A risk-benefit assessment of aprotinin in cardiac surgical procedures

Drug Safety

Volumn 18, Issue 1, 1998, Pages 21-41

  Dobkowski, Wojciech B ^a   Murkin, John M ^a  

^a LONDON HEALTH SCIENCES CENTRE   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

AMINOCAPROIC ACID; ANTIFIBRINOLYTIC AGENT; APROTININ; DESMOPRESSIN; SERINE PROTEINASE INHIBITOR; TRANEXAMIC ACID;

ANAPHYLAXIS; ANTICOAGULATION; ANTIINFLAMMATORY ACTIVITY; ARTERY THROMBOSIS; BLEEDING; BLOOD CLOTTING TIME; BLOOD TRANSFUSION; CLINICAL TRIAL; DISEASE TRANSMISSION; DRUG EFFICACY; GRAFT PATENCY; HEART ARREST; HEART SURGERY; HEMODILUTION; HUMAN; KIDNEY FAILURE; KIDNEY FUNCTION; MAJOR CLINICAL STUDY; META ANALYSIS; PARTIAL THROMBOPLASTIN TIME; PRIORITY JOURNAL; REVIEW; RISK BENEFIT ANALYSIS; SEPSIS; THROMBOCYTE PRESERVATION;

ANIMALS; APROTININ; BLOOD LOSS, SURGICAL; BLOOD TRANSFUSION; CARDIAC SURGICAL PROCEDURES; HUMANS; PROTEASE INHIBITORS;

EID: 0031965298     PISSN: 01145916     EISSN: None     Source Type: Journal    
DOI: 10.2165/00002018-199818010-00003     Document Type: Review

References (159)

1. Murphy WG, Davies MJ, Eduardo A. The haemostatic response to surgery and trauma. Br J Anaesth 1993; 70: 205-13
2. Schreiber GB, Busch MP, Kleinman SH, et al. The risk of transfusion - transmitted viral infections. N Engl J Med 1996; 334: 1686-90
3. Binder LS, Ginsberg V, Harmel MH. A six year study of incompatible blood transfusion. Surg Gynecol Obstet 1959; 108: 19-34
4. Murphy WG, McClelland DB. Deceptively low morbidity from failure to practice safe blood transfusion: an analysis of serious blood transfusion errors. Vox Sang 1989; 57: 59-62
5. Fernandez MC, Gottlieb M, Menitove JE. Blood transfusion and postoperative infection in orthopedic patients. Transfusion 1992; 32: 318-22
6. Warner MA, Faust RJ. Risks of transfusion. In: Speiss BD, editor. Anesthesiology Clinics of North America. Hemorrhagic Disorders. Philadelphia: WB Saunders, 1990; 8 (3): 501-17
7. Gaydos JC, Covan DN, Polk AJ, et al. Blood typing errors on US Army identification cards and tags. Milit Med 1988; 152: 618-20
8. Pineda AA, Taswell HF, Brzica SM. Delayed hemolytic transfusion reaction: an immunologic hazard of blood transfusion. Transfusion 1978; 18: 1-7
9. Nichols RL, Smith JW, Klein DB, et al. Risk of infection after penetrating abdominal trauma. N Engl J Med 1984; 311: 1065-70
10. Tartter PI, Driefuss RM, Malon AM, et al. Relationship of post-operative septic complications and blood transfusions in patients with Crohns disease. Am J Surg 1988; 155: 43-8
11. Graves TA, Cioffi WG, Mason Jr AD, et al. Relationship of transfusion and infection in burn population. J Trauma 1989; 29: 948-54
12. Takaya S, Bronsther O, Iwaki Y, et al. The adverse impact on liver transplantation of using positive cytotoxic crossmatch donors. Transplantation 1992; 53: 400-4
13. Smith JD, Danskine AJ, Rose ML, et al. Specificity of lymphocytotoxic antibodies formed after cardiac transplantation and correlation with rejection episodes. Transplantation 1992; 53: 1358-62
14. Donahue JG, Munoz A, Ness PM, et al. The declining risk of post transfusion hepatitis C virus infection. N Engl J Med 1992; 327: 369-73
15. Sirchia G, Giovanetti, AM, et al. Prospective evaluation of posttransfusion hepatitis. Transfusion 1991; 31: 299-302
16. Hewson JR, Neame PB, Kumar N, et al. Coagulopathy related to dilution and hypotension during massive transfusion. Crit Care Med 1985; 13: 387-91
