Drug Safety

, Volume 31, Issue 3, pp 217–230 | Cite as

A Benefit-Risk Review of Systemic Haemostatic Agents

Part 1: In Major Surgery
  • Ian S. Fraser
  • Robert J. Porte
  • Peter A. Kouides
  • Andrea S. Lukes
Review Article


Systemic haemostatic agents play an important role in the management of blood loss during major surgery where significant blood loss is likely and their use has increased in recent times as a consequence of demand for blood products outstripping supply and the risks associated with transfusions. Their main application is as prophylaxis to reduce bleeding in major surgery, including cardiac and orthopaedic surgery and orthotopic liver transplantation. Aprotinin has been the predominant agent used in this setting; of the other antifibrinolytic agents that have been studied, tranexamic acid is the most effective and e-aminocaproic acid may also have a role. Eptacog alfa (recombinant factor VIIa) has also shown promise. Tranexamic acid, e-aminocaproic acid and eptacog alfa are generally well tolerated; however, when considering the methods to reduce or prevent blood loss intra- and postoperatively, the benefits of these agents need to be weighed against the risk of adverse events. Recently, concerns have been raised about the safety of aprotinin after an association between increased renal dysfunction and mortality was shown in retrospective observational studies and an increase in allcause mortality with aprotinin relative to tranexamic acid or e-aminocaproic acid was seen after a pre-planned periodic analysis of the large BART (Blood conservation using Antifibrinolytics in a Randomized Trial) study. The latter finding resulted in the trial being halted, and aprotinin has subsequently been withdrawn from the market pending detailed analysis of efficacy and safety results from the study. Part 1 of this benefit-risk review examines the efficacy and adverse effect profiles of systemic haemostatic agents commonly used in surgery, and provides individual benefit-risk profiles that may assist clinicians in selecting appropriate pharmacological therapy in this setting.


Aprotinin Orthotopic Liver Transplantation Tranexamic Acid Desmopressin Transfusion Requirement 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Funding for the preparation of this manuscript was provided by Daiichi Sankyo Co., Ltd.

Dr Fraser has undertaken consultancies, given lectures for or received honoraria for scientific contributions to meetings for the Daiichi Sankyo, Organon and Schering companies. Dr Porte has previously received an unrestricted research grant from Bayer Pharmaceuticals and is involved in a trial that is co-sponsored by Johnson & Johnson. Dr Kouides serves on the advisory board of CSL Behring (which markets intranasal desmopressin), has been a consultant to the Ferring Pharmaceuticals (which manufactures desmopressin) and serves on the Drug Monitoring Safety Boards of Xanodyne Pharmaceuticals Inc. (which markets ε-aminocaproic acid and is developing a sustained-release form of oral tranexamic acid). Dr Lukes has been an investigator on several trials using tranexamic acid, including the CDC study on heavy periods using tranexamic acid and desmopressin, is a consultant to Xanodyne Pharmaceuticals Inc. (who are pursuing FDA approval for tranexamic acid in the US) and has been a speaker for Daiichi Sankyo Co. Ltd (FIGO 2006). Dr Lukes received a small stipend for contributing to this manuscript.

The authors would like to thank Dr Susan Keam, of Wolters Kluwer Health Medical Communications, for her assistance in the writing and editing of this manuscript.


  1. 1.
    Levi MM, Vink R, de Jonge E. Management of bleeding disorders by prohemostatic therapy. Int J Hematol 2002 Aug; 76 Suppl. 2: 139–44PubMedCrossRefGoogle Scholar
  2. 2.
    Levy JH. Hemostatic agents. Transfusion (Paris) 2004; 44 (12 Suppl.): 58–62SCrossRefGoogle Scholar
  3. 3.
    Fraser IS, Porte RJ, Kouides PA, et al. A benefit-risk review of systemic haemostatic agents. Part 2: in excessive or heavy menstrual bleeding. Drug Saf. In pressGoogle Scholar
  4. 4.
    Karski JM, Balatbat JT. Blood conservation strategies in cardiac surgery. Semin Cardiothorac Vasc Anesth 2003; 7(2): 175–88CrossRefGoogle Scholar
  5. 5.
    Beguin C, Closon M-C, Vanderkerckhove P, et al. Concentration of transfusion resources on a few pathologies and a few patients: analysis of a comprehensive in-hospital patient database. Transfusion (Paris) 2007; 47(2): 217–27CrossRefGoogle Scholar
  6. 6.
    Tobias JD. Strategies for minimizing blood loss in orthopedic surgery. Semin Hematol 2004 Jan; 41 (1 Suppl. 1): 145–56PubMedCrossRefGoogle Scholar
  7. 7.
    Norfolk DR, Seghatchian J. Pharmacological therapies to minimise platelet transfusion. Transfus Sci 2000 Jun; 22(3): 149–53PubMedCrossRefGoogle Scholar
  8. 8.
    Mannucci PM, Levi M. Prevention and treatment of major blood loss. N Engl J Med 2007 May 31; 356(22): 2301–11PubMedCrossRefGoogle Scholar
  9. 9.
    Barrons RW, Jahr JS. A Review of post-cardiopulmonary bypass bleeding, aminocaproic acid, tranexamic acid, and aprotinin. Am J Ther 1996 Dec; 3(12): 821–38PubMedCrossRefGoogle Scholar
  10. 10.
    Levy JH. Overview of clinical efficacy and safety of pharmacologic strategies for blood conservation. Am J Health Syst Pharm 2005; 62 Suppl. 4: S15–9PubMedCrossRefGoogle Scholar
  11. 11.
    Levy JH. Novel concepts in treatment and prevention of bleeding. Anesth Analg 2005; 100 (3. Suppl.): 43–7Google Scholar
  12. 12.
    Erstad BL. What is the evidence for using hemostatic agents in surgery? Eur Spine J 2004; 13 Suppl. 1: S28–33PubMedCrossRefGoogle Scholar
  13. 13.
