Bleeding complications of anticoagulant therapy

Czech version

Authors: J. Gumulec ¹; P. Kessler ²; V. Procházka ³; M. Brejcha ⁴; M. Penka ⁵; M. Zänger ⁶; E. Machytka ⁷; P. Klement ^1,8
Authors‘ workplace: Hemato-onkologické a transfuzní centrum FN Ostrava, přednosta prim. MUDr. Jaromír Gumulec ¹; Oddělení hematologie a transfuziologie nemocnice Pelhřimov, přednosta prim. MUDr. Petr Kessler ²; Ústav radiodiagnostický, Pracoviště intervenční neuroradiologie a angiologie FN Ostrava, přednosta prim. MUDr. Jana Chmelová, Ph. D. ³; Oddělení klinické hematologie Onkologického centra J. G. Mendela Nový Jičín, přednosta prim. MUDr. Martin Brejcha ⁴; Oddělení klinické hematologie FN Brno, pracoviště Bohunice, přednosta prof. MUDr. Miroslav Penka, CSc. ⁵; BW, Berlin, Spolková republika Německo ⁶; Interní klinika FN Ostrava, přednosta doc. MUDr. Arnošt Martínek, CSc. ⁷; McMaster University and Henderson Research Centre, Hamilton, CA, Head Prof. Paul O’Birne, MD, PhD. ⁸
Published in: Vnitř Lék 2009; 55(3): 277-289
Category: 15th Parizek's Days

Overview

Anticoagulant therapy is one of the most common forms of medical intervention. It is the mainstay of prevention and treatment of thrombotic events. Omission of adequate anticoagulant prophylaxis at least for moderate-risk and high‑risk patients is a widely recognized medical error. Bleeding is one of the most feared complications of anticoagulant therapy, and is a risk of all anticoagulants. Whereas unfractionated heparin and warfarin, the oldest and most widely used anticoagulants, have specific antidotes for their anticoagulant effect, many of the newer agents (direct and indirect inhibitors of coagulation factors Xa and/or IIa) do not have specific antidotes to reverse their actions. The use of novel anticoagulants is further complicated by a lack of easily available laboratory tests to measure their levels and thereby optimize their benefit and safety in clinical practice. In this review, we evaluate the risk of bleeding associated with current anticoagulants, review the data available on current and experimental agents used for the reversal of anticoagulation, and provide recommendations for the management of major bleeding associated with anticoagulant therapy and for the management of asymptomatic overdosing of the anticoagulants.

Key words:
anticoagulation – bleeding – warfarin – heparin – low molecular weight heparin – fondaparinux – refludan – dabigatran – rivaroxaban

Sources

1. Geerts WH, Bergqvist D, Pineo GF et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest 2008; 133 (Suppl 6): 381S–453S.

2. National Institute for Health and Clinical Excellence. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery. NICE clinical guideline 46: 1–160. Available from: http://www.nice.org.uk/CG046. Accessed March 1, 2008.

3. Kearon C, Kahn SR, Agnelli G et al. Antithrombotic therapy for venous thromboembolic Disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest 2008; 133 (Suppl 6): 454S–545S.

4. Singer DE, Albers GW, Dalen JE et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest 2008; 133 (Suppl 6): 546S–592S.

5. Harrington RA, Becker RC, Cannon CP et al. Antithrombotic therapy for non‑ST‑segment elevation acute coronary syndromes: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest 2008; 133 (Suppl 6): 670S–707S.

6. Goodman SG, Menon V, Cannon CP et al. Acute ST‑segment elevation myocardial infarction: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest 2008; 133 (Suppl 6): 708S–775S.

7. Salem DN, O’Gara PT, Madias C et al. Valvular and structural heart disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest 2008; 133 (Suppl 6): 593S–629S.

8. Shojania KG, Duncan BW, McDonald MM et al. Making health care safer: a critical analysis of patient safety practices. Evidence Report/Technology Assessment No. 43 (Prepared by the University of California at San Francisco – Stanford Evidence‑based Practice Center under Contract No. 290-97-0013), AHRQ Publication No. 01-E058, Rockville, MD: Agency for Healthcare Research and Quality. July 2001. Available from: http://www.ahrq.gov/clinic/ptsafety/. Accessed March 15, 2007.

9. Schulman S, Beyth RJ, Kearon C et al. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest 2008; 133 (Suppl 6): 257S–298S.

10. Ng HJ, Crowther MA. New anti‑thrombotic agents: emphasis on hemorrhagic complications and their management. Semin Hematol 2006; 43 (Suppl 1): S77–S83.

11. Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest 2008; 133 (Suppl 6): 234S–256S.

12. Hirsh J, Bauer KA, Donati MB et al. Parenteral anticoagulans: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest 2008; 133 (Suppl 6): 141S–159S.

