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The Journal of Thoracic and Cardiovascular Surgery, Vol 99, 788-796, Copyright © 1990 by The American Association for Thoracic Surgery and The Western Thoracic Surgical Association
W van Oeveren, MP Harder, KJ Roozendaal, L Eijsman and CR Wildevuur
Remarkable improvement in hemostasis after cardiopulmonary bypass has been
achieved by treatment with the proteinase inhibitor aprotinin, but the
mechanism is still unclear. The present study is designed to elucidate the
importance of platelet adhesive (glycoprotein Ib) or aggregatory
(glycoprotein IIbIIIa) receptors on this hemostatic function in
cardiopulmonary bypass and its improvement by aprotinin treatment. To
determine whether the first pass of blood through the circuit or a
continuous proteolytic attack is the main cause of platelet damage, we gave
two different dose regimens of aprotinin treatment to patients undergoing
coronary artery bypass grafting. Part I of the study consisted of a
double-blind trial on 60 patients. Patients received placebo or aprotinin
infusion (total 6.10(6) KIU) before and during bypass. A consecutive group
of 22 matching patients received one single bolus of aprotinin in the pump
prime (2.10(6) KIU). Blood samples were collected before and during
operation to assess the effect of bypass and aprotinin on platelets and the
activation of the various proteases in relation to hemostasis expressed in
blood loss and blood requirements. The adhesive platelet membrane Ib
glycoproteins were decreased by 50% in the untreated patients within 5
minutes of cardiopulmonary bypass and remained low during bypass, whereas
glycoprotein Ib did not decrease in either group of aprotinin-treated
patients. The platelet membrane IIbIIIa glycoproteins did not significantly
change during bypass in either group, but fibrinogen binding to these
receptors improved significantly in the 6.10(6) KIU aprotinin-treated group
at the end of bypass as compared with initial values. The high continuous
dose of 6.10(6) KIU aprotinin inhibited the clotting and kallikrein/kinin
system throughout the operation; the pump prime dose of 2.10(6) KIU
inhibited these systems only initially. Although the fibrinolytic activity
was effectively inhibited in both aprotinin groups, fibrinolytic activity
became apparent only at the end phase of bypass in the placebo group.
However, improved hemostasis was observed intraoperatively from the start
of bypass and resulted in a 40% lower blood loss intraoperatively and
postoperatively and consequently a 40% lower total blood requirement in the
aprotinin- treated patients than in the untreated patients. Our results
therefore demonstrate that the improved hemostasis during and after bypass
in patients treated with aprotinin has specifically to be attributed to a
preserved adhesive capacity of platelets that was affected in the first
pass of blood through the cardiopulmonary bypass circuit.
ARTICLES
Aprotinin protects platelets against the initial effect of cardiopulmonary bypass
Department of Cardiopulmonary Surgery, University Hospital Groningen, The Netherlands.
