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Warfarin anticoagulation reversal: management of the asymptomatic and bleeding patient

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Abstract

The management of patients with supra-therapeutic INR in a common clinical problem. The risk of bleeding is influenced by the intensity, variability and duration of anticoagulation, patient age, presence of co-morbidities and concomitant drug therapy. For the asymptomatic patient, warfarin discontinuation is all that is usually required but for individuals at high risk of bleeding and those with INR > 10, oral vitamin K administration is recommended. In the presence of major bleeding, treatment with intravenous vitamin K and prothrombin complex concentrate is the most effective therapy.

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References

  1. Schulman S, Kearon C (2005) Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 3(4):692–694

    Article  CAS  PubMed  Google Scholar 

  2. Palareti G, Leali N, Coccheri S et al (1996) Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet 348(9025):423–428

    Article  CAS  PubMed  Google Scholar 

  3. Go AS, Hylek EM, Chang Y et al (2003) Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice? JAMA 290(20):2685–2692

    Article  CAS  PubMed  Google Scholar 

  4. Poli D, Antonucci E, Grifoni E et al (2009) Stroke risk in atrial fibrillation patients on warfarin. Predictive ability of risk stratification schemes for primary and secondary prevention. Thromb Haemost 101(2):367–372

    CAS  PubMed  Google Scholar 

  5. Ost D, Tepper J, Mihara H et al (2005) Duration of anticoagulation following venous thromboembolism: a meta-analysis. JAMA 294(6):706–715

    Article  CAS  PubMed  Google Scholar 

  6. Poller L, Keown M, Ibrahim S et al (2009) A multicentre randomised assessment of the DAWN AC computer-assisted oral anticoagulant dosage program. Thromb Haemost 101(3):487–494

    CAS  PubMed  Google Scholar 

  7. Kearon C, Ginsberg JS, Kovacs MJ et al (2003) Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 349(7):631–639

    Article  CAS  PubMed  Google Scholar 

  8. Cannegieter SC, Rosendaal FR, Wintzen AR et al (1995) Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 333(1):11–17

    Article  CAS  PubMed  Google Scholar 

  9. Crowther MA, Ginsberg JS, Julian J et al (2003) A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 349(12):1133–1138

    Article  CAS  PubMed  Google Scholar 

  10. Torn M, van der Meer FJ, Rosendaal FR (2004) Lowering the intensity of oral anticoagulant therapy: effects on the risk of hemorrhage and thromboembolism. Arch Intern Med 164(6):668–673

    Article  CAS  PubMed  Google Scholar 

  11. van Leeuwen Y, Rosendaal FR, Cannegieter SC (2008) Prediction of hemorrhagic and thrombotic events in patients with mechanical heart valve prostheses treated with oral anticoagulants. J Thromb Haemost 6(3):451–456

    Article  PubMed  Google Scholar 

  12. Hutten BA, Lensing AW, Kraaijenhagen RA et al (1999) Safety of treatment with oral anticoagulants in the elderly. A systematic review. Drugs Aging 14(4):303–312

    Article  CAS  PubMed  Google Scholar 

  13. Kagansky N, Knobler H, Rimon E et al (2004) Safety of anticoagulation therapy in well-informed older patients. Arch Intern Med 164(18):2044–2050

    Article  PubMed  Google Scholar 

  14. Hart RG, Benavente O, Pearce LA (1999) Increased risk of intracranial hemorrhage when aspirin is combined with warfarin: a meta-analysis and hypothesis. Cerebrovasc Dis 9(4):215–217

    Article  CAS  PubMed  Google Scholar 

  15. Glasheen JJ, Fugit RV, Prochazka AV (2005) The risk of overanticoagulation with antibiotic use in outpatients on stable warfarin regimens. J Gen Intern Med 20(7):653–656

    Article  PubMed  Google Scholar 

  16. Schulman S, Beyth RJ, Kearon C et al (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  CAS  PubMed  Google Scholar 

  17. White RH, Beyth RJ, Zhou H et al (1999) Major bleeding after hospitalization for deep-venous thrombosis. Am J Med 107(5):414–424

    Article  CAS  PubMed  Google Scholar 

  18. Fihn SD, Callahan CM, Martin DC et al (1996) The risk for and severity of bleeding complications in elderly patients treated with warfarin. The National Consortium of Anticoagulation Clinics. Ann Intern Med 124(11):970–979

    CAS  PubMed  Google Scholar 

  19. Kangelaris KN, Bent S, Nussbaum RL et al (2009) Genetic testing before anticoagulation? A systematic review of pharmacogenetic dosing of warfarin. J Gen Intern Med 24(5):656–664

    Article  PubMed  Google Scholar 

  20. Landefeld CS, Goldman L (1989) Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am J Med 87(2):144–152

    Article  CAS  PubMed  Google Scholar 

  21. 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  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  23. Gage BF, Yan Y, Milligan PE et al (2006) Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J 151(3):713–719

