Emergency Reversal of Anticoagulants


Anticoagulant agents are often used for the prevention and treatment of a wide range of cardiovascular diseases. The most frequently used anticoagulants are heparin or its derivatives, vitamin K antagonists (such as warfarin or coumadin) and antiplatelet agents, including aspirin and thienopyridine derivatives, such as clopidogrel. A myriad of clinical studies have demonstrated that these agents (alone or in combination) can prevent or treat acute or chronic thromboembolic complications, such as in patients with atrial fibrillation or prosthetic heart valves, after myocardial infarction or ischemic stroke, and in patients with venous thrombosis or pulmonary embolism [1]. The most important complication of treatment with anticoagulants is hemorrhage, which may be serious, may cause long-term debilitating disease, or may even be life-threatening [2]. In well-controlled patients in clinical trials, treatment with vitamin K antagonists increases the risk of major bleeding by 0.5 %/year and the risk of intracranial hemorrhage by about 0.2 %/year [3]. In a very large series of 34146 patients with acute ischemic coronary syndromes, anticoagulant-associated bleeding was associated with a 5-fold increased risk of death during the first 30 days and a 1.5-fold higher mortality between 30 days and 6 months [4]. Major bleeding was an independent predictor of mortality across all subgroups that were analyzed. In some clinical situations, the incidence of serious bleeding complications may annihilate or even overwhelm the efficacy of antithrombotic agents, as has been shown in the secondary prevention of patients with ischemic stroke by vitamin K antagonists [5].


Disseminate Intravascular Coagulation Anticoagulant Effect Dabigatran Etexilate Recombinant Factor VIIa Protamine Sulfate 
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  1. 1.
    Hirsh J, Guyatt G, Albers GW, Harrington R, Schunemann HJ (2008) Antithrombotic and thrombolytic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133:110S–112SCrossRefPubMedGoogle Scholar
  2. 2.
    Mannucci PM, Levi M (2007) Prevention and treatment of major blood loss. N Engl J Med 356: 2301–2311CrossRefPubMedGoogle Scholar
  3. 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 (suppl 6):257S–298SCrossRefPubMedGoogle Scholar
  4. 4.
    Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S (2006) Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 114: 774–782CrossRefPubMedGoogle Scholar
  5. 5.
    Algra A (2007) Medium intensity oral anticoagulants versus aspirin after cerebral ischaemia of arterial origin (ESPRIT): a randomised controlled trial. Lancet Neurol. 6: 115–124CrossRefPubMedGoogle Scholar
  6. 6.
    Levi M (2008) Emergency reversal of antithrombotic treatment. Intern Emerg Med (in press)Google Scholar
  7. 7.
    Hirsh J, Bauer KA, Donati MB, Gould M, Samama MM, Weitz JI (2008) Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133 (suppl 6):141S–159SCrossRefPubMedGoogle Scholar
  8. 8.
    Lindblad B, Borgstrom A, Wakefield TW, Whitehouse WM Jr, Stanley JC (1987). Protamine reversal of anticoagulation achieved with a low molecular weight heparin. The effects on eicosanoids, clotting and complement factors. Thromb Res 48: 31–40CrossRefPubMedGoogle Scholar
  9. 9.
    Van Ryn-McKenna J, Cai L, Ofosu FA, Hirsh J, Buchanan MR (1990) Neutralization of enoxaparine-induced bleeding by protamine sulfate. Thromb Haemost 63: 271–274PubMedGoogle Scholar
  10. 10.
    Caplan SN, Berkman EM (1976) Protamine sulfate and fish allergy. N Engl J Med 295:172PubMedGoogle Scholar
  11. 11.
    Dellagrammaticas D, Lewis SC, Gough MJ (2008) Is heparin reversal with protamine after carotid endarterectomy dangerous? Eur J Vasc Endovasc Surg 36: 41–44CrossRefPubMedGoogle Scholar
  12. 12.
    Bijsterveld NR, Moons AH, Boekholdt SM, et al (2002). Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 106: 2550–2554CrossRefPubMedGoogle Scholar
  13. 13.
    Bijsterveld NR, Vink R, van Aken BE, et al (2004). Recombinant factor VIIa reverses the anticoagulant effect of the long-acting pentasaccharide idraparinux in healthy volunteers. Br J Haematol 124: 653–658CrossRefPubMedGoogle Scholar
  14. 14.