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 G. Escolar, J. G. White;, G. H. van Zanten, H. F.G. Heijnen, Y.-P. Wu, K. M. Schut-Hese, P. J. Slootweg, P. G. De Groot, J. J. Sixma, and R. Nieuwland Distribution of GPIb on and in Resting Platelets Blood, December 15, 1998; 92(12): 4874 - 4877. [Full Text] [PDF]
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J. A. Hyde, J. A Chinn, and T. R Graham Platelets and cardiopulmonary bypass Perfusion, December 1, 1998; 13(6): 389 - 407. [PDF]
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T. P. Carrel, M. Schwanda, P. R. Vogt, and M. I. Turina Aprotinin in pediatric cardiac operations: a benefit in complex malformations and with high-dose regimen only Ann. Thorac. Surg., July 1, 1998; 66(1): 153 - 158. [Abstract] [Full Text] [PDF]
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K. Mellgren, G. Mellgren, S. Lundin, A. Wennmalm, and H. Wadenvik Effect of Nitric Oxide Gas on Platelets During Open Heart Operations Ann. Thorac. Surg., May 1, 1998; 65(5): 1335 - 1341. [Abstract] [Full Text] [PDF]
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G. H. van Zanten, H. F.G. Heijnen, Y. Wu, K. M. Schut-Hese, P. J. Slootweg, P. G. de Groot, J. J. Sixma, and R. Nieuwland A Fifty Percent Reduction of Platelet Surface Glycoprotein Ib Does Not Affect Platelet Adhesion Under Flow Conditions Blood, April 1, 1998; 91(7): 2353 - 2359. [Abstract] [Full Text] [PDF]
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G. Cohen, J. Ivanov, R. D. Weisel, V. Rao, M. K. Mohabeer, and D. A. G. Mickle Aprotinin and Dipyridamole for the Safe Reduction of Postoperative Blood Loss Ann. Thorac. Surg., March 1, 1998; 65(3): 674 - 683. [Abstract] [Full Text] [PDF]
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 R. Pifarre Use of Aprotinin in the Control of Bleeding During Cardiopulmonary Bypass Surgery: Current Status Clinical and Applied Thrombosis/Hemostasis, January 1, 1998; 4(1): 2 - 6. [Abstract] [PDF]
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W. Dietrich, K. Schopf, M. Spannagl, M. Jochum, S. L. Braun, and H. Meisner Influence of High- and Low-Dose Aprotinin on Activation of Hemostasis in Open Heart Operations Ann. Thorac. Surg., January 1, 1998; 65(1): 70 - 77. [Abstract] [Full Text] [PDF]
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M. Ehrlich, M. Grabenwoger, F. Cartes-Zumelzu, D. Luckner, J. Kovarik, G. Laufer, A. Kocher, R. Konetschny, E. Wolner, and M. Havel Operations on the thoracic aorta and hypothermic circulatory arrest: Is aprotinin safe? J. Thorac. Cardiovasc. Surg., January 1, 1998; 115(1): 220 - 224. [Abstract] [Full Text] [PDF]
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B. D. Spiess Endothelial Cell-Blood Interface Actions and the Procoagulant Response Seminars in Cardiothoracic and Vascular Anesthesia, November 1, 1997; 1(4): 288 - 294. [Abstract] [PDF]
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S. Westaby Aprotinin Fifteen Years Later Seminars in Cardiothoracic and Vascular Anesthesia, November 1, 1997; 1(4): 366 - 375. [Abstract] [PDF]
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 G. J. Despotis, J. H. Joist, and L. T. Goodnough Monitoring of hemostasis in cardiac surgical patients: impact of point-of-care testing on blood loss and transfusion outcomes Clin. Chem., September 1, 1997; 43(9): 1684 - 1696. [Abstract] [Full Text] [PDF]
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N. Hayashida, T. Isomura, T. Sato, H. Maruyama, K. Kosuga, and S. Aoyagi EFFECTS OF MINIMAL-DOSE APROTININ ON CORONARY ARTERY BYPASS GRAFTING J. Thorac. Cardiovasc. Surg., August 1, 1997; 114(2): 261 - 269. [Abstract] [Full Text]
