Correspondence  |   December 1998
The Blood Sparing Effect of Aprotinin Should Be Revisited 
Author Notes
  • Associate Professor of Anesthesiology; Lapeyronie University Hospital; 371, Av du Doyen; Gaston Giraud Montpellier Cedex 5; Paris 34295, France
Article Information
Correspondence   |   December 1998
The Blood Sparing Effect of Aprotinin Should Be Revisited 
Anesthesiology 12 1998, Vol.89, 1599-1600. doi:
Anesthesiology 12 1998, Vol.89, 1599-1600. doi:
In Reply:-I would like to thank Dr. Lentschener and Dr. Benhamou for the attentive reading they have accorded to our article. [1] 
Although the mechanisms underlying the beneficial effects of aprotinin on blood loss during surgery were not fully elucidated, reconsidering the hypotheses evoked in the literature involving platelet receptor protection may not be fully justified.
The complex action of aprotinin, a natural serine protease inhibitor, is situated at the cross-section of several reactions triggered during surgery: contact phase activation, tissue factor and tissue plasminogen activator (tpa) release from subendothelial sites, plasmin activation by kallikrein and activated factor XII, as well as the release of kinins and activated C3b fragments. [2-4] Furthermore, aprotinin activation depends on blood aprotinin levels, and as such the administered perioperative dose, whether or not cardiopulmonary bypass (CPB) is used.
Major surgery can activate the extrinsic coagulation pathway by the release of tissue factor from the endothelial cells. [4,5] Aprotinin can limit the onset of disseminated intravascular coagulopathy (DIC) via its anti-VIIa activity. [6] 
Aprotinin's role in the inhibition of fibrinolysis, reported primarily in works concerning liver surgery, [7,8] is based on the limitation of contact phase activation, [9] direct anti-plasmin activity by inhibition of tpa release, [7,10] and protein C activity. [11] Aprotinin also has been shown to have a local antifibrinolytic effect, limiting perioperative bleeding when injected directly into the pericardial cavity. [12,13] During surgery performed without CPB, this antifibrinolytic effect probably implies aprotinin activity. Both the limited postoperative d-dimer values seen in our patients treated with aprotinin [1] and the greater number of patients in Janssens et al.'s [14] control group presenting higher than normal d-dimer values seem to confirm the hypothesis.
It is not improbable that aprotinin's role in limiting bleeding is based on a multimodal mechanism. During surgery with CPB, aprotinin activity seems to primarily involve platelet receptor protection from plasmin activity and contact phase activation. [15] In contrast, a more global action on fibrinolysis and DIC seems to predominate during major surgery without CPB.
In consequence, aprotinin would achieve one therapeutic goal by several different mechanisms of action.
Xavier Capdevila, M.D., Ph.D.
Associate Professor of Anesthesiology; Lapeyronie University Hospital; 371, Av du Doyen; Gaston Giraud Montpellier Cedex 5; Paris 34295, France
(Accepted for publication July 20, 1998.)
Capdevila X, Calvet Y, Biboulet PH, Biron C, Rubenovitch J, d'Athis F: Aprotinin decreases blood loss and homologous transfusions in patients undergoing major orthopedic surgery. Anesthesiology 1998; 88:50-7
Royston D: High-dose aprotinin therapy: A review of the first five year's experience. J Cardioth Vasc Anesth 1992; 6:76-100
Hardy JF, Desroches J: Natural and synthetic antifibrinolytics in cardiac surgery. Can J Anaesth 1992; 39:353-65
Murphy WG, Davies MJ, Eduardo A: The haemostatic response to surgery and trauma. Br J Anaesth 1993; 70:205-13
Harke H, Rahman S: Haemostatic disorders in massive transfusion. Bibl Haematol 1980; 46:179-88
Chabbat J, Porte P, Tellier M, Steinbuch M: Aprotinin is a competitive inhibitor of the factor VIIa-tissue factor complex. Thromb Res 1993; 71:205-15
Segal HC, Hunt BJ, Cottam S, Downing A, Beard C, Francis JL, Potter D, Tan KC: Fibrinolytic activity during orthotopic liver transplantation with and without aprotinin. Transplantation 1994; 58:1356-60
Lentschener C, Benhamou D, Mercier F, Boyer-Neumann C, Smadja C, Wolf M, Franco D: Aprotinin reduces blood loss in elective liver resection. Anesth Analg 1997; 84:875-81
Laurel MT, Ratnoff OD, Everson B: Inhibition of the activation of Hageman factor (factor XII) by aprotinin (Trasylol). J Lab Clin Med 1992; 119:580-5
Hunt BJ, Cottam S, Segal H, Ginsburg R, Potter D: Inhibition by aprotinin of tPA-mediated fibrinolysis during orthotopic liver transplantation (letter). Lancet 1990; 336(8711):381
Espana F, Estelles A, Griffin JH, Aznar J, Gilabert J: Aprotinin (trasylol) is a competitive inhibitor of activated protein C. Thromb Res 1989; 56:751-6
Tatar H, Cicek S, Demirkilic U, Ozal E, Suer H, Ozturk O, Isiklar H: Topical use of aprotinin in open heart operations. Ann Thorac Surg 1993; 55:659-61
O'Regan DJ, Giannopoulos N, Mediratta N, Kendall SW, Forni A, Pilai R, Westaby S: Topical aprotinin in cardiac operations. Ann Thorac Surg 1995; 60:1155
Janssens M, Joris J, Davis JL, Lemaire R, Lamy M: High-dose aprotinin reduces blood loss in patients undergoing total hip replacement surgery. Anesthesiology 1994; 80:23-9
Wachtfogel YT, Harpel PC, Edmunds LH Jr, Colman RW: Formation of C1s-inhibitor, kallikrein-C&-inhibitor and plasma-alpha2-plamins-inhibitor complexes during cardiopulmonary bypass. Blood 1989; 73:468-71