    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 (suppl 6):160S–198SCrossRefPubMedGoogle Scholar
  15. 15.
    Dentali F, Ageno W, Crowther M (2006) Treatment of coumarin-associated coagulopathy: a systematic review and proposed treatment algorithms. J Thromb Haemost 4: 1853–1863CrossRefPubMedGoogle Scholar
  16. 16.
    Baglin T (1998) Management of warfarin (coumarin) overdose. Blood Rev 12: 91–98CrossRefPubMedGoogle Scholar
  17. 17.
    Whitling AM, Bussey HI, Lyons RM (1998) Comparing different routes and doses of phytonadione for reversing excessive anticoagulation. Arch Intern Med 158: 2136–2140CrossRefPubMedGoogle Scholar
  18. 18.
    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 warfarinassociated coagulopathy. A randomized, controlled trial. Ann Intern Med 137: 251–254PubMedGoogle Scholar
  19. 19.
    Lubetsky A, Yonath H, Olchovsky D, Loebstein R, Halkin H, Ezra D (2003). Comparison of oral vs intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study. Arch Intern Med 163: 2469–2473CrossRefPubMedGoogle Scholar
  20. 20.
    van Geest-Daalderop JH, Hutten BA, Pequeriaux NC, de Vries-Goldschmeding HJ, Rakers E, Levi M (2007) Invasive procedures in the outpatient setting: Managing the short-acting acenocoumarol and the long-acting phenprocoumon. Thromb Haemost 98: 747–755PubMedGoogle Scholar
  21. 21.
    Aguilar MI, Hart RG, Kase CS, et al (2007) Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. Mayo Clin Proc 82: 82–92CrossRefPubMedGoogle Scholar
  22. 22.
    van Aart L, Eijkhout HW, Kamphuis JS, et al (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: 313–320CrossRefPubMedGoogle Scholar
  23. 23.
    Lankiewicz MW, Hays J, Friedman KD, Tinkoff G, Blatt PM (2006) Urgent reversal of warfarin with prothrombin complex concentrate. J Thromb Haemost 4: 967–970CrossRefPubMedGoogle Scholar
  24. 24.
    Pabinger I, Brenner B, Kalina U, Knaub S, Nagy A, Ostermann H (2008) Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost 6: 622–631CrossRefPubMedGoogle Scholar
  25. 25.
    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: 137–143CrossRefPubMedGoogle Scholar
  26. 26.
    Levi M (2007) Disseminated intravascular coagulation. Crit Care Med 35: 2191–2195CrossRefPubMedGoogle Scholar
  27. 27.
    Erhardtsen E, Nony P, Dechavanne M, Ffrench P, Boissel JP, Hedner U (1998) The effect of recombinant factor VIIa (NovoSeven) in healthy volunteers receiving acenocoumarol to an International Normalized Ratio above 2.0. Blood Coagul Fibrinolysis 9: 741–748CrossRefPubMedGoogle Scholar
  28. 28.
    Dager WE, King JH, Regalia RC, et al (2006) Reversal of elevated international normalized ratios and bleeding with low-dose recombinant activated factor VII in patients receiving warfarin. Pharmacotherapy 26: 1091–1098CrossRefPubMedGoogle Scholar
  29. 29.
    Deveras RA, Kessler CM (2002) Reversal of warfarin-induced excessive anticoagulation with recombinant human factor VIIa concentrate. Ann Intern Med 137: 884–888PubMedGoogle Scholar
  30. 30.
    Sorensen B, Johansen P, Nielsen GL, Sorensen JC, Ingerslev J (2003) ersal 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 14: 469–477CrossRefPubMedGoogle Scholar
  31. 31.
    Levi M (2005) New antithrombotics in the treatment of thromboembolic disease. Eur J Intern Med 16: 230–237CrossRefPubMedGoogle Scholar
  32. 32.
    Weitz JI, Buller HR (2002) Direct thrombin inhibitors in acute coronary syndromes: present and future. Circulation 105: 1004–1011CrossRefPubMedGoogle Scholar
  33. 33.
    Wahlander K, Lapidus L, Olsson CG, et al (2002) Pharmacokinetics, pharmacodynamics and clinical effects of the oral direct thrombin inhibitor ximelagatran in acute treatment of patients with pulmonary embolism and deep vein thrombosis. Thromb Res 107: 93–99CrossRefPubMedGoogle Scholar
  34. 34.
