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J Thorac Cardiovasc Surg 1995;109:400-401
© 1995 Mosby, Inc.

LETTERS TO THE EDITOR

Invited letter concerning: Topical aprotinin

L. Henry Edmunds, Jr., MD

Department of Surgery
4 Silverstein
Hospital of the University of Pennsylvania
3400 Spruce St.
Philadelphia, PA 19104

To the Editor:

The use of topical aprotinin as proposed by Tatar and associates Go 1 is based on an empiric observation and needs to be confirmed. The idea is interesting, but the mechanism is not clear. The data and insights presented by Tabuchi, de Haan, and van Oeveren Go 2 are very relevant and valuable.

The association constant (Ki) of aprotinin and plasmin is 023 nmol/L, but it is only 30 nmol/L for kallikrein. Go 3 The high-dose protocol (4 mg/kg load; 4 mg/kg in pump prime) produces blood concentrations during cardiopulmonary bypass (CPB) of approximately 175 to 275 KIU/ml; with the half-dose protocol, concentrations range from approximately 115 to 165 KIU/ml. Go 4 These concentrations established before and during the operation are sufficient to completely inhibit plasmin and succeed in attenuating production of D-dimer, a marker of fibrinolysis. Go 5 In addition, systemic aprotinin protects the platelet glycoprotein Ib receptor, probably by preventing plasmin-induced infolding of the receptor into platelet subcannicular canals as demonstrated by Cramer and associates. Go 6 This makes the glycoprotein Ib receptor available to participate in the formation of the hemostatic plug to produce the decrease in postoperative bleeding times associated with systemic aprotinin. Go 7 Platelet activation is also suppressed by unknown mechanisms that may be related to suppression of neutrophil activation. Go 8 However, kallikrein, which accelerates the intrinsic coagulation pathway, is only partially inhibited by systemic aprotinin, Go Go 9, 10 but this is sufficient to reduce thrombin formation during CPB. Because of the doses required, systemic aprotinin probably does not appreciably inhibit factor VIIa-tissue factor complex of the extrinsic pathway Go 12 or plasmin formation. Go 13

The mechanism by which aprotinin inhibits fibrinolysis in vivo is not precisely known. Unlike omega -aminocarboxylic acids, which bind to the high-affinity lysine receptor site of plasminogen, Go 14 aprotinin interacts with the active site of plasmin to produce essentially irreversible inhibition of the active enzyme. Go 15 However, in vivo fibrinolysis is a complicated business that involves activation of plasminogen primarily by tissue plasminogen activator. Activation of free plasminogen by tissue plasminogen activator is slow, but fibrin strongly attracts both proteins and accelerates binding, which results in plasmin formation and fibrinolysis. The{omega}2 -amino acids block plasminogen binding to fibrin and, in effect, block plasmin formation but do not directly inhibit plasmin. Go 14 Aprotinin competes with fibrin for the active site of plasmin and in the presence of fibrin inhibits plasmin with Ki = 2 nmol/L. Go 16 The mechanism differs from the{omega}-amino acids, and the drug may be a more effective inhibitor of fibrinolysis within clots than the natural plasmin inhibitors,{alpha}2-antiplasmin and{alpha}2-macroglobulin. Go 16 Numerous studies conclusively demonstrate that systemic aprotinin inhibits fibrinolysis Go 5 ; Tatar's observation that topical aprotinin also inhibits fibrinolysis highlights the question of how it does so.

Tabuchi and colleagues Go 17 earlier showed that active fibrinolysis occurs in pericardial blood during CPB. As their adjacent letter notes, Go 2 systemic aprotinin (half-dose protocol) halves this activity. Tatar's data suggest that wound fibrinolysis continues after CPB and that topical aprotinin reduces postoperative blood loss by inhibiting post-CPB fibrinolytic activity. However, aprotinin is a small molecule (about 7000 daltons) and probably is absorbed from the surface of the heart and pericardium. Thus it is not clear whether topical aprotinin acts as a topical or systemic agent or both.

