Aprotinin Has no Effect on Platelet Activation and Adhesion during Cardiopulmonary Bypass

Summary

Aprotinin reduces blood loss following cardiopulmonary bypass operations (CPB) by the prevention of hyperfibrinolysis. Its influence on circulating platelets is uncertain. In this prospective trial we investigated activation, adhesion, and aggregation receptors on the platelet surface in 20 patients who underwent elective coronary artery bypass grafting. These patients were randomly assigned to receive either a high dose of aprotinin or placebo. Flow cytometry was performed to determine platelet activation [P-selectin, glycoprotein (GP) 53], adhesive (GP Ib), and aggregatory (GP IIb-IIIa) receptors on circulating platelets, before, during, and after CPB. Aprotinin had neither a significant effect on platelet activation nor on adhesive and aggregatory receptors. Plasma levels of D-dimers were measured before and after CPB to assess fibrinolytic activity. D-dimers following CPB and chest tube drainage were significantly less in the aprotinin group. We conclude that aprotinin reduces blood loss by its effect on fibrinolysis but has no direct influence on platelet function.

• References

• 1 Woodman RC, Harker LA. Bleeding complications associated with cardiopulmonary bypass. Blood 1990; 76: 1680-1697
• 2 Wachtfogel YT, Harpel PC, Edmunds Jr LH, Colman RW. Formation of C1_S-C1 -inhibitor, kallikrein-Cl-inhibitor, and plasmin-μ₂-plasmin-inhibi-tor complexes during cardiopulmonary bypass. Blood 1989; 73: 468-471
• 3 Havel M, Grabenwöger F, Schneider J, Läufer G, Wollenek G, Owen A, Simon P, Teufelsbauer H, Wolner E. 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: 807-810
• 4 Van Oeveren W, Harder MP, Roozendaal KJ, Eijsman L, Wildevuur CRH. Aprotinin protects platelets against the initial effect of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990; 99: 788-797
• 5 Gram J, Janetzko T, Jespersen J, Bruhn HD. Enhanced effective fibrinolysis following the neutralization of heparin in open heart surgery increases the risk of post-surgical bleeding. Thromb Haemost 1990; 63: 241-245
• 6 Harker LA, Malpass TW, Branson HE, Hessel II EA, Slichter SJ. Mechanism of abnormal bleeding in patients undergoing cardiopulmonary bypass: acquired transient platelet dysfunction associated with selective α-granule release. Blood 1980; 56: 824-834
• 7 Kestin AS, Shukri CR, Loscalzo J, Ellis PA, MacGregor H, Birjiniuk V, Quimet H, Pasche B, Nelson MJ, Benoit SE, Rodino LJ, Barnard MR, Michelson AD. The platelet function defect of cardiopulmonary bypass. Blood 1993; 82: 107-117
• 8 Rinder CS, Mathew JP, Rinder HM, Bonan J, Ault KA, Smith BR. Modulation of platelet surface adhesion receptors during cardiopulmonary bypass surgery. Anesthesiology 1991; 75: 563-570
• 9 Wahba A, Black G, Koksch M, Rothe G, Preuner J, Schmitz G, Birnbaum DE. The effect of heparin and cardiopulmonary bypass on thrombocyte function: a flow cytometric assay of platelet surface antigens. EJCTS 1996, accepted for publication
• 10 Royston D. High-dose aprotinin therapy: a review of the first five years’ experience. J Cardiothorac Anesth 1992; 6: 076-100
• 11 Royston D, Taylor KM, Bidstrup BP, Sapsford RN. Effect of aprotinin on need for blood transusion after repeated open-heart surgery. Lancet 1987; II: 1289-1291
• 12 Kallis P, Tooze JA, Talbot S, Cowans D, Bevan DH, Treasure T. Aprotinin inhibits fibrinolysis, improves platelet adhesion and reduces blood loss. Eur J Cardiothorac Surg 1994; 8: 315-323
• 13 Westaby S, Forni A, Dunning J, Giannopoulus N, O’Regan D, Drossos G, Pillai R. Aprotinin and bleeding in profoundly hypothermic perfusion. Eur J Cardiothorac Surg 1994; 8: 82-86
• 14 Havel M, Teufelsbauer H, Knöbl P, Dalmatiner R, Jaksch P, Zwofel W, Müller W, Vukovich T. Effect of intraoperative aprotinin administration on postoperative bleeding in patients undergoing cardiopulmonary bypass operation. J Thorac Cardiovasc Surg 1991; 101: 968-972
• 15 Blauhut B, Gross Ch, Necek S, Doran JE, Späth P, Lundsgaard-Hansen P. Effects of high-dose aprotinin on blood loss, platelet function, fibrinolysis, complement, and renal function after cardiopulmonary bypass. J Throrac Cardiovasc Surg 1991; 101: 958-967