    Article  PubMed  Google Scholar 

  24. Hylek EM, Chang Y, Skates SJ et al (2000) Prospective study of the outcomes of ambulatory patients with excessive warfarin anticoagulation. Arch Intern Med 160(11):1612–1617

    Article  CAS  PubMed  Google Scholar 

  25. Ageno W, Crowther M, Steidl L et al (2002) Low dose oral vitamin K to reverse acenocoumarol-induced coagulopathy: a randomized controlled trial. Thromb Haemost 88(1):48–51

    CAS  PubMed  Google Scholar 

  26. Fondevila CG, Grosso SH, Santarelli MT et al (2001) Reversal of excessive oral anticoagulation with a low oral dose of vitamin K1 compared with acenocoumarine discontinuation. A prospective, randomized, open study. Blood Coagul Fibrinolysis 12(1):9–16

    Article  CAS  PubMed  Google Scholar 

  27. Poli D, Antonucci E, Lombardi A et al (2003) Safety and effectiveness of low dose oral vitamin K1 administration in asymptomatic out-patients on warfarin or acenocoumarol with excessive anticoagulation. Haematologica 88(2):237–238

    CAS  PubMed  Google Scholar 

  28. Glover JJ, Morrill GB (1995) Conservative treatment of overanticoagulated patients. Chest 108(4):987–990

    Article  CAS  PubMed  Google Scholar 

  29. Lousberg TR, Witt DM, Beall DG et al (1998) Evaluation of excessive anticoagulation in a group model health maintenance organization. Arch Intern Med 158(5):528–534

    Article  CAS  PubMed  Google Scholar 

  30. Garcia DA, Regan S, Crowther M et al (2006) The risk of hemorrhage among patients with warfarin-associated coagulopathy. J Am Coll Cardiol 47(4):804–808

    Article  CAS  PubMed  Google Scholar 

  31. Hylek EM, Regan S, Go AS et al (2001) Clinical predictors of prolonged delay in return of the international normalized ratio to within the therapeutic range after excessive anticoagulation with warfarin. Ann Intern Med 135(6):393–400

    CAS  PubMed  Google Scholar 

  32. Crowther MA, Julian J, McCarty D et al (2000) Treatment of warfarin-associated coagulopathy with oral vitamin K: a randomised controlled trial. Lancet 356(9241):1551–1553

    Article  CAS  PubMed  Google Scholar 

  33. Pengo V, Banzato A, Garelli E et al (1993) Reversal of excessive effect of regular anticoagulation: low oral dose of phytonadione (vitamin K1) compared with warfarin discontinuation. Blood Coagul Fibrinolysis 4(5):739–741

    CAS  PubMed  Google Scholar 

  34. Ageno W, Garcia D, Silingardi M et al (2005) A randomized trial comparing 1 mg of oral vitamin K with no treatment in the management of warfarin-associated coagulopathy in patients with mechanical heart valves. J Am Coll Cardiol 46(4):732–733

    Article  CAS  PubMed  Google Scholar 

  35. Patel RJ, Witt DM, Saseen JJ et al (2000) Randomized, placebo-controlled trial of oral phytonadione for excessive anticoagulation. Pharmacotherapy 20(10):1159–1166

    Article  CAS  PubMed  Google Scholar 

  36. Fetrow CW, Overlock T, Leff L (1997) Antagonism of warfarin-induced hypoprothrombinemia with use of low-dose subcutaneous vitamin K1. J Clin Pharmacol 37(8):751–757

    CAS  PubMed  Google Scholar 

  37. Crowther MA, Donovan D, Harrison L et al (1998) Low-dose oral vitamin K reliably reverses over-anticoagulation due to warfarin. Thromb Haemost 79(6):1116–1118

    CAS  PubMed  Google Scholar 

  38. Duong TM, Plowman BK, Morreale AP et al (1998) Retrospective and prospective analyses of the treatment of overanticoagulated patients. Pharmacotherapy 18(6):1264–1270

    CAS  PubMed  Google Scholar 

  39. Pendry K, Bhavnani M, Shwe K (2001) The use of oral vitamin K for reversal of over-warfarinization. Br J Haematol 113(3):839–840

    Article  CAS  PubMed  Google Scholar 

  40. Watson HG, Baglin TP, Makris M (2002) The use of oral vitamin K for reversal of over-warfarinization. Br J Haematol 116(1):237

    Article  PubMed  Google Scholar 

  41. Watson HG, Baglin T, Laidlaw SL et al (2001) A comparison of the efficacy and rate of response to oral and intravenous vitamin K in reversal of over-anticoagulation with warfarin. Br J Haematol 115(1):145–149

    Article  CAS  PubMed  Google Scholar 

  42. Lubetsky AM, Yonath HM, Olchovsky DM et al (2003) Comparison of oral vs intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study. Arch Intern Med 163(20):2469–2473

    Article  CAS  PubMed  Google Scholar 

  43. Hung A, Singh S, Tait RC (2000) A prospective randomized study to determine the optimal dose of intravenous vitamin K in reversal of over-warfarinization. Br J Haematol 109(3):537–539

