation Annotation. Br J Haematol. 2001;114(2):271–80.

    Article  CAS  PubMed  Google Scholar 

  52. Crawford JH, Augustson BM. Prothrombinex use for the reversal of warfarin: is fresh frozen plasma needed? Med J Aust. 2006;184(7):365–6.

    PubMed  Google Scholar 

  53. Holland L, Warkentin TE, Refaai M, Crowther MA, Johnston MA, Sarode R. Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion. 2009;49(6):1171–7.

    Article  CAS  PubMed  Google Scholar 

  54. Blatt PM, Lundblad RL, Kingdon HS, McLean G, Roberts HR. Thrombogenic materials in prothrombin complex concentrates. Ann Intern Med. 1974;81(6):766–70.

    CAS  PubMed  Google Scholar 

  55. Schimpf K, Zeltsch C, Zeltsch P. Myocardial infarction complicating activated prothrombin complex concentrate substitution in patient with hemophilia A. Lancet. 1982;2(8306):1043.

    Article  CAS  PubMed  Google Scholar 

  56. Hampton KK, Preston FE, Lowe GD, Walker ID, Sampson B. Reduced coagulation activation following infusion of a highly purified factor IX concentrate compared to a prothrombin complex concentrate. Br J Haematol. 1993;84(2):279–84.

    Article  CAS  PubMed  Google Scholar 

  57. Aledort LM. Factor IX and thrombosis. Scand J Haematol Suppl. 1977;30:40–2.

    CAS  PubMed  Google Scholar 

  58. Kohler M, Heiden M, Harbauer G, Miyashita C, Morsdorf S, Braun B, et al. Comparison of different prothrombin complex concentrates–in vitro and in vivo studies. Thromb Res. 1990;60(1):63–70.

    Article  CAS  PubMed  Google Scholar 

  59. Hellstern P, Beeck H, Fellhauer A, Fischer A, Faller-Stockl B. Factor VII and activated-factor-VII content of prothrombin complex concentrates. The PCC Study Group. Vox Sang. 1997;73(3):155–61.

    Article  CAS  PubMed  Google Scholar 

  60. Kohler M. Thrombogenicity of prothrombin complex concentrates. Thromb Res. 1999;95(4 Suppl 1):S13–7.

    Article  CAS  PubMed  Google Scholar 

  61. White GC II, Roberts HR, Kingdon HS, Lundblad RL. Prothrombin complex concentrates: potentially thrombogenic materials and clues to the mechanism of thrombosis in vivo. Blood. 1977;49(2):159–70.

    CAS  PubMed  Google Scholar 

  62. Gray E, Tubbs J, Thomas S, Oates A, Boisclair M, Kemball-Cook G, et al. Measurement of activated factor IX in factor IX concentrates: correlation with in vivo thrombogenicity. Thromb Haemost. 1995;73(4):675–9.

    CAS  PubMed  Google Scholar 

  63. Giles AR, Nesheim ME, Hoogendoorn H, Tracy PB, Mann KG. The coagulant-active phospholipid content is a major determinant of in vivo thrombogenicity of prothrombin complex (Factor IX) concentrates in rabbits. Blood. 1982;59(2):401–7.

    CAS  PubMed  Google Scholar 

  64. Lusher JM. Prediction and management of adverse events associated with the use of factor IX complex concentrates. Semin Hematol. 1993;30(2 Suppl 1):36–40.

    CAS  PubMed  Google Scholar 

  65. Roddie PH, Stirling C, Mayne EE, Ludlam CA. Thrombosis and disseminated intravascular coagulation following treatment with the prothrombin complex concentrate, DEFIX. Thromb Haemost. 1999;81(4):667.

    CAS  PubMed  Google Scholar 

  66. Pindur G, Morsdorf S, Schenk JF, Krischek B, Heinrich W, Wenzel E. The overdosed patient and bleedings with oral anticoagulation. Semin Thromb Hemost. 1999;25(1):85–8.

    Article  CAS  PubMed  Google Scholar 

  67. Preiss DU, Eberspacher B, Abdullah D, Rosner I. Safety of vapour heated prothrombin complex concentrate (PCC) Prothromplex S-TIM 4. Thromb Res. 1991;63(6):651–9.

    Article  CAS  PubMed  Google Scholar 

  68. Morfini M, Longo G, Berntorp E, Cinotti S, Filimberti E, Messori A, et al. Pharmacokinetics, thrombogenicity and safety of a double-treated prothrombin complex concentrate. Thromb Res. 1993;71(3):175–84.

    Article  CAS  PubMed  Google Scholar 

  69. Horowitz B, Bonomo R, Prince AM, Chin SN, Brotman B, Shulman RW. Solvent/detergent-treated plasma: a virus-inactivated substitute for fresh frozen plasma. Blood. 1992;79(3):826–31.

    CAS  PubMed  Google Scholar 

  70. Seitz R, Dodt J. Virus safety of prothrombin complex concentrates and factor IX concentrates. Thromb Res. 1999;95(4 Suppl 1):S19–23.

    Article  CAS  PubMed  Google Scholar 

  71. Taketomi T, Szlam F, Levy JH, Tanaka KA. Warfarin reversal with prothrombin complex concentrate confers better antifibrinolytic activity compared with recombinant activated factor VII. Blood Coagul Fibrinolysis. 2008;19(1):106–8.

    Article  PubMed  Google Scholar 

  72. Dickneite G. Prothrombin complex concentrate versus recombinant factor VIIa for reversal of coumarin anticoagulation. Thromb Res. 2007;119(5):643–51.

    Article  CAS  PubMed  Google Scholar 

  73. Huttner HB, Schellinger PD, Hartmann M, Kohrmann M, Juettler E, Wikner J, 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(6):1465–70.

    Article  CAS  PubMed  Google Scholar 

  74. Kalina M, Tinkoff G, Gbadebo A, Veneri P, Fulda G. A protocol for the rapid normalization of INR in trauma patients with intracranial hemorrhage on prescribed warfarin therapy. Am Surg. 2008;74(9):858–61.

    PubMed  Google Scholar 

  75. Nitu IC, Perry DJ, Lee CA. Clinical experience with the use of clotting factor concentrates in oral anticoagulation reversal. Clin Lab Haematol. 1998;20(6):363–7.

    Article  CAS  PubMed  Google Scholar 

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  1. Baylor College of Medicine, Houston, TX, USA

    Eric M. Bershad & Jose I. Suarez

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Correspondence to Eric M. Bershad.

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Bershad, E.M., Suarez, J.I. Prothrombin Complex Concentrates for Oral Anticoagulant Therapy-Related Intracranial Hemorrhage: A Review of the Literature. Neurocrit Care 12, 403–413 (2010). https://doi.org/10.1007/s12028-009-9310-0

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