    Eriksson BI, Dahl OE, Rosencher N, et al (2007) Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, doubleblind, non-inferiority trial. Lancet 370: 949–956CrossRefPubMedGoogle Scholar
  35. 35.
    Wolzt M, Levi M, Sarich TC, et al (2004) Effect of recombinant factor VIIa on melagatraninduced inhibition of thrombin generation and platelet activation in healthy volunteers. Thromb Haemost 91: 1090–1096PubMedGoogle Scholar
  36. 36.
    Agnelli G, Gallus A, Goldhaber SZ, et al (2007) Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) study. Circulation 116: 180–187CrossRefPubMedGoogle Scholar
  37. 37.
    Shantsila E, Lip GY (2008) Apixaban, an oral, direct inhibitor of activated Factor Xa. Curr Opin Investig Drugs 9: 1020–1033PubMedGoogle Scholar
  38. 38.
    Stassens P, Bergum PW, Gansemans Y, et al (1996) Anticoagulant repertoire of the hookworm Ancylostoma caninum. Proc Natl Acad Sci USA 93: 2149–2154CrossRefPubMedGoogle Scholar
  39. 39.
    Moons AH, Peters RJ, Bijsterveld NR, et al (2003) Recombinant nematode anticoagulant protein c2, an inhibitor of the tissue factor/factor VIIa complex, in patients undergoing elective coronary angioplasty. J Am Coll Cardiol 41: 2147–2153CrossRefPubMedGoogle Scholar
  40. 40.
    Allen GA, Hoffman M, Roberts HR, Monroe DM III (2002) Recombinant activated factor VII: its mechanism of action and role in the control of hemorrhage. Can J Anaesth 49:S7–14Google Scholar
  41. 41.
    Friederich PW, Levi M, Bauer KA, et al (2001) Ability of recombinant factor VIIa to generate thrombin during inhibition of tissue factor in human subjects. Circulation 103: 2555–2559PubMedGoogle Scholar
  42. 42.
    Patrono C, Baigent C, Hirsh J, Roth G (2008). Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133 (Suppl 6): 199S–233SCrossRefPubMedGoogle Scholar
  43. 43.
    Merritt JC, Bhatt DL (2004) The efficacy and safety of perioperative antiplatelet therapy. J Thromb Thrombolysis 17: 21–27CrossRefPubMedGoogle Scholar
  44. 44.
    Ferrari E, Benhamou M, Cerboni P, Marcel B (2005) Coronary syndromes following aspirin withdrawal: a special risk for late stent thrombosis. J Am Coll Cardiol 45: 456–459CrossRefPubMedGoogle Scholar
  45. 45.
    Richardson DW, Robinson AG (1985) Desmopressin. Ann Intern Med 103: 228–239PubMedGoogle Scholar
  46. 46.
    Reiter RA, Mayr F, Blazicek H, et al (2003) Desmopressin antagonizes the in vitro platelet dysfunction induced by GPIIb/IIIa inhibitors and aspirin. Blood 102: 4594–4599CrossRefPubMedGoogle Scholar
  47. 47.
    CAPRIE Steering Committee (1996) A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 348: 1329–1339CrossRefGoogle Scholar
  48. 48.
    Vilahur G, Choi BG, Zafar MU, et al (2007) Normalization of platelet reactivity in clopidogrel-treated subjects. J Thromb Haemost 5: 82–90CrossRefPubMedGoogle Scholar
  49. 49.
    Leithauser B, Zielske D, Seyfert UT, Jung F (2008) Effects of desmopressin on platelet membrane glycoproteins and platelet aggregation in volunteers on clopidogrel. Clin Hemorheol Microcirc 39: 293–302PubMedGoogle Scholar
  50. 50.
    Reiter R, Jilma-Stohlawetz P, Horvath M, Jilma B (2005) Additive effects between platelet concentrates and desmopressin in antagonizing the platelet glycoprotein IIb/IIIa inhibitor eptifibatide. Transfusion 45: 420–426CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • M. Levi
    • 1
  1. 1.Department of Medicine (F-4) Academic Medical CenterUniversity of AmsterdamAmsterdamNetherlands

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