17. Toy PTCY, Strauss RG, Stehlin LC, et al. Predeposited autologous blood for elective surgery. N Engl J Med 1987; 316: 517-20
18. Briiton LW, Eastlund T, Dziuban SW, et al. Predonated autolopous blood use in elective cardiac surgery. Ann Thorac Surg 1989; 47: 529-32
19. Counts RB, Haisch C, Simon TL, et al. Hemostasis in massively transfused trauma patients. Ann Surg 1979; 190: 91-9
20. Tuman KJ, Speiss BD, McCarthy RJ, et al. Effects of progressive blood loss on coagulation as measured by thromboelastography. Anesth Analg 19987; 66: 856-63
21. McLoughliln TM, Fontana JL, Alving B, et al. Profound normovolemic hemodilution: hemostatic effects in patients and in a porcine model. Anesth Analg 1996; 83: 459-65
22. Williamson KR, Taswell HF. Intraoperative blood salvage: a review. Transfusion 1991; 31: 662-75
23. Murray DJ, Gress K, Weinstein SL. Coagulopathy after reinfusion of autologous scavenged red blood cells. Anesth Analg 1992; 75: 125-9
24. Kongsgaard UE, Tollofsrud S, Brosstad F, et al. Autotransfusion after open heart surgery: characteristics of shed mediastinal blood and its influence on the plasma proteases in circulating blood. Acta Anaesthesiol Scand 1991; 35: 71-63
25. DelRossi AJ, Cernaianu AC, Vertrees RA, et al. Platelet-rich plasma reduces postoperative blood loss after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990; 100: 281-6
26. Boldt J. Acute platelet-rich plasmapheresis for cardiac surgery. J Cardiothorac Vasc Anesth 1995; 9: 79-88
27. Mannucci PM. Desmopressin: a nontransfusional form of treatment for congenital and acquired bleeding disorders. Blood 1988; 72: 1449-52
28. Salzman EW, Weinstein MJ, Weintraub RM, et al. Treatment with desmopressin acetate to reduce blood loss alter cardiac surgery. N Engl J Med 1986; 314: 1402-6
29. Hackmann T, Gascoyne RD, Naiman SC, et al. A trial of desmopressin (1-desamino-8-D-arginine vasopressin) to reduce blood loss in uncomplicated cardiac surgery. N Engl J Med 1989; 321: 1437-43
30. Horrow JC, Van Riper DF, Strong MD, et al. Hemostatic effects of tranexamic acid and desmopressin during cardiac surgery. Circulation 1991; 84: 2063-70
31. Despotis GJ, Levine V, Filos KS, et al. Evaluation of a new point-of-care test that measures PAF-mediated acceleration of coagulation in cardiac surgical patients. Anesthesiology 1996; 85: 1311-23
32. Verstraete M. Clinical application of inhibitors of fibrinolysis. Drugs 1985; 29: 236-61
33. Karski JM, Teasdale SJ, Norman PH, et al. Prevention of postbypass bleeding with tranexamic acid and ε-aminocaproic acid. J Cardiothorac Vasc Anesth 1993; 7: 431-5
34. Fremes SE, Wong BI, Lee E, et al. Metaanalysis of prophylactic drug treatment in the prevention of postoperative bleeding. Ann Thorac Surg 1994; 58: 1580-8
35. Hiippala S, Strid L, Wennerstrand M, et al. Tranexamic acid (cyclokapron) reduces perioperative blood-loss associated with total hip arthroplasty. Br J Anaesth 1995; 74: 534-7
36. Benoni G, Fredin H. Fibrinolytic inhibition with tranexamic acid reduces blood-loss and blood-transfusion after knee arthroplasty - a prospective randomized, double-blind study of 86 patients. J Bone Joint Surg Br 1996; 78B: 434-40
37. Scudmore CH, Randall TE, Jewesson PR, et al. Aprotinin reduces the need for blood products during liver transplantation. Am J Surg 1995; 169: 546-9