    Porte RJ, Leebeek FWG. Pharmacological strategies to decrease transfusion requirements in patients undergoing surgery. Drugs 2002; 62(15): 2193–211PubMedCrossRefGoogle Scholar
  14. 14.
    Roy SN, Bhattacharya S. Benefits and risks of pharmacological agents used for the treatment of menorrhagia. Drug Saf 2004; 27(2): 75–90PubMedCrossRefGoogle Scholar
  15. 15.
    Marietta M, Facchini L, Pedrazzi P, et al. Pathophysiology of bleeding in surgery. Transplant Proc 2006 Apr; 38(3): 812–4PubMedCrossRefGoogle Scholar
  16. 16.
    Xia VW, Steadman RH. Antifibrinolytics in orthotopic liver transplantation: current status and controversies. Liver Transpl 2005 Jan; 11(1): 10–8PubMedCrossRefGoogle Scholar
  17. 17.
    Bayer HealthCare. Trasylol (aprotinin injection). US prescribing information. West Haven (CT): Bayer Pharmaceuticals Corporation, 2006 DecGoogle Scholar
  18. 18.
    Horrow JC, Van Riper DF, Strong MD, et al. Hemostatic effects of tranexamic acid and desmopressin during cardiac surgery. Circulation 1991; 84(5): 2063–70PubMedCrossRefGoogle Scholar
  19. 19.
    Karkouti K, Beattie WS, Wijeysundera DN, et al. Recombinant factor VIIa for intractable blood loss after cardiac surgery: a propensity score-matched case-control analysis. Transfusion (Paris) 2005 Jan; 45(1): 26–34CrossRefGoogle Scholar
  20. 20.
    Diprose P, Herbertson MJ, O’Shaughnessy D, et al. Activated recombinant factor VII after cardiopulmonary bypass reduces allogeneic transfusion in complex non-coronary cardiac surgery: randomized double-blind placebo-controlled pilot study. Br J Anaesth 2005 Nov; 95(5): 596–602PubMedCrossRefGoogle Scholar
  21. 21.
    Dunn CJ, Goa KL. Tranexamic acid: a review of its use in surgery and other indications. Drugs 1999; 57(6): 1005–32PubMedCrossRefGoogle Scholar
  22. 22.
    Slaughter TF, Greenberg CS. Antifibrinolytic drugs and perioperative hemostasis. Am J Hematol 1997 Sep; 56(1): 32–6PubMedCrossRefGoogle Scholar
  23. 23.
    US FDA. FDA requests marketing suspension of Trasylol [online]. Available from URL: [Accessed 2007 Nov 6]
  24. 24.
    Bayer Healthcare Pharmaceuticals. Important Trasylol safety information [online]. Available from URL: [Accessed 2007 Nov 6]
  25. 25.
    Electronic Medicines Compendium. Trasylol SPC from the eMC [online]. Available from URL: [Accessed 2007 Apr 24]
  26. 26.
    Menichetti A, Tritapepe L, Ruvolo G, et al. Changes in coagulation patterns, blood loss and blood use after cardiopulmonary bypass: aprotinin vs tranexamic acid vs epsilon aminocaproic acid. J Cardiovasc Surg (Torino) 1996; 37(4): 401–7Google Scholar
  27. 27.
    Diprose P, Herbertson MJ, O’Shaughnessy D, et al. Reducing allogeneic transfusion in cardiac surgery: a randomized double-blind placebo-controlled trial of antifibrinolytic therapies used in addition to intra-operative cell salvage. Br J Anaesth 2005 Mar; 94(3): 271–8PubMedCrossRefGoogle Scholar
  28. 28.
    Cosgrove III DM, Heric B, Lytle BW, et al. Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study. Ann Thorac Surg 1992 Dec; 54(6): 1031–6; discussion 1036–8PubMedCrossRefGoogle Scholar
  29. 29.
    Lemmer Jr JH, Stanford W, Bonney SL, et al. Aprotinin for coronary bypass operations: efficacy, safety, and influence on early saphenous vein graft patency: a multicenter, randomized, double-blind, placebo-controlled study. J Thorac Cardiovasc Surg 1994 Feb; 107(2): 543–51, discussion 551–3PubMedGoogle Scholar
  30. 30.
    Bidstrup BP, Royston D, Sapsford RN, et al. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (Trasylol). J Thorac Cardiovasc Surg 1989 Mar; 97(3): 364–72PubMedGoogle Scholar
  31. 31.
    Vanek T, Jares M, Fajt R, et al. Fibrinolytic inhibitors in off-pump coronary surgery: a prospective, randomized, double-blind TAP study (tranexamic acid, aprotinin, placebo). Eur J Cardiothorac Surg 2005 Oct; 28(4): 563–8PubMedCrossRefGoogle Scholar
  32. 32.
    Bailey CR, Wielogorski AK. Randomised placebo controlled double blind study of two low dose aprotinin regimens in cardiac surgery. Br Heart J 1994 Apr; 71(4): 349–53PubMedCrossRefGoogle Scholar
  33. 33.
    Ray MJ, O’Brien MF. Comparison of epsilon aminocaproic acid and low-dose aprotinin in cardiopulmonary bypass: efficiency, safety and cost. Ann Thorac Surg 2001 Mar; 71(3): 838–43PubMedCrossRefGoogle Scholar
  34. 34.
    Pugh SC, Wielogorski AK. A comparison of the effects of tranexamic acid and low-dose aprotinin on blood loss and homologous blood usage in patients undergoing cardiac surgery. J Cardiothorac Vasc Anesth 1995 Jun; 9(3): 240–4PubMedCrossRefGoogle Scholar
  35. 35.
    Landymore RW, Murphy JT, Lummis H, et al. The use of low-dose aprotinin, epsilon-aminocaproic acid or tranexamic acid for prevention of mediastinal bleeding in patients receiving aspirin before coronary artery bypass operations [letter]. Eur J Cardiothorac Surg 1997 Apr; 11(4): 798–800PubMedCrossRefGoogle Scholar
  36. 36.