• 16 Adelman B, Michelson AD, Loscalzo J, Greenberg J, Handin RI. Plasmin effect on platelet glycoprotein Ib-von Willebrand factor interactions. Blood 1985; 65: 32-40
• 17 Penny WF, Ware JA. Platelet activation and subsequent inhibition by and recombinant tissue-type plasminogen activator. Blood 1992
• 18 Pasche B, Ouimet H, Francis S, Loscalzo J. Structural changes in platelet glycoprotein IIb/IIIa by plasmin: determinants and functional consequences. Blood 1994; 83: 404-414
• 19 Nurden AT, Macchi L, Bihour C, Durrieu C, Besse P, Nurden P. Markers of platelet activation in coronary heart disease patients. Eur J Clin Invest 1994; 24 Suppl I 42-45
• 20 Van Oeveren W, Jansen NJG, Bidstrup BP, Royston D, Westaby S, Neuhof H, Wildevuur CR. Effects of aprotinin on hemostatic mechanisms during cardiopulmonary bypass. Ann Thorac Surg 1987; 44: 640-645
• 21 George JN, Nurden AT, Phillips DR. Molecular defects in interactions of platelets with the vessel wall. N Engl J Med 1984; 311: 1084-1098
• 22 Matzdorff AC, Green D, Cohen I, Bauer KD. Effect of recombinant aprotinin on platelet activation in patients undergoing open heart surgery. Haemostasis 1993; 23: 293-300
• 23 Mirshahi M, Soria J, Soria C, Perrot J-Y, Boucheix C. A latex immunoassay of fibrin/fibrinogen degradation products in plasma using a monoclonal antibody. Thromb Res 1986; 44: 715-728
• 24 Huang H, Ding W, Su Z, Zhang W. Mechanism of the preserving effect of aprotinin on platelet function and its use in cardiac surgery. J Thorac Cardiovasc Surg 1993; 106: 11-18
• 25 Valen G, Eriksson E, Risberg B, Vaage J. Fibrinolysis during cardiac surgery. Release of tissue plasminogen activator in arterial and coronary sinus blood. Eur J Cardiothorac Surg 1994; 8: 324-330
• 26 Páramo JA, Rifon J, Llorens R, Casares J, Paloma MJ, Rocha E. Intra- and postoperative fibrinolysis in patients undergoing cardiopulmonary bypass surgery. Haemostasis 1991; 21: 58-64
• 27 Valeri CR, Khabbaz K, Khuri SF, Marquardt C, Ragno G, Feingold H, Gray AD, Axford T. Effect of skin temperature on platelet function in patients undergoing extracorporeal bypass. J Thorac Cardiovasc Surg 1992; 104: 108-116
• 28 Wachtfogel YT, Kucich U, Hack CE, Gluszko P, Niewiarowski S, Colman RW, Edmunds Jr LH. Aprotinin inhibits the contact, neutrophil, and platelet activation system during simulated extracorporeal perfusion. J Thorac Cardiovasc Surg 1993; 106: 01-10
• 29 Wenger RK, Lukasiewicz H, Mikuta BS, Niewiarowski S, Edmunds LH. Loss of platelet fibrinogen receptors during clinical cardiopulmonary bypass. J Thorac Cardiovasc Surg 1989; 97: 235-239
• 30 van Oeveren W, Eijsman L, Roozendaal KJ, Wildevuur ChRH. Platelet preservation by aprotinin during cardiopulmonary bypass. Lancet 1988; 1586: 644
• 31 Orchard MA, Goodchild CS, Prentice CR, Davies JA, Benoit SE, Creighton-Kemsford LJ, Gaffney PJ, Michelson AD. Aprotinin reduces cardiopulmonary bypass-induced blood loss and inhibits fibrinolysis without influencing platelets. Br J Haematol 1993; 85: 533-541
• 32 Lu H, Soria C, Commin P-L, Soria J, Piwnica A, Schumann F, Regnier O, Legrand Y, Caen JP. Hemostasis in patients undergoing extracorporeal circulation: the effect of aprotinin (Trasylol). Thromb Haemost 1991; 66: 633-637
• 33 Matzdorff AC, Green D, Cohen I, Bauer KD. Effect of recombinant aprotinin on platelet activation in patients undergoing open heart surgery. Haemostasis 1993; 23: 293-300
• 34 Tabuchi N, De Haan J, Boonstra PW, Gallandat HuetRCG, van Oeveren W. Aprotinin effect on platelet function and clotting during cardiopulmonary bypass. Eur J Cardiothorac Surg 1994; 8: 87-90
• 35 Lavee J, Raviv Z, Smolinsky A, Savion N, Varon D, Goor DA, Mohr R. Platelet protection by low-dose aprotinin in cardiopulmonary bypass: electron microscopic study. Ann Thorac Surg 1993; 55: 114-119
• 36 Edmunds Jr LH, Ellison N, Colman RW, Niewiarowski S, Rao AK, Addonizio Jr VP, Stephenson LW, Edie RN. Platelet function during cardiac operations: comparison of membrane and bubble oxygenators. J Cardiovasc Surg 1982; 83: 805-812