38. Kang Y. Clinical use of synthetic antifibrinolytic agents during liver transplantation. Semin Thromb Hemost 1993; 19: 258-61
39. Kang Y, Lewis JH, Navalgund A, et al. Epsilon-aminocaproic acid for treatment of fibrinolysis during liver transplantation. Anesthesiology 1987; 66: 766-3
40. Ovrum E, Holen EA, Abdelnoor M, et al. Tranexamic acid (Cyclokapron) is not necessary to reduce blood loss after coronary artery bypass operations. J Thorac Cardiovasc Surg 1993; 105: 78-83
41. Woo KS. Massive pulmonary thromboembolism after tranexamic acid antifibrinolytic therapy. Br J Clin Pract 1989; 43: 465-6
42. Davies D, Howell DA. Tranexamic acid and arterial thrombosis [letter]. Lancet 1977; 1: 49
43. Rydin E, Lundberg PO. Tranexamic acid and intracranial thrombosis [letter]. Lancet 1976; 11: 49
44. Hoffman EP, Koo AH. Cerebral thrombosis associated with amicar therapy. Radiology 1979; 131: 687-9
45. Naeye RL. Thrombotic state alter a homorrhagic diathesis, a possible complication of therapy with epsilon-aminocaproic acid. Blood 1962; 19: 694-701
46. Ratnoff OD. Epsilon-aminocaproic acid: a dangerous weapon. N Engl J Med 1969; 280: 1124-5
47. Sonntag VKH, Stein BM. Arteriopathic complications during treatment of subarachnoid hemorrhage with ε-aminocaproic acid. J Neurosurg 1974; 40: 480-5
48. Fletcher AP, Alkjaersig N, Sherry S. Fibrinolytic mechanisms and the development of thrombolytic therapy. Am J Med 1962; 33: 738-52
49. Gibbon JH, Camishon RC. Problems in hemostasis with extracorporeal apparatus. Ann NY Acad Sci 1964; 115: 195-8
50. Lewis JH, Doyle AP. Effects of epsilon-aminocaproic acid on coagulation and fibrinolytic mechanisms. JAMA 1064; 188: 56-63
51. Sharp AA. Pathological fibrinolysis. Br Med J Bull 1964; 20: 240-6
52. Fritz H, Wunderer G. Biochemistry and applications of aprotinin, the kallikrein inhibitor from bovine lungs. Arzneim Forsch 1983; 33: 479-94
53. Royston D. High-dose aprotinin therapy: a review of the first five years experience. J Cardiothorac Case Anesth 1992; 6: 76-100
54. 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; 97: 364-72
55. Mallett SV, Cox D, Burroughs AK, et al. The intra-operative use of trasylol (aprotinin) in liver transplantation. Transplant Int 1991; 4: 227-30
56. Marcel RJ, Stegall WC, Suit CT, et al. Continuous small-dose aprotinin controls fibrinolysis during orthotopic liver transplantation. Anesth Analg 1996; 82: 1122-5
57. Speekenbrink RGH, Wildevuur CRH, Sturk A, et al. Low-dose and high-dose aprotinin improve hemostasis in coronary operations. J Thorac Cardiovasc Surg 1996; 112: 523-30
58. Blauhut B, Harringer W, Bettelheim P et al. Comparison of the effects of aprotinin and tranexamic acid on blood loss and related variables after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1994; 108: 1083-91
59. Casas JI, Zuazu-Jausoro I, Mateo J, et al. Aprotinin versus desmopressin for patients undergoing operations with cardiopulmonary bypass. J Thorac Cardiovasc Surg 1995; 110: 1107-7
60. Thompson JF, Roath OS, Francis JL, et al. Aprotinin in peripheral vascular surgery [letter]. Lancet 1990; 335: 911
61. Murkin JM, Shannon NA, Bourne RB, et al. Aprotinin decreases blood loss in patients undergoing revision or bilateral total hip arthroplasty. Anesth Analg 1995; 80: 343-8
62. Janssens M, Joris J, David JL, et al. High-close aprotinin reduces blood loss in patients undergoing total hip replacement surgery. Anesthesiology 1994; 80: 23-9