    Nuttall GA, Oliver WC, Ereth MH, et al. Comparison of blood-conservation strategies in cardiac surgery patients at high risk for bleeding. Anesthesiology 2000 Mar; 92(3): 674–82PubMedCrossRefGoogle Scholar
  37. 37.
    Corbeau JJ, Monrigal JP, Jacob JP, et al. Comparison of effects of aprotinin and tranexamic acid on blood loss in heart surgery [in French]. Ann Fr Anesth Reanim 1995; 14(2): 154–61PubMedCrossRefGoogle Scholar
  38. 38.
    Bennett-Guerrero E, Sorohan JG, Gurevich ML, et al. Cost-benefit and efficacy of aprotinin compared with epsilon-aminocaproic acid in patients having repeated cardiac operations: a randomized, blinded clinical trial. Anesthesiology 1997 Dec; 87(6): 1373–80PubMedCrossRefGoogle Scholar
  39. 39.
    Hekmat K, Zimmermann T, Kampe S, et al. Impact of tranexamic acid vs. aprotinin on blood loss and transfusion requirements after cardiopulmonary bypass: a prospective, randomised, double-blind trial. Curr Med Res Opin 2004; 20(1): 121–6PubMedCrossRefGoogle Scholar
  40. 40.
    Lentschener C, Cottin P, Bouaziz H, et al. Reduction of blood loss and transfusion requirement by aprotinin in posterior lumbar spine fusion. Anesth Analg 1999 Sep; 89(3): 590–7PubMedGoogle Scholar
  41. 41.
    Murkin JM, Haig GM, Beer KJ, et al. Aprotinin decreases exposure to allogeneic blood during primary unilateral total hip replacement. J Bone Joint Surg Am 2000 May; 82(5): 675–84PubMedGoogle Scholar
  42. 42.
    Lentschener C, Benhamou D, Mercier FJ, et al. Aprotinin reduces blood loss in patients undergoing elective liver resection. Anesth Analg 1997 Apr; 84(4): 875–81PubMedGoogle Scholar
  43. 43.
    Garcia-Huete L, Domenech P, Sabate A, et al. The prophylactic effect of aprotinin on intraoperative bleeding in liver transplantation: a randomized clinical study. Hepatology 1997 Nov; 26(5): 1143–8PubMedCrossRefGoogle Scholar
  44. 44.
    Porte RJ, Molenaar IQ, Begliomini B, et al. Aprotinin and transfusion requirements in orthotopic liver transplantation: a multicentre randomised double-blind study. EMSALT Study Group. Lancet 2000 Apr 15; 355(9212): 1303–9PubMedCrossRefGoogle Scholar
  45. 45.
    Ickx BE, van der Linden PJ, Melot C, et al. Comparison of the effects of aprotinin and tranexamic acid on blood loss and red blood cell transfusion requirements during the late stages of liver transplantation. Transfusion (Paris) 2006 Apr; 46(4): 595–605CrossRefGoogle Scholar
  46. 46.
    Horrow JC, Van Riper DF, Strong MD, et al. The dose-response relationship of tranexamic acid. Anesthesiology 1995; 82(2): 383–92PubMedCrossRefGoogle Scholar
  47. 47.
    Nakashima A, Matsuzaki K, Fukumura F, et al. Tranexamic acid reduces blood loss after cardiopulmonary bypass. ASAIO J 1993; 39(3): M185–9PubMedCrossRefGoogle Scholar
  48. 48.
    Karski J, Djaiani G, Carroll J, et al. Tranexamic acid and early saphenous vein graft patency in conventional coronary artery bypass graft surgery: a prospective randomized controlled clinical trial. J Thorac Cardiovasc Surg 2005 Aug; 130(2): 309–14PubMedCrossRefGoogle Scholar
  49. 49.
    Katsaros D, Petricevic M, Snow NJ, et al. Tranexamic acid reduces postbypass blood use: a double-blinded, prospective, randomized study of 210 patients. Ann Thorac Surg 1996 Apr; 61(4): 1131–5PubMedCrossRefGoogle Scholar
  50. 50.
    Wei M, Jian K, Guo Z, et al. Tranexamic acid reduces postoperative bleeding in off-pump coronary artery bypass grafting. Scand Cardiovasc J 2006 Apr; 40(2): 105–9PubMedCrossRefGoogle Scholar
  51. 51.
    Benon G, Fredin H. Fibrinolytic inhibition with tranexamic acid reduces blood loss and blood transfusion after knee arthroplasty. J Bone Joint Surg [Br] 1996; 78-B: 434–40Google Scholar
  52. 52.
    Zohar E, Ellis M, Ifrach N, et al. The postoperative blood-sparing efficacy of oral versus intravenous tranexamic acid after total knee replacement. Anesth Analg 2004 Dec; 99(6): 1679–83PubMedCrossRefGoogle Scholar
  53. 53.
    Hiippala ST, Strid LJ, Wennerstrand MI, et al. Tranexamic acid radically decreases blood loss and transfusions associated with total knee arthroplasty. Anesth Analg 1997 Apr; 84(4): 839–44PubMedGoogle Scholar
  54. 54.
    Camarasa MA, Olle G, Serra-Prat M, et al. Efficacy of aminocaproic, tranexamic acids in the control of bleeding during total knee replacement: a randomized clinical trial. Br J Anaesth 2006 May; 96(5): 576–82PubMedCrossRefGoogle Scholar
  55. 55.
    Johansson T, Pettersson LG, Lisander B. Tranexamic acid in total hip arthroplasty saves blood and money: a randomized, double-blind study in 100 patients. Acta Orthopaedica 2005; 76(3): 314–9PubMedGoogle Scholar
  56. 56.
    Wu CC, Ho WM, Cheng SB, et al. Perioperative parenteral tranexamic acid in liver tumor resection: a prospective randomized trial toward a “blood transfusion”-free hepatectomy. Ann Surg 2006 Feb; 243(2): 173–80PubMedCrossRefGoogle Scholar
  57. 57.