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O. Shigeta, H. Kojima, T. Jikuya, Y. Terada, N. Atsumi, Y. Sakakibara, T. Nagasawa, and T. Mitsui Aprotinin Inhibits Plasmin-Induced Platelet Activation During Cardiopulmonary Bypass Circulation, July 15, 1997; 96(2): 569 - 574. [Abstract] [Full Text]
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C. C Hlozek, N. G Smedira, T. J Kirby, A. N Patel, and M. Perl Cardiopulmonary bypass (CPB) for lung transplantation Perfusion, March 1, 1997; 12(2): 107 - 112. [Abstract] [PDF]
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S. Allen, N. Anastasiou, D. Royston, R. Paniagua, and M. Yacoub EFFECT OF APROTININ ON VASCULAR REACTIVITY OF CORONARY BYPASS GRAFTS J. Thorac. Cardiovasc. Surg., February 1, 1997; 113(2): 319 - 326. [Abstract] [Full Text]
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C. Baufreton, P. G. M. Jansen, P. Le Besnerais, H. Velthuis, C. M. Thijs, C. R. H. Wildevuur, and D. Y. Loisance Heparin Coating With Aprotinin Reduces Blood Activation During Coronary Artery Operations Ann. Thorac. Surg., January 1, 1997; 63(1): 50 - 56. [Abstract] [Full Text]
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S. Ashraf, Y. Tian, D. Cowan, U. Nair, R. Chatrath, N. R. Saunders, K. G. Watterson, and P. G. Martin ""Low-Dose"" Aprotinin Modifies Hemostasis but Not Proinflammatory Cytokine Release Ann. Thorac. Surg., January 1, 1997; 63(1): 68 - 73. [Abstract] [Full Text]
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J. H. Lemmer Jr, E. W. Dilling, J. R. Morton, J. B. Rich, F. Robicsek, D. L. Bricker, C. B. Hantler, J. G. Copeland III, J. L. Ochsner, P. O. Daily, et al. Aprotinin for Primary Coronary Artery Bypass Grafting: A Multicenter Trial of Three Dose Regimens Ann. Thorac. Surg., December 1, 1996; 62(6): 1659 - 1668. [Abstract] [Full Text]
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S. Cicek, U. Demirkilic, E. Ozal, E. Kuralay, H. Bingol, H. Tatar, and O. Y. Ozturk POSTOPERATIVE USE OF APROTININ IN CARDIAC OPERATIONS: AN ALTERNATIVE TO ITS PROPHYLACTIC USE J. Thorac. Cardiovasc. Surg., December 1, 1996; 112(6): 1462 - 1467. [Abstract] [Full Text]
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R. E. Helm, J. D. Klemperer, T. K. Rosengart, J. P. Gold, P. Peterson, W. DeBois, N. K. Altorki, S. Lang, S. Thomas, O. W. Isom, et al. Intraoperative Autologous Blood Donation Preserves Red Cell Mass But Does Not Decrease Postoperative Bleeding Ann. Thorac. Surg., November 1, 1996; 62(5): 1431 - 1441. [Abstract] [Full Text]
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E. M. Boyle Jr, E. D. Verrier, and B. D. Spiess Endothelial Cell Injury in Cardiovascular Surgery: The Procoagulant Response Ann. Thorac. Surg., November 1, 1996; 62(5): 1549 - 1557. [Abstract] [Full Text]
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T. J. Vander Salm, S. Kaur, R. A. Lancey, O. N. Okike, A. T. Pezzella, R. F. Stahl, L. Leone, J.-M. Li, C. R. Valeri, and A. D. Michelson REDUCTION OF BLEEDING AFTER HEART OPERATIONS THROUGH THE PROPHYLACTIC USE OF EPSILON-AMINOCAPROIC ACID J. Thorac. Cardiovasc. Surg., October 1, 1996; 112(4): 1098 - 1107. [Abstract] [Full Text]
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T. W. Prendergast, S. Furukawa, A. J. Beyer III, H. J. Eisen, J. B. McClurken, and V. Jeevanandam Defining the Role of Aprotinin in Heart Transplantation Ann. Thorac. Surg., September 1, 1996; 62(3): 670 - 674. [Abstract] [Full Text]
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Y. J. Gu, J. de Haan, U. P. M. Brenken, W. J. de Boer, Jm. Prop, W. van Oeveren, and G. L. T. Group CLOTTING AND FIBRINOLYTIC DISTURBANCE DURING LUNG TRANSPLANTATION: EFFECT OF LOW-DOSE APROTININ J. Thorac. Cardiovasc. Surg., September 1, 1996; 112(3): 599 - 606. [Abstract] [Full Text]
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