13. Crowther MA, Warkentin TE. Bleeding risk and the management of bleeding complications in patients undergoing anticoagulant therapy: focus on new anticoagulant agents. Blood 2008; 111: 4871–4879.

14. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non‑surgical patients. J Thromb Haemost 2005; 3: 692–694.

15. Černý V, Cvachovec K, Kasal M et al. Zásady podpory koagulace u život ohrožujícího a neztišitelného krvácení. Dostupné z: www.thrombosis.cz.

16. Worley TP, Heit JA, Pruthi RK. Bleeding disorders. In: Oliveira GHM, Nesbitt GC, Murphy JG (eds). Mayo Clinic Medical Manual. Rochester: Mayo Clinic Scientific Press 2006: 41–54.

17. Laposata M, Green D, Van Cott EM et al. College of american pathologists conference XXXI on laboratory monitoring of anticoagulant therapy: the clinical use and laboratory monitoring of low-molecular-weight heparin, danaparoid, hirudin and related compounds, and argatroban. Arch Pathol Lab Med 1998; 122: 799–807.

18. Shanafelt TD, Fonseca R. Thrombocytopenia. In: Oliveira GHM, Nesbit GC, Murphy JG (eds). Mayo Clinic Medical Manual. Rochester: Mayo Clinic Scientific Press 2006: 259–269.

19. Fernandez F, N’guyen P, Van Ryn J et al. Hemorrhagic doses of heparin and other glycosaminoglycans induce a platelet defect. Thromb Res 1986; 43: 491–495.

20. Blajchman MA, Young E, Ofosu FA. Effects of unfractionated heparin, dermatan sulfate and low molecular weight heparin on vessel wall permeability in rabbits. Ann N Y Acad Sci 1989; 556: 245–254.

21. Crowther MA, Berry LR, Monagle PT et al. Mechanisms responsible for the failure of protamine to inactivate low-molecular-weight heparin. Br J Haematol 2002; 116: 178–186.

22. American Society of Health-System Pharmacists. Protamine sulfate: antiheparin agents: Bethesda, MD: American Society of Health-System Pharmacists, 1999. Avaible from: http://www.ashp.org/mngrphs/Essentials/a382278e.htm.

23. Weiler JM, Gellhaus MA, Carter JG et al. A prospective study of the risk of an immediate adverse reaction to protamine sulfate during cardiopulmonary bypass surgery. J Allergy Clin Immunol 1990; 85: 713–719.

24. Hirsh J, Levine M. Low molecular weight heparin. Blood 1992; 79: 1–17.

25. Makris M, Hough RE, Kitchen S. Poor reversal of low molecular weight heparin by protamine. Br J Haematol 2000; 108: 884–885.

26. Kessler CM. Current and future challenges of antithrombotic agents and anticoagulants: strategies for reversal of hemorrhagic complications. Semin Hematol 2004; 41 (Suppl 1): 44–50.

27. Warkentin TE, Crowther MA. Reversing anticoagulants both old and new. Can J Anaesth 2002; 49: S11–S25.

28. Deloughery TG. Management of acute hemorrhage. In: Colman RW, Marder VJ, Clowes AW et al (eds). Hemostasis and Thrombosis: Basic Principles and Practice (5th ed). Philadelphia: Lippincott 2006: 1159–1171.

29. Levi M, Bijsterveld NR, Keller TT. Recombinant factor VIIa as an antidote for anticoagulant treatment. Semin Hematol 2004; 41 (Suppl 1): 65–69.

30. Lauritzen B, Hedner U, Johansen PB et al. Recombinant human factor VIIa and a factor VIIa-analogue reduces heparin and low molecular weight heparin (LMWH)‑induced bleeding in rats. J Thromb Haemost 2008; 6: 804–811.

31. Crowther M, Lim W. Low molecular weight heparin and bleeding in patients with chronic renal failure. Curr Opin Pulm Med 2007; 13: 409–413.

32. Ng HJ, Koh LP, Lee LH. Successful control of postsurgical bleeding by recombinant factor VIIa in a renal failure patient given low molecular weight heparin and aspirin. Ann Hematol 2003; 82: 257–258.

33. Boneu B, Necciari J, Cariou R et al. Pharmacokinetics and tolerance of the natural pentasaccharide (SR90107/Org31540) with high affinity to antithrombin III in man. Thromb Haemost 1995; 74: 1468–1473.

34. Turpie AG, Bauer KA, Eriksson BI et al. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta‑analysis of 4 randomized double-blind studies. Arch Intern Med 2002; 162: 1833–1840.