    Dalmau A, Sabate A, Acosta F, et al. Tranexamic acid reduces red cell transfusion better than epsilon-aminocaproic acid or placebo in liver transplantation. Anesth Analg 2000; 91(1): 29–34PubMedGoogle Scholar
  58. 58.
    DelRossi AJ, Cernaianu AC, Botros S, et al. Prophylactic treatment of postperfusion bleeding using EACA. Chest 1989 Jul; 96(1): 27–30PubMedCrossRefGoogle Scholar
  59. 59.
    Arom KV, Emery RW. Decreased postoperative drainage with addition of epsilon-aminocaproic acid before cardiopulmonary bypass. Ann Thorac Surg 1994 May; 57(5): 1108–12; discussion 1112–3PubMedCrossRefGoogle Scholar
  60. 60.
    Salzman EW, Weinstein MJ, Weintraub RM, et al. Treatment with desmopressin acetate to reduce blood loss after cardiac surgery. A double-blind randomized trial. N Engl J Med 1986 May 29; 314(22): 1402–6PubMedCrossRefGoogle Scholar
  61. 61.
    Kobrinsky NL, Letts RM, Patel LR, et al. l-Desamino-8-D-arginine vasopressin (desmopressin) decreases operative blood loss in patients having Harrington rod spinal fusion surgery: a randomized, double-blinded, controlled trial. Ann Intern Med 1987 Oct; 107(4): 446–50PubMedGoogle Scholar
  62. 62.
    Karnezis TA, Stulberg SD, Wixson RL, et al. The hemostatic effects of desmopressin on patients who had total joint arthroplasty. A double-blind randomized trial. J Bone Joint Surg Am 1994 Oct; 76(10): 1545–50PubMedGoogle Scholar
  63. 63.
    Schott U, Sollen C, Axelsson K, et al. Desmopressin acetate does not reduce blood loss during total hip replacement in patients receiving dextran. Acta Anaesthesiol Scand 1995 Jul; 39(5): 592–8PubMedCrossRefGoogle Scholar
  64. 64.
    Dobkowski WB, Murkin JM. A risk-benefit assessment of aprotinin in cardiac surgical procedures. Drug Saf 1998 Jan; 18(1): 21–41PubMedCrossRefGoogle Scholar
  65. 65.
    Royston D, Chhatwani A. Safety aspects of aprotinin therapy in cardiac surgery patients. Expert Opin Drug Saf 2006 Jul; 5(4): 539–52PubMedCrossRefGoogle Scholar
  66. 66.
    Laupacis A, Fergusson D. Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses using perioperative blood transfusion as the outcome. Anesth Analg 1997; 85(6): 1258–67PubMedGoogle Scholar
  67. 67.
    Levy JH. Efficacy and safety of aprotinin in cardiac surgery. Orthopedics 2004 Jun; 27 (6 Suppl.): S659–62PubMedGoogle Scholar
  68. 68.
    Samama CM. A direct antifibrinolytic agent in major orthopedic surgery. Orthopedics 2004 Jun; 27 (6 Suppl.): S675–80PubMedGoogle Scholar
  69. 69.
    Bitan FD. Aprotinin in spine surgery: review of the literature. Orthopedics 2004 Jun; 27 (6 Suppl.): S681–3PubMedGoogle Scholar
  70. 70.
    Amar D, Grant FM, Zhang H, et al. Antifibrinolytic therapy and perioperative blood loss in cancer patients undergoing major orthopedic surgery. Anesthesiology 2003 Feb; 98(2): 337–42 228PubMedCrossRefGoogle Scholar
  71. 71.
    Shiga T, Wajima Z, Inoue T, et al. Aprotinin in major orthopedic surgery: a systematic review of randomized controlled trials. Anesth Analg 2005 Dec; 101(6): 1602–7PubMedCrossRefGoogle Scholar
  72. 72.
    Sodha NR, Boodhwani M, Bianchi C, et al. Aprotinin in cardiac surgery. Expert Rev Cardiovasc Ther 2006 Mar; 4(2): 151–60PubMedCrossRefGoogle Scholar
  73. 73.
    Molenaar IQ, Warnaar N, Groen H, et al. Efficacy and safety of antifibrinolytic drugs in liver transplantation: a systematic review and meta-analysis. Am J Transplant 2007 Jan; 7(1): 185–94PubMedCrossRefGoogle Scholar
  74. 74.
    Levi M, Cromheecke ME, De Jonge E, et al. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 1999; 354(9194): 1940–7PubMedCrossRefGoogle Scholar
  75. 75.
    Sedrakyan A, Treasure T, Elefteriades JA. Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg 2004 Sep; 128(3): 442–8PubMedCrossRefGoogle Scholar
  76. 76.
    Henry DA, Moxey AJ, Carless PA, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2001; (1): CD001886Google Scholar
  77. 77.
    Nuttall GA, Brost BC, Connis RT, et al. Practice guidelines for perioperative blood transfusion and adjuvant therapies: an updated report by the American Society of Anesthesiologists Task Force on perioperative blood transfusion and adjuvant therapies. Anesthesiology 2006; 105(1): 198–208CrossRefGoogle Scholar
  78. 78.
    Beattie WS, Karkouti K. Con: aprotinin has a good efficacy and safety profile relative to other alternatives for prevention of bleeding in cardiac surgery. Anesth Analg 2006 Dec; 103(6): 1360–4PubMedCrossRefGoogle Scholar
  79. 79.
    Ceriana P, Maurelli M, Locatelli A, et al. Anaphylactic reaction to aprotinin [letter]. J Cardiothorac Vasc Anesth 1995 Aug; 9(4): 477–8PubMedCrossRefGoogle Scholar
  80. 80.
    Wuthrich B, Schmid P, Schmid ER, et al. IgE-mediated anaphylactic reaction to aprotinin during anaesthesia [letter]. Lancet 1992 Jul 18; 340(8812): 173–4PubMedCrossRefGoogle Scholar
  81. 81.
