Hemostasis in Patients Undergoing Extracorporeal Circulation: The Effect of Aprotinin (Trasylol)

Summary

The administration of aprotinin during extracorporeal circulation (ECC) reduces blood loss. To explore the mechanism of this effect, a placebo-controlled double-blind study was performed in 20 patients (10 were administered with a high dose of aprotinin, 10 with placebo) undergoing a primary, elective operation of coronary artery bypass grafting (CABG) with ECC. Biological tests were performed at 4 different time points during the operation.

A marked reduction in the placebo group of ristocetin-induced platelet agglutination (binding of von Willebrand factor [vWF] to platelet glycoprotein [GP] Ib) was shown during ECC and at the end of surgery, but not in the aprotinin group. This abnormality is not related to the hydrolysis of vWF or GP Ib, since washed platelets were resuspended in pooled normal plasma which provided a constant amount of vWF in this test and since the plasma concentration of the fragment of GP Ib (glycocalicin) did not correlate with this abnormality.

Despite a high concentration of heparin (5-7 IU/ml) in patient's plasma during bypass, activation of blood coagulation in both groups was evidenced by an increase in ATm (thrombin-modified antithrombin III) level. The level of ATm in the placebo group reached a maximum at the end of ECC during rewarming, while in the aprotinin group, ATm level at this time point was significantly lower than in the control group. In comparison to the placebo group, the generation of the fibrin degradation products (DDE complexes) was inhibited by aprotinin during ECC, but the level of DDE complexes in the aprotinin group was slightly elevated after ECC, although much less than in the placebo group. Other parameters measured did not show significant differences between the two groups.

These results indicate that the hemostatic defect in patients during and after ECC may result, at least in part, from the impairment of GP Ib-dependent platelet adhesion. Therefore, the administration of aprotinin in ECC may improve hemostasis by abrogating this impairment, in addition to the protective effect of aprotinin on hemostatic plug. Activation of blood coagulation occurs during cardiopulmonary bypass despite heparin therapy and this activation seems to be partially inhibited by aprotinin administration.

• References

• 1 Bick RL. Hemostasis defects associated with cardiac surgery, prosthetic devices, and other extracorporeal circuits. Semin Thromb Hemostas 1982; 11: 3249-80
• 2 Harker LA. Bleeding after cardiopulmonary bypass. N Engl J Med 1986; 314: 1446-8
• 3 Woodman RC, Harker LA. Bleeding complications associated with cardiopulmonary bypass. Blood 1990; 76: 1680-97
• 4 Harker LA, Malpass TW, Branson HE, Hessel 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: 824-34
• 5 Van Oeveren W, Eijsman L, Roozendaal KJ, Wildevuur CR. Platelet preservation by aprotinin during cardiopulmonary bypass. Lancet 1988; I: 644
• 6 de Smet AAEA, Joen MCN, van Oeveren W, Roozendaal KJ, Harder MP, Eijsman Wildevuur. Increased anticoagulation during cardiopulmonary bypass by aprotinin. J Thorac Cardiovasc Surg 1990; 100: 520-7
• 7 Tanaka K, Morimoto T, Yada I, Kusagawa M, Deguchi K. Physiologic role of enhanced fibrinolytic activity during cardiopulmonary bypass in open heart surgery. Trans Am Soc Artif Intern Organs 1987; 33: 505-9
• 8 Bidstrup BP, Roystrom D, Sapsford RN, Taylor KM. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (Trasylol). J Thorac Cardiovasc Surg 1990; 97: 364-72
• 9 Verstraete M. Clinical application of inhibitors of fibrinolysis. Drugs 1985; 29: 236-61
• 10 Adelman B, Michelson AD, Loscalzo J, Greenberg J, Handin R. Plasmin effect on platelet glycoprotein Ib-von Willebrand factor interactions. Blood 1985; 65: 32-40
• 11 Cramer EM, Lu H, Caen JP, Soria C, Tenza D. Differential redistribution of platelet glycoproteins Ib and IIb-IIIa after plasmin stimulation. Blood 1991; 77: 694-9
• 12 Schafer AI, Maas AN, Ware JA, Johnson PC, Rittenhouse SE, Salzman EW. Platelet protein phosphorylation, elevation of cytosolic calcium, and inositol phospholipid breakdown in platelet activation induced by plasmin. J Clin Invest 1986; 78: 73-9
• 13 Lu H, Soria C, Cramer EM, Soria J, Perrot JY, Li H, Commin PL, Schumann F, Regnier O, Lijnen RH, Caen JP. Temperature dependence of plasmin-induced platelet activation or inhibition of human platelets. Blood 1991; 77: 996-1105
• 14 Coller BS, Gralnick HR. Studies on the mechanism of ristocetin-induced platelet agglutination. Effect of structural modification of ristocetin and vancomycin. J Clin Invest 1977; 60: 302-12
• 15 Okumura T, Lombart C, Jamieson GA. Platelet glycocalicin. II. Purification and characterization. J Biol Chem 1976; 252: 5950-5
• 16 Michelson AD, Melnick B, Loscalzo J, Handin RI. Partial characterization of a binding site for von Willebrand's factor on glycocalicin. Blood 1983; 62: 953 a (abstr)
• 17 Amiral J, Vissac AM, Mimilla F, Grosley B. Assay of blood activation by measurement of AT III-serine esterases complexes (ATM) using a specific monoclonal antibody 4C9. Thromb Haemostas 1989; 62: 479 (abstr)
• 18 Soria J, Soria C, Mirshahi Mc, Mirshahi M, Boucheix C, Pujade E, Perrot JY, Samama M, Bernadou A, Caen JP. Le complexe DDE. CR Acad Sci Paris 1987; 3 04: III(11) 307-11
• 19 Ruan C, Du X, Xi X, Castaldi PA, Berndt MC. A murine antiglycoprotein Ib complex monoclonal antibody SZ 2, inhibitis platelet aggregation induced by both ristocetin and collagen. Blood 1987; 69: 570-7
• 20 Nagaoka H, Katori M. Inhibition of kinin formation by a kallikrein inhibitor during extracorporeal circulation in open heart surgery. Circulation 1975; 52: 325-32
• 21 Wachtfogel YT, Kucich U, James HL, Scott CF, Schapira M, Zimmermann M, Cohen AB. Human plasma kallikrein releases neutrophil elastase during blood coagulation. J Clin Invest 1983; 72: 1672-7
• 22 Gram J, Janetzko T, Jespersen J, Bruhn HD. Enhanced effective fibrinolysis following the neutralization of heparin in open heart surgery increases the risk of postsurgical bleeding. Thromb Haemostas 1990; 63: 241-5