35. Yusuf S, Mehta SR, Chrolavicius S et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006; 354: 1464–1476.

36. Gerotziafas GT, Depasse F, Chakroun T et al. Recombinant factor VIIa partially reverses the inhibitory effect of fondaparinux on thrombin generation after tissue factor activation in platelet rich plasma and whole blood. Thromb Haemost 2004; 91: 531–537.

37. Lisman T, Bijsterveld NR, Adelmeijer J et al. Recombinant factor VIIa reverses the in vitro and ex vivo anticoagulant and profibrinolytic effects of fondaparinux. J Thromb Haemost 2003; 1: 2368–2373.

38. 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: 2550–2554.

39. Gumulec J, Kessler P, Penka M et al. Krvácivé komplikace při léčbě warfarinem. Vnitř Lék 2006; 52 (Suppl 1): 79–91.

40. Kessler P. Farmakogenetika warfarinu. Vnitř Lék 2006; 52 (Suppl 1): 31–34.

41. Kessler P. Léčba orálními antikoagulancii. Praha: Orion Pharma 2002.

42. Matýšková M, Penka M. Interakce antikoagulačních léků s potravinami a potravinovými doplňky. Interní Med 2000; 5: 29–33.

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

44. Ansell J, Hirsh J, Hylek E et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest 2008; 133 (Suppl 6): 160S–198S.

45. Gunneman T, Ruybalid RL, Jacobson AK et al. Frequent prothrombin time testing reduces inappropriate warfarin dose changes. Thromb Haemost 1999; 82: 676.

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

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

48. Hylek EM, Regan S, Go AS et al. 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 2001; 135: 393–400.

49. Hirsh J, Fuster V, Ansell J et al. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation 2003; 107: 1692–1711.

50. Crowther MA, Douketis JD, Schnurr Tet al. 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 2002; 137: 251–254.

51. Baker RI, Coughlin PB, Gallus AS et al. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust 2004; 181: 492–497.

52. Hanley JP. Warfarin reversal. J Clin Pathol 2004; 57: 1132–1139.

53. Nitu IC, Perry DJ, Lee CA. Clinical experience with the use of clotting factor concentrates in oral anticoagulation reversal. Clin Lab Haematol 1998; 20: 363–367.

54. Aguilar MI, Hart RG, Kase CS et al. Treatment of warfarin‑associated intracerebral hemorrhage: literature review and expert opinion. Mayo Clin Proc 2007; 82: 82–92.

55. Lankiewicz MW, Hays J, Friedman KD et al. Urgent reversal of warfarin with prothrombin complex concentrate. J Thromb Haemost 2006; 4: 967–970.

56. Pabinger-Fasching I. Warfarin‑reversal: results of a phase III study with pasteurised, nanofiltrated prothrombin complex concentrate. Thromb Res 2008; 122 (Suppl 2): S19–S22.

57. Riess HB, Meier-Hellmann A, Motsch Jet al. Prothrombin complex concentrate (Octaplex) in patients requiring immediate reversal of oral anticoagulation. Thromb Res 2007; 121: 9–16.

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

59. Makris M, Greaves M, Phillips WS et al. 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: 477–480.

60. Dentali F, Ageno W, Crowther M. Treatment of coumarin‑associated coagulopathy: a systematic review and proposed treatment algorithms. J Thromb Haemost 2006; 4: 1853–1863.

61. Dezee KJ, Shimeall WT, Douglas KM et al. Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta‑analysis. Arch Intern Med 2006; 166: 391–397.

62. Warkentin TE, Greinacher A, Koster Aet al. Treatment and prevention of heparin‑induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest 2008; 133 (Suppl 6): 340S–380S.

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

64. 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: 998–1001.

65. Yasaka M, Sakata T, Naritomi H et al. Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation. Thromb Res 2005; 115: 455–459.

66. Deveras RA, Kessler CM. Reversal of warfarin‑induced excessive anticoagulation with recombinant human factor VIIa concentrate. Ann Intern Med 2002; 137: 884–888.

67. Freeman WD, Brott TG, Barrett KM et al. Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clin Proc 2004; 79:1495–1500.

68. Sørensen B, Johansen P, Nielsen GL et al. Reversal 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 2003; 14: 469–477.

69. Erhardtsen E, Nony P, Dechavanne M et al. The effect of recombinant factor VIIa (NovoSeven) in healthy volunteers receiving acenocoumarol to an International Normalized Ratio above 2.0. Blood Coagul Fibrinolysis 1998; 9: 741–748.

70. Mayer SA, Brun MC, Begtrup K et al. Recombinant activated factor VII for acute intracererbral hemorrhage. N Engl J Med 2005; 352: 277–285.