    Bohrer H, Bach A, Fleischer F, et al. Adverse haemodynamic effects of high-dose aprotinin in a paediatric cardiac surgical patient. Anaesthesia 1990 Oct; 45(10): 853–4PubMedCrossRefGoogle Scholar
  82. 82.
    Chiu J, Ketchum LH, Reid TJ. Transfusion-sparing hemostatic agents. Curr Opin Hematol 2002 Nov; 9(6): 544–50PubMedCrossRefGoogle Scholar
  83. 83.
    Levy JH, Sypniewski E. Aprotinin: a pharmacologic overview. Orthopedics 2004 Jun; 27 (6 Suppl): S653–8PubMedGoogle Scholar
  84. 84.
    Vucicevic Z, Suskovic T. Acute respiratory distress syndrome after aprotinin infusion. Ann Pharmacother 1997 Apr; 31(4): 429–32PubMedGoogle Scholar
  85. 85.
    Augoustides JG, Lin J, Gambone AJ, et al. Fatal thrombosis in an adult after thoracoabdominal aneurysm repair with aprotinin and deep hypothermie circulatory arrest [letter]. Anesthesiology 2005 Jul; 103(1): 215–6PubMedCrossRefGoogle Scholar
  86. 86.
    Augoustides JG, Kilbaugh T, Harris H, et al. Fatal thrombosis after mitral valve replacement for endocarditis: aprotinin and disseminated intravascular coagulation [letter]. Anesthesiology 2006 Jan; 104(1): 213PubMedCrossRefGoogle Scholar
  87. 87.
    Ramsay MA, Randall HB, Burton EC. Intravascular thrombosis and thromboembolism during liver transplantation: antifibrinolytic therapy implicated? Liver Transpl 2004 Feb; 10(2): 310–4PubMedCrossRefGoogle Scholar
  88. 88.
    Westaby S. Aprotinin in perspective. Ann Thorac Surg 1993 Apr; 55(4): 1033–41PubMedCrossRefGoogle Scholar
  89. 89.
    Karkouti K, Beattie WS, Dattilo KM, et al. A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery. Transfusion (Paris) 2006; 46(3): 327–38CrossRefGoogle Scholar
  90. 90.
    Mangano DT, Miao Y, Vuylsteke A, et al. Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery. JAMA 2007 Feb 7; 297(5): 471–9PubMedCrossRefGoogle Scholar
  91. 91.
    Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006 Jan 26; 354(4): 353–65PubMedCrossRefGoogle Scholar
  92. 92.
    Warnaar N, Mallett SV, de Boer MT, et al. The impact of aprotinin on renal function after liver transplantation: an analysis of 1,043 patients. Am J Transplant 2007 Oct; 7(10): 2378–87PubMedCrossRefGoogle Scholar
  93. 93.
    US Food and Drug Administration. FDA statement regarding new Trasylol data [online]. Available from URL: [Accessed 2006 Oct 5]
  94. 94.
    Royston D, van Haaften N, De Vooght P. Aprotinin: friend or foe? A review of recent medical literature. Eur J Anaesthesiol 2007 Jan; 24(1): 6–14PubMedGoogle Scholar
  95. 95.
    Body SC, Mazer CD. Pro: aprotinin has a good efficacy and safety profile relative to other alternatives for prevention of bleeding in cardiac surgery. Anesth Analg 2006 Dec; 103(6): 1354–9PubMedCrossRefGoogle Scholar
  96. 96.
    Current Controlled Trials Ltd. Blood conservation using antifib-rinolytics: a randomized trial in a cardiac surgery population. The BART study [online]. Available from URL: [Accessed 2007 Apr 27]
  97. 97.
    Ottawa Health Research Institute. Information about the Blood conservation using Antifibrinolytics in a Randomized Trial (BART) study [online]. Available from URL: [Accessed 2007 Nov 7]
  98. 98.
    Wellington K, Wagstaff AJ. Tranexamic acid: a review of its use in the management of menorrhagia. Drugs 2003; 63(13): 1417–33PubMedCrossRefGoogle Scholar
  99. 99.
    Murphy GJ, Mango E, Lucchetti V, et al. A randomized trial of tranexamic acid in combination with cell salvage plus a meta-analysis of randomized trials evaluating tranexamic acid in off-pump coronary artery bypass grafting. J Thorac Cardiovasc Surg 2006 Sep; 132(3): 475–80PubMedCrossRefGoogle Scholar
  100. 100.
    Zufferey P, Merquiol F, Laporte S, et al. Do antifibrinolytics reduce allogeneic blood transfusion in orthopedic surgery? Anesthesiology 2006; 105(5): 1034–46PubMedCrossRefGoogle Scholar
  101. 101.
    Carless PA, Moxey AJ, Stokes BJ, et al. Are antifibrinolytic drugs equivalent in reducing blood loss and transfusion in cardiac surgery? A meta-analysis of randomized head-to-head trials. BMC Cardiovascular Disorders 2005; 5: 19PubMedCrossRefGoogle Scholar
  102. 102.
    Erstad BL. Systemic hemostatic medications for reducing surgical blood loss. Ann Pharmacother 2001 Jul-2001 31; 35(7–8): 925–34PubMedCrossRefGoogle Scholar
  103. 103.
    Cid J, Lozano M. Tranexamic acid reduces allogeneic red cell transfusions in patients undergoing total knee arthroplasty: results of a meta-analysis of randomized controlled trials. Transfusion (Paris) 2005 Aug; 45(8): 1302–7CrossRefGoogle Scholar
  104. 104.
    Gill JB, Rosenstein A. The use of antifibrinolytic agents in total hip arthroplasty: a meta-analysis. J Arthroplasty 2006 Sep; 21(6): 869–73PubMedCrossRefGoogle Scholar
  105. 105.
    Gai MY, Wu LF, Su QF, et al. Clinical observation of blood loss reduced by tranexamic acid during and after Caesarian section: a multi-center, randomized trial. Eur J Obstet Gynecol Reprod Biol 2004; 112(2): 154–7PubMedCrossRefGoogle Scholar
  106. 106.