63. John LC, Rees GM, Kovacs IB. Reduction of heparin binding to and inhibition of platelets by aprotinin. Ann Thorac Surg 1993; 55: 1175-9
64. Espana F, Estelle SA, Griffin J. Aprotinin (Trasylol) is a competitive inhibitor of activated protein C. Thromb Res 1989; 56: 751-6
65. Van Oeveren W, Harden MP, Roozendaal, et al. Aprotinin protects platelets against the initial effect of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990; 99: 788-98
66. Kalter R, Saul CM, Wetstein L, et al. Cardiopulmonary bypass. Associated hemostatic abnormalities. J Thorac Cardiovasc Surg 1979; 77: 427-35
67. Harke H, Gennrich M. Aprotinin-ACD-blood. I: experimental studies on the effect of aprotinin on the plasmatic and thrombocytic coagulation. Anaesthetist 1980; 29: 266-76
68. Dietrich W, Spannagl M, Jochum M, et al. Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization. Anesthesiology 1990; 73: 1119-26
69. Lu H, Du-Boit C, Soria J, et al. Postoperative hemostasis and fibrinolysis in patients undergoing cardiopulmonary bypass with and without aprotinin therapy. Thromb Haemost 1994; 72: 438-43
70. Nagaoka H, Innami R, Murayama F, et al. Effects of aprotinin on prostaglandin metabolism and platelet function in open heart surgery. J Cardiovasc Surg 1991; 32; 31-7
71. Lavee J, Raviv Z, Smolinsky A, et al. Platelet protection by low-dose aprotinin in cardiopulmonary bypass: electron microscopy study. Ann Thorac Surg 1993; 55: 114-9
72. Lu H, Soria C, Soria J, et al. Reversible translocation of glycoprotein Ib in plasmin-treated patients: consequences for platelet function. Eur J Clin Invest 1993; 23: 785-93
73. Adelman B, Michelson A, Losclazo J, et al. Plasmin effect on platelet glycoprotein Ib-von Willebrand factor interactions. Blood 1985; 65: 32-40
74. John LCH, Rees GM, Kovacs IB. Inhibition of platelet function by heparin. J Thorac Cardiovasc Surg 1993; 105: 816-22
75. John LCH, Rees GM, Kovacs IB. Reduction of heparin binding to and inhibition of platelets by aprotinin. J Thorac Cardiovasc Surg 1993; 55: 1175-9
76. Moake JL, Turner NA, Stathopolous NA, et al. Shear-induced platelet aggregation can be mediated by vWF release from platelets as well as by exogenous large or unusually large vWF multimers, required adenosine diphosphate and is resistant to aspirin. Blood 1988; 71: 1366-74
77. Hanson SR, Harker LA. Interruption of acute platelet-dependent thrombosis by the synthetic antithrombin D-phenylalanyl-L-proplyl-L-arginyl chloromethylketone. Proc Natl Acad Sci USA 1988; 85: 3184-8
78. Taggart DP, Siddiqi A, Wheatley DJ. Low-dose preoperative aspirin therapy, postoperative blood loss, and transfusion requirements. Ann Thorac Surg 1990; 50: 425-8
79. Bidstrup BP, Royston D, McGuiness C, et al. Aprotinin in aspirin-pretreated patients. Perfusion 1990; 5 Suppl.: 77-81
80. Murkin JM, Lux J, Shannon NA, et al. Aprotinin significantly decreases bleeding and transfusion requirements in patients receiving aspirin and undergoing cardiac operations. J Thorac Cardiovasc Surg 1994; 107: 554-61
81. Kirklin J, Westaby S, Blackstone E. Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983; 86: 845-52
82. Westaby S. Organ system dysfunction after cardiopulmonary bypass: a systemic inflammatory reaction initiated by the extracorporeal circuit. Intensive Care Med 1987; 13: 89-95