71. Mayer SA. Recombinant activated factor VII for acute intracerebral hemorrhage. Stroke 2007; 38 (Suppl 2): 763–764.

72. Mayer SA, Brun NC, Begtrup K et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2008; 358: 2127–2137.

73. Ehrlich HJ, Henzl MJ, Gomperts ED. Safety of factor VIII inhibitor bypass activity (FEIBA): 10-year compilation of thrombotic adverse events. Haemophilia 2002; 8: 83–90.

74. Makris M, Watson HG. Reversal of coumarin‑induced over–anticoagulation: reply to Escobar. Br J Haematol 2002; 118: 925–926.

75. Douketis JD, Berger PB, Dunn AS et al. The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest 2008; 133 (Suppl 6): 299S–339S.

76. Weitz JI, Crowther M. Direct thrombin inhibitors. Tromb Res 2002; 106: V275–V284.

77. Bauer KA. New anticoagulants. Hematology Am Soc Hematom Educ Program 2006; 450–456.

78. Mahdy AM, Webster NR. Perioperative systemic haemostatic agents. Br J Anaesth 2004; 93: 842–858.

79. Mannucci PM, Bettega D, Cattaneo M. Patterns of development of tachyphylaxis in patients with haemophilia and von Willebrand disease after repeated doses of desmopressin (DDAVP). Br J Haematol 1992; 82: 87–93.

80. Ibbotson SH, Grant PJ, Kerry R et al. The influence of infusions of 1-desamino-8-D-arginine vasopressin (DDAVP) in vivo on the anticoagulant effect of recombinant hirudin (CGP39393) in vitro. Thromb Haemost 1991; 65: 64–66.

81. Bove CM, Casey B, Marder VJ. DDAVP reduces bleeding during continued hirudin administration in the rabbit. Thromb Haemost 1996; 75: 471–475.

82. Fischer KG. Hemodialysis in heparin‑induced thrombocytopenia. In: Warkentin TE, Greinacher A (eds). Heparin‑Induced Thrombocytopenia (4th ed). New York: Informa Healthcare 2007: 463–485.

83. Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47: 285–295.

84. Stangier J, Stähle H, Rathgen K et al. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008; 47: 47–59.

85. Kvasnička J, Slíva J. Dabigatran. Farmakoterapie 2008; 4: 359–364.

86. Souhrn údajů o přípravku Xarelto. SÚKL Praha, 2008.

87. Ho KM, Ismail H. Use of intravenous tranexamic acid to reduce allogeneic blood transfusion in total hip and knee arthroplasty: a meta‑analysis. Anaesth Intensive Care 2003; 31: 529–537.

88. Niskanen RO, Korkala OL. Tranexamic acid reduces blood loss in cemented hip arthroplasty: a randomized, double-blind study of 39 patients with osteoarthritis. Acta Orthop 2005; 76: 829–832.

89. Barthels M, Poliwoda H. Gerinnungsanalysen. Interpretation – Schlellorientierung – Therapiekontrollen. 4. überarbeitete und erweiterte Auflage. Thieme 1993: 150–151, 226–234.

90. Chlumský J et al. Antikoagulační léčba. Praha: Grada Publishing 2005.

91. Choudari CP, Palmer KR. Acute gastrointestinal haemorrhage in patients treated with anticoagulant drugs. Gut 1995; 36: 483–484.

92. Vreeburg EM, de Bruijne HW, Snel P et al. Previous use of non‑steroidal anti‑inflammatory drugs and anticoagulants: the influence on clinical outcome of bleeding gastroduodenal ulcers. Eur J Gastroenterol Hepatol 1997; 9: 41–44.

93. Kim K et al. Acute gastrointestinal bleeding – diagnosis and treatment. Humana Press. New Jersey 2003.

94. Dítě P et al. Akutní nevarikózní krvácení do horní části trávicího ústrojí. In: Akutní stavy v gastroenterologii. Praha: Galén 2005.

95. Palmer K. Management of haematemesis and melaena. Postgrad Med J 2004; 80: 399–404.

96. Thomopoulos KC, Theocharis GJ, Nikolopoulou VN et al. Acute upper gastrointestinal bleeding in patients on long‑term oral anticoagulation therapy: endoscopic findings, clinical management and outcome. World J Gastroenterol 2005; 11: 1365–1368.

97. Keil R et al. Gastroskopie. Praha: Maxdorf 2006.

98. Kohout P. Vředová choroba. Praha: Maxdorf 2005.

99. Machytka E, Ehrmann J, Svoboda P et al. Dlouhodobé sledování pacientů s klinickými známkami krvácení do horní části trávicího traktu a negativním endoskopickým nálezem. Vnitř Lék 2007; 53: 942–946.

100. Machytka E, Ehrmann J, Svoboda P et al. Incidence krvácení do horní části zažívacího traktu v regionu Ostrava-Poruba v letech 2002–2005. Čes a Slov Gastroent a Hepatol 2007; 61: 124–128.