    Federici AB, Sacco R, Stabile F, et al. Optimising local therapy during oral surgery in patients with von Willebrand disease: effective results from a retrospective analysis of 63 cases. Haemophilia 2000 Mar; 6(2): 71–7PubMedCrossRefGoogle Scholar
  107. 107.
    Nitu-Whalley IC, Griffioen A, Harrington C, et al. Retrospective review of the management of elective surgery with 229 desmopressin and clotting factor concentrates in patients with von Willebrand disease. Am J Hematol 2001 Apr; 66(4): 280–4PubMedCrossRefGoogle Scholar
  108. 108.
    Pharmacia and Upjohn Company. Cyclokapron® (tranexamic acid tablets and tranexamic acid injection) [prescribing information]. Kalamazoo (MI): Pharmacia and Upjohn Company, 2005 NovGoogle Scholar
  109. 109.
    Carrion-Carrion C, Del Pozo-Losada J, Gutierrez-Ramos R, et al. Bullous eruption induced by tranexamic acid [letter]. Ann Pharmacother 1994; 28(11): 1305–6PubMedGoogle Scholar
  110. 110.
    Kavanagh GM, Sansom JE, Harrison P, et al. Tranexamic acid (Cyklokapron)-induced fixed-drug eruption [letter]. Br J Dermatol 1993; 128(2): 229–30PubMedCrossRefGoogle Scholar
  111. 111.
    Lucas-Polomeni MM, Delavai Y, Menestret P, et al. A Case of anaphylactic shock with tranexamique acid (Exacyl) [in French]. Ann Fr Anesth Reanim 2004; 23(6): 607–9PubMedCrossRefGoogle Scholar
  112. 112.
    Cravens GT, Brown MJ, Brown DR, et al. Antifibrinolytic therapy use to mitigate blood loss during staged complex major spine surgery: Postoperative visual color changes after tranexamic acid administration. Anesthesiology 2006; 105(6): 1274–6PubMedCrossRefGoogle Scholar
  113. 113.
    Snir M, Axer-Siegel R, Buckman G, et al. Central venous stasis retinopathy following the use of tranexamic acid. Retina 1990; 10(3): 181–4PubMedGoogle Scholar
  114. 114.
    Thiagarajamurthy S, Levine A, Dunning J. Does prophylactic tranexamic acid safely reduce bleeding without increasing thrombotic complications in patients undergoing cardiac surgery? Interact Cardiovasc Thorac Surg 2004; 3(3): 489–94PubMedCrossRefGoogle Scholar
  115. 115.
    Rydin E, Lundberg PO. Tranexamic acid and intracranial throm-bosis [letter]. Lancet 1976 Jul 3; 2(7975): 49PubMedCrossRefGoogle Scholar
  116. 116.
    Woo KS, Tse LK, Woo JL, et al. Massive pulmonary thromboembolism after tranexamic acid antifibrinolytic therapy. Br J Clin Pract 1989 Dec; 43(12): 465–6PubMedGoogle Scholar
  117. 117.
    Mandai AKJ, Missouris CG. Tranexamic acid and acute myocardial infarction. Br J Cardiol 2005; 12(4): 306–7Google Scholar
  118. 118.
    Taparia M, Cordingley FT, Leahy MF. Pulmonary embolism associated with tranexamic acid in severe acquired haemophilia. Eur J Haematol 2002 May; 68(5): 307–9PubMedCrossRefGoogle Scholar
  119. 119.
    Koo JR, Lee YK, Kim YS, et al. Acute renal cortical necrosis caused by an antifibrinolytic drug (tranexamic acid). Nephrol Dial Transplant 1999; 14(3): 750–2PubMedCrossRefGoogle Scholar
  120. 120.
    Lindoff C, Rybo G, Astedt B. Treatment with tranexamic acid during pregnancy, and the risk of thrombo-embolic complications. Thromb Haemost 1993; 70(2): 238–40PubMedGoogle Scholar
  121. 121.
    Sundstrom A, Seaman H, Alfredsson L. tranexamic acid, menorrhagia, and venous thromboembolism: a case control study using the GRPD [abstract no. 214]. Pharmacoepidemiol Drug Saf 2005; 14 Suppl.: S108Google Scholar
  122. 122.
    Bekassy Z, Astedt B. Treatment with the fibrinolytic inhibitor tranexamic acid: risk for thrombosis? Acta Obstet Gynecol Scand 1990; 69(4): 353–4PubMedCrossRefGoogle Scholar
  123. 123.
    Tanaka K, Kondo C, Takagi K, et al. Effects of nafamostat mesilate on platelets and coagulofibrinolysis during cardiopulmonary bypass surgery. ASAIO J 1993 Jul-1993 30; 39(3): M545–9PubMedCrossRefGoogle Scholar
  124. 124.
    Sato T, Tanaka K, Kondo C, et al. Nafamostat mesilate administration during cardiopulmonary bypass decreases postoperative bleeding after cardiac surgery. ASAIO Trans 1991 Jul-1991 30; 37(3): M194–5PubMedGoogle Scholar
  125. 125.
    Murase M, Usui A, Tomita Y, et al. Nafamostat mesilate reduces blood loss during open heart surgery. Circulation 1993 Nov; 88 (5 Pt 2): II432–6PubMedGoogle Scholar
  126. 126.
    Miyamoto Y, Nakano S, Kaneko M, et al. Clinical evaluation of a new synthetic protease inhibitor in open heart surgery. Effect on plasma serotonin and histamine release and blood conservation. ASAIO J 1992 Jul-1992 30; 38(3): M395–8PubMedCrossRefGoogle Scholar
  127. 127.
    Shimada M, Matsumata T, Shirabe K, et al. Effect of nafamostat mesilate on coagulation and fibrinolysis in hepatic resection. J Am Coll Surg 1994 May; 178(5): 498–502PubMedGoogle Scholar
  128. 128.