83. Murkin JM. Cardiopulmonary bypass and the inflammatory response: a role for serine protease inhibitors? J Cardiothorac Vase Anesth 1997; 11: 19-23
84. Murkin JM, Martzke JS, Buchan AM, et al. A randomized study of the influence of perfusion technique and pH management in 316 patients undergoing coronary artery bypass surgery. II: neurological and cognitive outcomes. J Thorac Cardiovasc Surg 1995; 110: 349-62
85. Harris DNF, Bailey S, Smith P, et al. Brain swelling in the first hour after cardiopulmonary bypass surgery. Lancet 1993; 342: 586-7
86. Kamiya T, Katayama Y, Kashiwagi F, et al. The role of bradykinin in mediating ischemic brain edema in rats. Stroke 1993; 24: 571-6
87. Stump DA, Rogers AT, Hammon JW, et al. Cerebral emboli and cognitive outcome after cardiac surgery. J Cardiothorac Vasc Anesth 1996; 10: 113-9
88. Levy JH, Pifarre R, Schaff HV, et al. A multicenter, double-blind, placebo-controlled trial of aprotinin for reducing blood loss and the requirement for donor-blood transfusion in patients undergoing repeat coronary artery bypass grafting. Circulation 1995; 92: 2236-44
89. Concha M, Munoz I. Experience with low-dose aprotinin. In: Pifarre R, editor. Blood conservation with aprotinin. Philadelphia. PA: Hanley & Belfus, 1995: 293-312
90. Smith PK, Muhlbaier LH. Aprotinin: safe and effective only with the full-dose regimen [editorial]. Ann Thorac Surg 1996; 62: 1575-7
91. Yanamoto H, Kikuchi H, Okamoto S, et al. Preventive effect of synthetic serine protease inhibitor. FUT-175, administered in the acute stage after subarachnoid hemorrhage. Neurosurgery 1992; 30: 351-6
92. Yanamoto H, Kikuchi H, Sato M, et al. Therapeutic trial of cerebral vasospasm with the serine protease inhibitor. FUT-175, administered in the acute stage after subarachnoid hemorrhage. Neurosurgery 1992; 330: 358-63
93. Royston D, Bidstrup BP, Taylor KM, et al. Effect of aprotinin on the need for blood transfusion after repeat open heart surgery. Lancet 1987; 11: 1289-91
94. Rocha E, Llorens R,. Paramo JA, et al. Does desmopressin acetate reduce blood loss after cardiac surgery? Circulation 1988; 77: 1319-23
95. Seear MD, Wadsworth LD, Rogers PC, et al. The effects of desmopressin acetate (DDAVP) on postoperative blood loss in children. J Thorac Cardiovasc Surg 1989; 98: 217-9
96. Brown MR, Swygert TH, Whitten CW, et al. Desmopressin acetate following cardiopulmonary bypass: evaluation of coagulation parameters. J Cardiothorac Anesth 1989; 3: 726-9
97. Hedderich GS, Petsikas DJ, Cooper BA, et al. Desmopressin acetate in uncomplicated coronary bypass surgery: a prospective clinical trial. Can J Surg 1990; 33: 33-6
98. Andersson TLG, Solem JO, Tengborn L, et al. Effects of desmopressin acetate on platelet aggregation, von Willebrand factor, and blood loss after cardiac surgery with extracorporeal circulation. Circulation 1990; 81: 872-8
99. Reich DL, Hammerschlag BC, Rand JH, et al. Desmopressin acetate is a mild vasodilator that does not reduce blood loss in uncomplicated cardiac surgical procedures. J Cardiothorac Vase Anesth 1991; 5: 142-5
100. Frankville DD, Harper B, Lake CL, et al. Hemodynamic consequences of desmopressin administration after cardiopulmonary bypass. Anesthesiology 1991; 74: 988-6
101. Mongan PD, Hosking MP. The role of desmopressin acetate in patients undergoing coronary artery bypass surgery. Anesthesiology 1992; 77: 38-46