    Article  CAS  PubMed  Google Scholar 

  44. Brophy MT, Fiore LD, Deykin D (1997) Low-dose vitamin K therapy in excessively anticoagulated patients: a dose-finding study. J Thromb Thrombolysis 4(2):289–292

    Article  CAS  PubMed  Google Scholar 

  45. Shetty HG, Backhouse G, Bentley DP et al (1992) Effective reversal of warfarin-induced excessive anticoagulation with low dose vitamin K1. Thromb Haemost 67(1):13–15

    CAS  PubMed  Google Scholar 

  46. Crowther MA, Douketis JD, Schnurr T et al (2002) Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy: a randomized, controlled trial. Ann Intern Med 137(4):251–254

    CAS  PubMed  Google Scholar 

  47. Nee R, Doppenschmidt D, Donovan DJ et al (1999) Intravenous versus subcutaneous vitamin K1 in reversing excessive oral anticoagulation. Am J Cardiol 83(2):286–287

    Article  CAS  PubMed  Google Scholar 

  48. Raj G, Kumar R, McKinney WP (1999) Time course of reversal of anticoagulant effect of warfarin by intravenous and subcutaneous phytonadione. Arch Intern Med 159(22):2721–2724

    Article  CAS  PubMed  Google Scholar 

  49. Byrd DC, Stephens MA, Hamann GL et al (1999) Subcutaneous phytonadione for reversal of warfarin-induced elevation of the International Normalized Ratio. Am J Health Syst Pharm 56(22):2312–2315

    CAS  PubMed  Google Scholar 

  50. DeZee KJ, Shimeall WT, Douglas KM et al (2006) Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis. Arch Intern Med 166(4):391–397

    Article  CAS  PubMed  Google Scholar 

  51. Riegert-Johnson DL, Volcheck GW (2002) The incidence of anaphylaxis following intravenous phytonadione (vitamin K1): a 5-year retrospective review. Ann Allergy Asthma Immunol 89(4):400–406

    Article  CAS  PubMed  Google Scholar 

  52. Dentali F, Crowther MA (2008) Management of excessive anticoagulant effect due to vitamin K antagonists. Hematology Am Soc Hematol Educ Program 2008:266–270

    Google Scholar 

  53. Crowther MA, Ageno W, Garcia D et al (2009) Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin: a randomized trial. Ann Intern Med 150(5):293–300

    PubMed  Google Scholar 

  54. Lubetsky A, Shasha Y, Olchovsky D et al (2003) Impact of pre-treatment INR level on the effect of intravenous low dose vitamin K in patients with excessive anticoagulation. Thromb Haemost 90(1):71–76

    CAS  PubMed  Google Scholar 

  55. Ozgonenel B, O’Malley B, Krishen P et al (2007) Warfarin reversal emerging as the major indication for fresh frozen plasma use at a tertiary care hospital. Am J Hematol 82(12):1091–1094

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  57. Vigue B, Ract C, Tremey B et al (2007) Ultra-rapid management of oral anticoagulant therapy-related surgical intracranial hemorrhage. Intensive Care Med 33(4):721–725

    Article  CAS  PubMed  Google Scholar 

  58. Makris M, Greaves M, Phillips WS et al (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(3):477–480

    CAS  PubMed  Google Scholar 

  59. Boulis NM, Bobek MP, Schmaier A et al (1999) Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery 45(5):1113–1118

    Article  CAS  PubMed  Google Scholar 

  60. Cartmill M, Dolan G, Byrne JL et al (2000) Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies. Br J Neurosurg 14(5):458–461

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  63. Pabinger I, Brenner B, Kalina U et al (2008) Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost 6(4):622–631

    Article  CAS  PubMed  Google Scholar 

  64. Holland L, Warkentin TE, Refaai M et al (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 

  65. Rosovsky RP, Crowther MA (2008) What is the evidence for the off-label use of recombinant factor VIIa (rFVIIa) in the acute reversal of warfarin? Hematology Am Soc Hematol Educ Program 2008:36–38

    Google Scholar 

  66. Hsia CC, Chin-Yee IH, McAlister VC (2008) Use of recombinant activated factor VII in patients without hemophilia: a meta-analysis of randomized control trials. Ann Surg 248(1):61–68

    Article  PubMed  Google Scholar 

  67. Ansell J, Hirsh J, Hylek E et al (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

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Sheffield Haemophilia and Thrombosis Centre, University of Sheffield, Sheffield, UK

    Michael Makris, Joost J. van Veen & Rhona Maclean

  2. Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF, UK

    Michael Makris

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  1. Michael Makris
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Correspondence to Michael Makris.

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Makris, M., van Veen, J.J. & Maclean, R. Warfarin anticoagulation reversal: management of the asymptomatic and bleeding patient. J Thromb Thrombolysis 29, 171–181 (2010). https://doi.org/10.1007/s11239-009-0412-5

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