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DOI: 10.1055/s-0032-1326788
Approaches to Diagnosing and Managing Anticoagulant-Related Bleeding
Publication History
Publication Date:
03 October 2012 (online)
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Abstract
Anticoagulant therapy reduces deaths and disability in patients with or at risk of both arterial and venous thromboembolism. Highly effective antithrombotic therapies now exist that reduce the risk of both arterial thrombosis and venous thrombosis. Anticoagulant strategies include platelet inhibition, using a variety of potent platelet inhibitors, and antithrombotic therapy, designed to interfere with thrombosis by blocking activation of the coagulation cascade. All anticoagulants increase the risk of bleeding. Older antithrombotic agents have, in most cases, effective antidotes and well-developed (although perhaps not very evidence-based) treatment strategies. Newer anticoagulants, and most antiplatelet drugs, do not have effective antidotes or well-tested reversal strategies. This narrative review will provide advice on the diagnosis and management of anticoagulant bleeding with a particular focus on the antithrombotic drugs, including warfarin, heparin, and the novel agents.
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References
- 1 Guyatt G, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2) 7S-47S
- 2 Fuster V, Rydén LE, Cannom DS , et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation) developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol 2006; 48: e149-e246
- 3 Bauersachs RM. Use of anticoagulants in elderly patients. Thromb Res 2012; 129 (2) 107-115
- 4 Engbers MJ, van Hylckama Vlieg A, Rosendaal FR. Venous thrombosis in the elderly: incidence, risk factors and risk groups. J Thromb Haemost 2010; 8 (10) 2105-2112
- 5 Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrøm J. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost 2007; 5 (4) 692-699
- 6 Wardrop D, Keeling D. The story of the discovery of heparin and warfarin. Br J Haematol 2008; 141 (6) 757-763
- 7 Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed.: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2 Suppl) e44S-e88S
- 8 Deitcher SR. Interpretation of the international normalised ratio in patients with liver disease. Lancet 2002; 359 (9300) 47-48
- 9 Dzik S. Reversal of drug-induced anticoagulation: old solutions and new problems. Transfusion 2012; 52 (Suppl. 01) 45S-55S
- 10 Palareti G, Leali N, Coccheri S , et al; Italian Study on Complications of Oral Anticoagulant Therapy. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet 1996; 348 (9025) 423-428
- 11 Abdelhafiz AH, Wheeldon NM. Results of an open-label, prospective study of anticoagulant therapy for atrial fibrillation in an outpatient anticoagulation clinic. Clin Ther 2004; 26 (9) 1470-1478
- 12 Jackson SL, Peterson GM, Vial JH, Daud R, Ang SY. Outcomes in the management of atrial fibrillation: clinical trial results can apply in practice. Intern Med J 2001; 31 (6) 329-336
- 13 Hutten BA, Lensing AW, Kraaijenhagen RA, Prins MH. Safety of treatment with oral anticoagulants in the elderly. A systematic review. Drugs Aging 1999; 14 (4) 303-312
- 14 Levi M, Eerenberg E, Kamphuisen PW. Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents. J Thromb Haemost 2011; 9 (9) 1705-1712
- 15 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) 2469-2473
- 16 Dentali F, Ageno W. Management of coumarin-associated coagulopathy in the non-bleeding patient: a systematic review. Haematologica 2004; 89 (7) 857-862
- 17 Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G ; American College of Chest Physicians. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest 2008; 133: 160S-198S
- 18 Crowther MA, Ageno W, Garcia D , et al. Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin: a randomized trial. Ann Intern Med 2009; 150 (5) 293-300
- 19 Pabinger -Fasching I. Warfarin-reversal: results of a phase III study with pasteurised, nanofiltrated prothrombin complex concentrate. Thromb Res 2008; 122 (Suppl. 02) S19-S22
- 20 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) 1171-1177
- 21 Bauer KA. Reversal of antithrombotic agents. Am J Hematol 2012; 87 (Suppl. 01) S119-S126
- 22 Kaatz S, Kouides PA, Garcia DA , et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol 2012; 87 (Suppl. 01) S141-S145
- 23 Garcia DA, Baglin TP, Weitz JI, Samama MM ; American College of Chest Physicians. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2 Suppl) e24S-43S
- 24 Nieuwenhuis HK, Albada J, Banga JD, Sixma JJ. Identification of risk factors for bleeding during treatment of acute venous thromboembolism with heparin or low molecular weight heparin. Blood 1991; 78 (9) 2337-2343
- 25 Bounameaux H, de Moerloose P. Is laboratory monitoring of low-molecular-weight heparin therapy necessary? No. J Thromb Haemost 2004; 2 (4) 551-554