102. Ansell J, Klassen V, Lew R, et al. Does desmopressin acetate prophylaxis reduce blood loss after valvular heart operations? J Thorac Cardiovasc Surg 1992; 104: 117-23
103. Gratz I, Koehler J, Olsen D, et al. The effect of desmopressin acetate on postoperative hemorrhage in patients receiving aspirin therapy before coronary artery bypass operations. J Thorac Cardiovasc Surg 1992; 104: 1417-22
104. Marques J, Koehler S, Strelec SR, et al. Repeated dose administration of desmopressin acetate in uncomplicated cardiac surgery: a prospective, blinded, randomized study. J Cardiothorac Vasc Anesth 1992; 6: 674-6
105. Vander Salm TJ, Ansel JE, Okike ON, et al. The role of epsilon-aminocaproic acid in reducing bleeding after cardiac operations: a double-blind randomized study. J Thorac Cardiovasc Surg 1988; 95: 538-40
106. DelRossi AJ, Cernaianu AC, Botros S, et al. Prophylactic treatment of postperfusion bleeding using EACA. Chest 1989; 96: 27-30
107. Horrow JC, Hlavacek J, Strong MD, et al. Prophylactic tranexamic acid decreases bleeding after cardiac operations. J Thorac Cardiovasc Surg 1990; 99: 70-4
108. Van Oeveren W, Janssen NJG, Bidstrup BP, et al. Effects of aprotinin on hemostatic mechanisms during cardiopulmonary bypass. Ann Thorac Surg 1987; 44: 640-5
109. Alajmo F, Calamai G, Perna AM, et al. High-dose aprotinin: hemostatic effects in open heart operations. Ann Thorac Surg 1989; 48: 536-9
110. Dietrich W, Spannagl M, Jochum M, et al. Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization. Anesthesiology 1990; 73: 1119-26
111. Boldt J, Zidkmann B, Czeke A, et al. Blood conservation techniques and platelet function in cardiac surgery. Anesthesiology 1991; 75: 426-32
112. Havel M, Teufelsbauer H, Knobl P, et al. Effect of intraoperative aprotinin administration on postoperative bleeding in patients undergoing cardiopulmonary bypass operation. J Thorac Caridovasc Surg 1991; 101: 968-72
113. Harder MP, Eijsman L, Roozendaal KJ, et al. Aprotinin reduces intraoperalive and postoperative blood loss in membrane oxygenator cardiopulmonary bypass. Ann Thorac Surg 1991; 51: 936-41
114. Dietrich W, Barankay A, Hahnel C, et al. High-dose aprotinin in cardiac surgery: three years experience in 1784 patients. J Cardiothorac Vasc Anesth 1992; 6: 324-7
115. Mohr R, Goor DA, Lusky A, et al. Aprotinin prevents cardiopulmonary bypass-induced platelet dysfunction: a scanning electron microscope study. Circulation 1992; 86 Suppl. 2: 405-9
116. Baele PL, Gomez-Ruiz J, Londot C, et al. Systemic use of aprotinin in cardiac surgery: influence on total homologous exposure and hospital cost. Acta Anaesthesiol Belg 1992; 43: 103-2
117. Cosgrove DM, Heric B, Lytle BW, et al. Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study. Ann Thorac Surg 1992; 54: 1031-8
118. Kawasuji M, Ueyama K, Sakakibara N, et al. Effect of low-dose aprotinin on coagulation and fibrinolysis in cardiopulmonary bypass. Ann Thorac Surg 1993; 55: 1205-9
119. Lemmer Jr JH, Stanford W, Bonney SL, et al. Aprotinin for coronary bypass operations: efficacy, safety, and influence on early saphenous vein graft patency. J Thorac Cardiovasc Surg 1994; 107: 543-53
120. Lemmer Jr JH, Dilling EW, Morton JR, et al. Aprotinin for primary coronary artery bypass grafting: a multicenter trial of three dose regimens. Ann Thorac Surg 1996; 62: 1659-68