    Kaminishi Y, Hiramatsu Y, Watanabe Y, et al. Effects of nafamostat mesilate and minimal-dose aprotinin on blood-foreign surface interactions in cardiopulmonary bypass. Ann Thorac Surg 2004 Feb; 77(2): 644–50PubMedCrossRefGoogle Scholar
  129. 129.
    Munoz JJ, Birkmeyer NJ, Birkmeyer JD, et al. Is epsilon-aminocaproic acid as effective as aprotinin in reducing bleeding with cardiac surgery: a meta-analysis. Circulation 1999 Jan 5–1999; 99(1): 81–9PubMedCrossRefGoogle Scholar
  130. 130.
    Xanodyne Pharmaceuticals Inc. Amicar® (aminocaproic acid) injection, syrup and tablets [prescribing information]. Florence (KY): Xanodyne Pharmaceuticals Inc, 2004 SepGoogle Scholar
  131. 131.
    Seymour BD, Rubinger M. Rhabdomyolysis induced by epsi-lon-aminocaproic acid. Ann Pharmacother 1997 Jan; 31(1): 56–8PubMedGoogle Scholar
  132. 132.
    Achiron A, Gornish M, Melamed E. Cerebral sinus thrombosis as a potential hazard of antifibrinolytic treatment in menorrhagia. Stroke 1990 May; 21(5): 817–9PubMedCrossRefGoogle Scholar
  133. 133.
    Fanashawe MP, Shore-Lesserson L, Reich DL. Two cases of fatal thrombosis after aminocaproic acid therapy and deep hypothermic circulatory arrest. Anesthesiology 2001 Dec; 95(6): 1525–7PubMedCrossRefGoogle Scholar
  134. 134.
    Aprile AE, Palmer TJ. The intraoperative use of Amicar to reduce bleeding associated with open heart surgery. AANA J 1995 Aug; 63(4): 325–31PubMedGoogle Scholar
  135. 135.
    Sonntag VK, Stein BM. Arteriopathic complications during treatment of subarachnoid hemorrhage with epsilon-aminocaproic acid. J Neurosurg 1974 Apr; 40(4): 480–5PubMedCrossRefGoogle Scholar
  136. 136.
    Balduini CL, Noris P, Belletti S, et al. In vitro and in vivo effects of desmopressin on platelet function. Haematologica 1999 Oct; 84(10): 891–6PubMedGoogle Scholar
  137. 137.
    DiMichele DM, Hathaway WE. Use of DDAVP in inherited and acquired platelet dysfunction. Am J Hematol 1990 Jan; 33(1): 39–45PubMedCrossRefGoogle Scholar
  138. 138.
    Avenus Pharmaceuticals Inc. DDAVP injection (desmopressin) [prescribing information]. Kansas City (MO): Avenus Pharmaceuticals Inc., 2004Google Scholar
  139. 139.
    Bertholini DM, Butler CS. Severe hyponatraemia secondary to desmopressin therapy in von Willebrand’s disease. Anaesth Intensive Care 2000 Apr; 28(2): 199–201PubMedGoogle Scholar
  140. 140.
    Das P, Carcao M, Hitzler J. DDAVP-induced hyponatremia in young children. J Pediatr Hematol Oncol 2005 Jun; 27(6): 330–2PubMedCrossRefGoogle Scholar
  141. 141.
    Garcia EB, Ruitenberg A, Madretsma GS, et al. Hyponatraemic coma induced by desmopressin and ibuprofen in a woman with von Willebrand’s disease. Haemophilia 2003 Mar; 9(2): 232–4CrossRefGoogle Scholar
  142. 142.
    Garcia VV, Silva IA, Borrasca AL. Response of factor VIII/von Willebrand factor to intranasal DDAVP in healthy subjects and mild haemophiliacs (with observations in patients with combined deficiency of factors V and VIII). Thromb Haemost 1982 Aug 24; 48(1): 91–3PubMedGoogle Scholar
  143. 143.
    Mannucci PM, Canciani MT, Rota L, et al. Response of factor VIII/von Willebrand factor to DDAVP in healthy subjects and patients with haemophilia A and von Willebrand’s disease. Br J Haematol 1981 Feb; 47(2): 283–93PubMedCrossRefGoogle Scholar
  144. 144.
    Kamphuisen PW, Eikenboom JC, Bertina RM. Elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol 2001 May; 21(5): 731–8PubMedCrossRefGoogle Scholar
  145. 145.
    Mannucci PM, Lusher JM. Desmopressin and thrombosis [letter]. Lancet 1989 Sep 16; 2(8664): 675–6PubMedCrossRefGoogle Scholar
  146. 146.
    Byrnes JJ, Larcada A, Moake JL. Thrombosis following desmopressin for uremic bleeding. Am J Hematol 1988 May; 28(1): 63–5PubMedCrossRefGoogle Scholar
  147. 147.
    Franchini M, Salvagno GL, Manzato F, et al. Are thrombotic complications in patients with von Willebrand’s disease expression of a multifactorial disease? Haematologica 2005 Nov; 90 Suppl: ECR34PubMedGoogle Scholar
  148. 148.
    Grainge C, Nokes T. Cerebral arterial thrombosis in a young woman following vasopressin for von Willebrand’s disease. Thromb Haemost 2005 Feb; 93(2): 380PubMedGoogle Scholar
  149. 149.
    Siddiqui MA, Scott LJ. Recombinant factor VIIa (Eptacog Alfa): a review of its use in congenital or acquired haemophilia and other congenital bleeding disorders. Drugs 2005; 65(8): 1161–77PubMedCrossRefGoogle Scholar
  150. 150.
    O’Connell KA, Wood JJ, Wise RP, et al. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 2006 Jan 18; 295(3): 293–8PubMedCrossRefGoogle Scholar
  151. 151.
    Roberts HR, Monroe DM, Hoffman M. Molecular biology of the coagulation factors and pathways of hemostasis. In: Beutler E, Lichtman MA, Coller BS, et al, editors. Williams hematology. 6th ed. New York: McGraw Hill, 2001: 1409–34Google Scholar
  152. 152.