We surgeons must retreat to the bottom line; nothing is ever simple in the enzymatic stew of coagulation. If subsequent studies confirm the observation that topical aprotinin saves a pint of blood per case, why not use it? In the meantime, systemic aprotinin remains a proven method to reduce blood loss after cardiac operations.

References

  1. Tatar H, Cicek S, Demirkilic U, et al. Topical use of aprotinin in open heart operations. Ann Thorac Surg 1993;55:659-61.[Abstract]
  2. Tabuchi N, de Haan J, van Oeveren W. Topical effect of aprotinin on the surgical wound in cardiac surgery. J THORAC CARDIOVASC SURG 1995;109:399-400.[Free Full Text]
  3. Gallimore MJ, Fuhrer G, Heller W, Hoffmeister HE. Augmentation of kallikrein and plasmin inhibition capacity by aprotinin using a new assay to monitor therapy. Adv Exp Med Biol 1989;247B:55-60.
  4. Levy JH, Salmenpera M, Bailey JM, Jones E, Martin T. Is there a difference between full dose and half dose aprotinin in chest tube drainage following cardiac surgery? Anesthesiology 1992;77:3A.
  5. Dietrich W, Spannagi 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.[Medline]
  6. Cramer EM, Lu H, Caen JP, Soria C, Berndt MC, Tenza D. Differential redistribution of platelet glycoproteins Ib and IIb-IIIa after plasmin stimulation. Blood 1991;77:894-9.
  7. Bidstrup BP, Royston D, Sapsford RN, Taylor KM. Reduction in blood loss and blood use after cardiopulmonary bypass with high-dose aprotinin (Trasylol). J THORAC CARDIOVASC SURG 1989;97:364-72.[Abstract]
  8. Wachtfogel YT, Kucich U, Hack CE, et al. Aprotinin inhibits the contact, neutrophil, and platelet activation systems during simulated extracorporeal perfusion. J THORAC CARDIOVASC SURG 1993;106:1-10.[Abstract]
  9. Levy JH, Bailer JM, Salmenpera M. Pharmacokinetics of aprotinin in preoperative cardiac surgical patients. Anesthesiology 1994;80:1013-8.[Medline]
  10. Heller W, Fuhrer G, Gallimore MJ, Michel J, Hoffmeister H-E. Changes in the kallikrein-kinin system after different dose regimen of aprotinin during cardiopulmonary bypass operation. Adv Exp Med Biol 1989;247B:43-8.
  11. Spannagl M, Dietrich W, Beck A, Schramm W. High dose aprotinin reduces prothrombin and fibrinogen conversion in patients undergoing extracorporeal circulation for myocardial revascularization. Thromb Haemost 1994;72:159-60.[Medline]
  12. Chabbat J, Porte M, Tellier M, Steinbuch M. Aprotinin is a competitive inhibitor of the factor VIIa-tissue factor complex. Thromb Res 1993;71:205-15.[Medline]
  13. Royston D. The serine antiprotease aprotinin (Trasylol): a novel approach to reducing postoperative bleeding. Blood Coag Fibrinol 1990;1:55-69.[Medline]
  14. Bachman F. The plasminogen-plasmin enzyme system. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and thrombosis: basic principles and clinical practice. 3rd ed. Philadelphia: JB Lippincott, 1994:1592-622.
  15. Wiman B. On the reaction of plasmin or plasmin streptokinase complex with aprotinin or alpha-2-antitrypsin. Thromb Res 1980;17:143-52.[Medline]
  16. Longstaff C. Studies on the mechanisms of action of aprotinin and tranexamic acid as plasmin inhibitors and antifibrinolytic agents. Blood Coag Fibrinol [In press].
  17. Tabuchi N, de Haan J, Boonstra PW, van Overen W. Activation of fibrinolysis in the pericardial cavity during cardiopulmonary bypass. J THORAC CARDIOVASC SURG 1993;106:828-33.[Abstract]




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