121. D'Ambra MN, Akins CW, Blackstone EH, et al. Aprotinin in primary valve replacement and reconstruction: a multicenter, double-blind, placebo-controlled trial. J Thorac Cardiovasc Surg 1996; 112: 1081-9
122. Cicek S, Demirkilic U, Ozal B, et al. Postoperative use of aprotinin in cardiac operations: an alternative to its prophylactic use. J Thorac Cardiovasc Surg 1996; 112: 1462-7
123. Bidstrup BP, Harrison J, Royston D, et al. Aprotinin therapy in cardiac operations: a report on use in 41 cardiac centers in the United Kingdom. Ann Thorac Surg 1993; 55: 971-6
124. Levy J, Bailey J, Salmenpera M. Pharmacokinetics of aprotinin in preoperative cardiac surgical patients. Anesthesiology 1994; 80: 1013-8
125. Wang JS, Lin CY, Hung WT, et al. In vitro effects of aprotinin on activated clotting time measured with different activators. J Thorac Cardiovasc Surg 1992; 104: 1135-40
126. Dietrich W, Dilthey G, Spannagl M, et al. Influence of high-dose aprotinin on anticoagulation, heparin requirement, and celite-and kaolin-activated clotting time in heparin-pretreated patients undergoing open-heart surgery. Anesthesiology 1995; 83: 679-89
127. Dietrich W, Jochum M. Effect of celite and kaolin on activated clotting time in the presence of aprotinin: activated clotting time is reduced by binding of aprotinin to kaolin. J Thorac Cardiovasc Surg 1995; 109: 177-8
128. DeSmet AA, Joen MCN, van Oeveren W, et al. Increased anti-coagulation during cardiopulmonary bypass by aprotinin. J Thorac Cardiovasc Surg 1990; 100: 520-7
129. Chabbat J, Porte P, Tellier M, et al. Aprotinin is a competitive inhibitor of the factor VIIa-tissue factor complex. Thromb Res 1993; 71: 205-15
130. Boisclair MD, Lane DA, Philippou H, et al. Mechanisms of thrombin generation during surgery and cardiopulmonary bypass. Blood 1993; 82: 3350-7
131. van Oeveren W, van Oeveren B, Wildevuur CR. Anticoagulation policy during use of aprotinin in cardiopulmonary bypass [letter]. J Thorac Cardiovasc Surg 1992; 104: 210-1
132. Hunt BJ, Segal HC, Yacoub M. Guidelines for monitoring heparin by the activated clotting time when aprotinin is used during cardiopulmonary bypass [letter]. J Thorac Cardiovasc Surg 1992; 104: 211-2
133. Murkin JM, Hunt BJ. Heparin resistance after aprotinin [letter]. Lancet 1993; 341: 126
134. Josa AM, Lie J, Bianco R, et al. Reduction of thrombosis in canine coronary bypass vein grafts with dipyridamole and aspirin. Am J Cardiol 1981; 47: 1248-54
135. Wendel HP, Heller W, Galleinere MJ. Aprotinin in therapeutic doses inhibits chromogenic peptide substrate assays for protein C. Thromb Res 1994; 74: 543-8
136. Feindt P, Seyfert U, Volkmer I, et al. Is there a phase of hypercoagulability when aprotinin is used in cardiac surgery? J Cardiothorac Surg 1994; 8: 308-14
137. Jegaden O, Vedrinne C, Rossi R. Aprotinin does not compromise arterial graft patency in coronary bypass operations [letter]. J Thorac Cardiovasc Surg 1993; 106: 180-1
138. Bidstrup BP, Underwood SR, Sapsford RN, et al. Effects of aprotinin (Trasylol) on aorto-coronary bypass graft patency. J Thorac Cardiovasc Surg 1993; 105: 147-53
139. Havel M, Grabenwoger F, Schneider J, et al. Aprotinin does not decrease early graft patency after coronary artery bypass grafting despite reducing postoperative bleeding and use of donated blood. J Thorac Cardiovasc Surg 1994; 107: 807-10