    Roberts HR, Monroe DM, White GC. The use of recombinant factor VIIa in the treatment of bleeding disorders. Blood 2004 Dec 15; 104(13): 3858–64PubMedCrossRefGoogle Scholar
  153. 153.
    Deveras RA, Kessler CM. Reversal of warfarin-induced excessive anticoagulation with recombinant human factor VIIa concentrate. Ann Intern Med 2002 Dec 3; 137(11): 884–8PubMedGoogle Scholar
  154. 154.
    Eikelboom JW, Bird R, Blythe D, et al. Recombinant activated factor VII for the treatment of life-threatening haemorrhage. Blood Coagul Fibrinolysis 2003 Dec; 14(8): 713–7PubMedCrossRefGoogle Scholar
  155. 155.
    Hoots WK. Challenges in the therapeutic use of a “so-called” universal hemostatic agent: recombinant factor VIIa. Hematology Am Soc Hematol Educ Program 2006, 426–31Google Scholar
  156. 156.
    Mayer SA, Brun NC, Broderick J, et al. Safety and feasibility of recombinant factor VIIa for acute intracerebral hemorrhage. Stroke 2005 Jan; 36(1): 74–9PubMedCrossRefGoogle Scholar
  157. 157.
    Mayer SA, Bran NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005 Feb 24; 352(8): 777–85PubMedCrossRefGoogle Scholar
  158. 158.
    Uhlmann EJ, Eby CS. Recombinant activated factor VII for non-hemophiliac bleeding patients. Curr Opin Hematol 2004 May; 11(3): 198–204PubMedCrossRefGoogle Scholar
  159. 159.
    Lodge JP, Jonas S, Jones RM, et al. Efficacy and safety of repeated perioperative doses of recombinant factor VIIa in liver transplantation. Liver Transpl 2005 Aug; 11(8): 973–9PubMedCrossRefGoogle Scholar
  160. 160.
    Planinsic RM, van der Meer J, Testa G, et al. Safety and efficacy of a single bolus administration of recombinant factor VIIa in liver transplantation due to chronic liver disease. Liver Transpl 2005 Aug; 11(8): 895–900PubMedCrossRefGoogle Scholar
  161. 161.
    Shao YF, Yang JM, Chau GY, et al. Safety and hemostatic effect of recombinant activated factor VII in cirrhotic patients undergoing partial hepatectomy: a multicenter, randomized, double-blind, placebo-controlled trial. Am J Surg 2006 Feb; 191(2): 245–9PubMedCrossRefGoogle Scholar
  162. 162.
    Porte RJ, Caldwell SH. The role of recombinant factor VIIa in liver transplantation. Liver Transpl 2005 Aug; 11(8): 872–4PubMedCrossRefGoogle Scholar
  163. 163.
    Abshire T, Kenet G. Recombinant factor VIIa: review of efficacy, dosing regimens and safety in patients with congenital and acquired factor VIII or IX inhibitors. J Thromb Haemost 2004 Jun; 2(6): 899–909PubMedCrossRefGoogle Scholar
  164. 164.
    Levy JH, Fingerhut A, Brott T, et al. Recombinant factor VIIa in patients with coagulopathy secondary to anticoagulant therapy, cirrhosis, or severe traumatic injury: review of safety profile. Transfusion (Paris) 2006 Jun; 46(6): 919–33CrossRefGoogle Scholar
  165. 165.
    Garay RP, Chiavaroli C, Hannaert P. Therapeutic efficacy and mechanism of action of ethamsylate, a long-standing hemostatic agent. Am J Ther 2006 May-2006 30; 13(3): 236–47PubMedCrossRefGoogle Scholar
  166. 166.
    Schulte J, Osbome J, Benson JW, et al. Developmental outcome of the use of etamsylate for prevention of periventricular haemorrhage in a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 2005 Jan; 90(1): F31–5PubMedCrossRefGoogle Scholar
  167. 167.
    Benson JW, Drayton MR, Hayward C, et al. Multicentre trial of ethamsylate for prevention of periventricular haemorrhage in very low birthweight infants. Lancet 1986 Dec 6; 2(8519): 1297–300PubMedCrossRefGoogle Scholar
  168. 168.
    Livio M, Mannucci PM, Vigano G, et al. Conjugated estrogens for the management of bleeding associated with renal failure. N Engl J Med 1986 Sep 18; 315(12): 731–5PubMedCrossRefGoogle Scholar
  169. 169.
    Seth S, Geier TM. Use of conjugated estrogens to control gastrointestinal tract bleeding in two patients with chronic renal failure. Clin Pharm 1988 Dec; 7(12): 906–9PubMedGoogle Scholar
  170. 170.
    Heunisch C, Resnick DJ, Vitello JM, et al. Conjugated estrogens for the management of gastrointestinal bleeding secondary to uremia of acute renal failure. Pharmacotherapy 1998 Jan-1998 28; 18(1): 210–7PubMedGoogle Scholar
  171. 171.
    Frenette L, Cox J, McArdle P, et al. Conjugated estrogen reduces transfusion and coagulation factor requirements in orthotopic liver transplantation. Anesth Analg 1998 Jun; 86(6): 1183–6PubMedGoogle Scholar
  172. 172.
    Warren MP. A comparative review of the risks and benefits of hormone replacement therapy regimens. Am J Obstet Gynecol 2004; 190(4): 1141–67PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  • Ian S. Fraser
    • 1
  • Robert J. Porte
    • 2
  • Peter A. Kouides
    • 3
  • Andrea S. Lukes
    • 4
  1. 1.Department of Obstetrics and GynaecologyUniversity of SydneySydneyAustralia
  2. 2.Department of SurgeryUniversity Medical Center Groningenm University of GroningenGroningenThe Netherlands
  3. 3.Mary M. Gooely Hemophilia Center of RochesterRochesterUSA
  4. 4.Carolina Women’s Research and Wellness CenterDurhamUSA

Personalised recommendations