- 26 Eikelboom JW, Hirsh J. Monitoring unfractionated heparin with the aPTT: time for a fresh look. Thromb Haemost 2006; 96 (5) 547-552
- 27 Bijsterveld NR, Vink R, van Aken BE , et al. Recombinant factor VIIa reverses the anticoagulant effect of the long-acting pentasaccharide idraparinux in healthy volunteers. Br J Haematol 2004; 124 (5) 653-658
- 28 Bijsterveld NR, Moons AH, Boekholdt SM , et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 2002; 106 (20) 2550-2554
- 29 Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 2012; 23 (2) 138-143
- 30 van Ryn J, Stangier J, Haertter S , et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103 (6) 1116-1127
- 31 Ganetsky M, Babu KM, Salhanick SD, Brown RS, Boyer EW. Dabigatran: review of pharmacology and management of bleeding complications of this novel oral anticoagulant. J Med Toxicol 2011; 7 (4) 281-287
- 32 Eikelboom JW, Wallentin L, Connolly SJ , et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 2011; 123 (21) 2363-2372
- 33 Connolly SJ, Ezekowitz MD, Yusuf S , et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
- 34 Granger CB, Alexander JH, McMurray JJ , et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
- 35 Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124 (14) 1573-1579
- 36 Van Ryn J, Kink-Eiband M, Clemens A. The successful reversal of dabigatran-induced bleeding by coagulation factor concentrates in a rat tail bleeding model do not correlate with ex vivo markers of anticoagulation. 53rd ASH Annual Meeting and Exposition. San Diego, CA. Blood 2011; 118 (21) 2316
- 37 Van Ryn J, Ruehl D, Priepke H, Hauel N, Wienen W. Reversibility of the anticoagulant effect of high doses of the direct thrombin inhibitor Dabigatran, by recombinant factor VIIA or activated prothrombin complex concentrate. Paper presented at: 13th Congress of the European Hematology Association; June 12–15, 2008; Copenhagen, Denmark. Haematologica 2008;93(s1):148 (Abstract 0370)
- 38 Zhou W, Schwarting S, Illanes S , et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke 2011; 42 (12) 3594-3599
- 39 Marlu R, Hodaj E, Paris A, Albaladejo P, Crackowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. A randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012; 108 (2) 217-224
- 40 Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010; 49 (4) 259-268
- 41 Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet 2009; 48 (1) 1-22
- 42 Patel MR, Mahaffey KW, Garg J , et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
- 43 Tripodi A. Measuring the anticoagulant effect of direct factor Xa inhibitors. Is the anti-Xa assay preferable to the prothrombin time test?. Thromb Haemost 2011; 105 (4) 735-736
- 44 Raghavan N, Frost CE, Yu Z , et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos 2009; 37 (1) 74-81
- 45 Tinel H, Huetter J, Perzborn E. Recombinant factor VIIA partially reverses the anticoagulant effect of high-dose rivaroxaban: a novel, oral, direct factor XA inhibitor in rats. J Thromb Haemost 2007; 5 (Suppl. 02) P-W-652
- 46 Gruber A, Marzec U, Buetehorn U, Hanson S, Perzborn E. Potential of activated prothrombin complex concentrate and activated factor VII to reverse the anticoagulant effects of rivaroxaban in primates [abstract]. 50th Annual Meeting of the American Society of Hematology. San Francisco, CA. Blood 2008; 112: 3825
- 47 Hillarp A, Baghaei F, Fagerberg Blixter I , et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost 2011; 9 (1) 133-139
- 48 Asmis LM, Alberio L, Angelillo-Scherrer A , et al. Rivaroxaban: quantification by anti-FXa assay and influence on coagulation tests: a study in 9 Swiss laboratories. Thromb Res 2012; 129 (4) 492-498
- 49 van Ryn J, Stangier J, Haertter S , et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103 (6) 1116-1127
- 50 Serebruany VL, Malinin AI, Ziai W , et al. Effects of clopidogrel and aspirin in combination versus aspirin alone on platelet activation and major receptor expression in patients after recent ischemic stroke: for the Plavix Use for Treatment of Stroke (PLUTO-Stroke) trial. Stroke 2005; 36 (10) 2289-2292
- 51 Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood 1997; 90 (7) 2515-2521
- 52 Vilahur G, Choi BG, Zafar MU , et al. Normalization of platelet reactivity in clopidogrel-treated subjects. J Thromb Haemost 2007; 5 (1) 82-90
- 53 Leithäuser B, Zielske D, Seyfert UT, Jung F. Effects of desmopressin on platelet membrane glycoproteins and platelet aggregation in volunteers on clopidogrel. Clin Hemorheol Microcirc 2008; 39 (1-4) 293-302
- 54 Taneja R, Marwaha G, Sinha P , et al. Elevated activated partial thromboplastin time does not correlate with heparin rebound following cardiac surgery. Can J Anaesth 2009; 56 (7) 489-496
- 55 Holbrook A, Schulman S, Witt DM , et al. American College of Chest Physicians Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2 Suppl) e152S-1584S