140. Lass M, Welz A, Kochs M, et al. Aprotinin in elective primary bypass surgery: graft patency and clinical efficacy. Eur J Cardiothorac Surg 1995; 9: 206-10
141. Sundt TM III, Kouchoukos NT, Saffitz JE, et al. Renal dysfunction and intravascular coagulation with aprotinin and hypothermic circulatory arrest. Ann Thorac Surg 1993; 55: 1418-24
142. Westaby S, Form A, Dunning J, et al. Aprotinin and bleeding in profoundly hypothermic perfusion. Eur J Cardiothorac Surg 1994; 8: 82-6
143. Smith CR, Mongero LB, DeRosa CM, et al. Safety of aprotinin in profound hypothermia and circulatory arrest [letter]. Ann Thorac Surg 1994; 58: 603-9
144. Goldstein DJ, DeRosa CM, Mongero LB, et al. Safety and efficacy of aprotinin under conditions of deep hypothermia and circulatory arrest. J Thorac Cardiovasc Surg 1995; 110: 1615-22
145. Mossinger H, Dietrich W, Spannagel M, et al. Influence of aprotinin on coagulation patterns and blood loss in infants undergoing surgery for congenital heart defects [abstract]. Anesthesiology 1991; 75: A77
146. Dietrich W, Mossinger H. The use of aprotinin in pediatric cardiopulmonary bypass. In: Pifarre R, editor. Blood conservation with aprotinin. Philadelphia (PA): Hanley & Belfus, 1995: 275-86
147. Seto S, Kher V, Scicli AG, et al. The effect of aprotinin (a serine protease inhibitor) on renal function and renin release. Hypertension 1983; 5: 893-9
148. Emerson Jr TE. Pharmacology of aprotinin and efficacy during cardiopulmonary bypass. Cardiovasc Drug Rev 1989; 7: 127-40
149. Fischer JH, Knupfer P. High-dose aprotinin (Trasylol) therapy - harmless to the kidney? [in German] Langenceck Arch Chir 1983; 5: 893-9
150. Blahut B, Gross C, Necek S, et al. Effects of high-dose aprotinin on blood loss, platelet function, fibrinolysis, complement, and renal function after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1991; 101: 958-67
151. Lemmer Jr JH, Metzdorff MT, Krause AH, et al. Aprotinin use in patients with dialysis-dependent renal failure undergoing cardiac operations. J Thorac Cardiovasc Surg 1996; 112: 192-4
152. Lemmer Jr JH, Stanford W, Bonney SL, et al. Aprotinin for coronary artery bypass grafting: effect on postoperative renal function. Ann Thorac Surg 1995; 59: 132-6
153. Leskiw U, Levy JH. Antigenicity of protamine and aprotinin in cardiac surgery. In: Pifarre R, editor. Blood conservation with aprotinin. Philadelphia (PA): Hanley & Belfus, 1995: 253-66
154. Dietrich W, Hahnel C, Richter JA. Routine application of high-dose aprotinin in open-heart surgery: a study on 1784 patients [abstract]. Anesthesiology 1940; 73: A146
155. Fraedrich G, Neukamm K, Schneider T, et al. Safety and risk/benefit assessment of aprotinin in primary CABG. In: Friedel N, Hertzer R, Royston D, editors. Blood use in cardiac surgery. New York: Springer-Verlag, 1941: 221-31
156. Dewachter P, Mouton C, Gueant JL, et al. Anaphylactic reaction to aprotinin during cardiac surgery [letter]. Anaesthesia 1993; 48: 1110-1
157. Yanagihara Y, Shida T. Immunological studies on patients who received aprotinin therapy [in Japanese]. Arerugi 1985; 34: 899-904
158. Ceriana P, Maurelli M, Locatelli A, et al. Anaphylactic reaction to aprotinin [letter]. J Cardiothorac Vasc Anesth 1995; 9: 477-8
159. Royston D. Control of perioperative bleeding with serine protease inhibitors. In: Weschler AS, editor. Pharmacological management of perioperative bleeding. Southampton (NY): CME Network Publishing, 1996: 35-45