title: Aprotinin inhibits the contact, neutrophil, and platelet activation systems during simulated extracorporeal perfusion.
abstract: Aprotinin reduces blood loss after cardiac operations and decreases the bleeding time. The mechanism of action of aprotinin that produces these effects is not clear. During simulated extracorporeal circulation the contact and complement systems, platelets, and neutrophils are activated. We investigated the effect of aprotinin on kallikrein-C1-inhibitor complex and C1-C1-inhibitor complex formation, neutrophil degranulation, and platelet release and aggregation during simulated extracorporeal circulation. Fresh heparinized human blood was recirculated at 37 degrees C for 2 hours in a spiral coil membrane oxygenator-roller pump perfusion circuit. Changes in platelet count, leukocyte count, platelet response to adenosine diphosphate, and plasma levels of beta-thromboglobulin, kallikrein-C1-inhibitor complexes, C1-C1-inhibitor complexes, and neutrophil elastase were measured before and at 5, 30, 60, and 120 minutes of recirculation at 0, 0.015, 0.03, 0.06, and 0.12 mg/ml doses of aprotinin. Platelet counts decreased to 36% +/- 12% of control values at 5 minutes and increased to 56% +/- 13% at 120 minutes without aprotinin. Aprotinin did not affect platelet counts, but it did prevent the decrease in sensitivity of platelets to adenosine diphosphate and it attenuated beta-thromboglobulin release. In the absence of aprotinin, kallikrein-C1-inhibitor and C1-C1-inhibitor complexes increased progressively to 0.53 +/- 0.14 U/ml and 2.38 +/- 0.33 U/ml, respectively, at 120 minutes. Kallikrein-C1-inhibitor complexes were completely inhibited and C1-C1-inhibitor complexes were partially inhibited at aprotinin concentrations of 0.03 mg/ml or greater. Release of neutrophil elastase was partially but not completely inhibited at the highest dose of aprotinin and was 50% inhibited at a dose of 0.03 mg/ml. Because activation of the fibrinolytic system does not occur in this system, the changes were independent of the inhibition of plasmin. We conclude that aprotinin in high doses completely inhibited kallikrein-induced activation of neutrophils and partially inhibited complement-induced activation. Aprotinin did not directly affect platelet adhesion or aggregation, but it indirectly preserved platelet sensitivity to agonists and also attenuated release of alpha-granule contents. The data indicate that in the presence of aprotinin platelet function was partially preserved, kallikrein production was totally inhibited, complement activation was partially inhibited, and neutrophil release was partially inhibited, thus attenuating the "whole body inflammatory response" associated with cardiopulmonary bypass.
authors.affiliation: Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pa.
authors.forename: Y T
authors.initials: YT
authors.lastname: Wachtfogel
authors.forename: U
authors.initials: U
authors.lastname: Kucich
authors.forename: C E
authors.initials: CE
authors.lastname: Hack
authors.forename: P
authors.initials: P
authors.lastname: Gluszko
authors.forename: S
authors.initials: S
authors.lastname: Niewiarowski
authors.forename: R W
authors.initials: RW
authors.lastname: Colman
authors.forename: L H
authors.initials: LH
authors.lastname: Edmunds
mesh_terms: D007611:Aprotinin / Q000008:administration & dosage / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D003167:Complement Activation / Q000187:drug effects; D003174:Complement C1 Inactivator Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005112:Extracorporeal Circulation; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007610:Kallikreins / Q000378:metabolism; D007958:Leukocyte Count / Q000187:drug effects; D019272:Leukocyte Elastase; D008955:Models, Cardiovascular; D009504:Neutrophils / Q000187:drug effects*; D010196:Pancreatic Elastase / Q000097:blood; D015539:Platelet Activation / Q000187:drug effects*; D010976:Platelet Count / Q000187:drug effects; D001620:beta-Thromboglobulin / Q000032:analysis
chemical_list: D003174:Complement C1 Inactivator Proteins; D001620:beta-Thromboglobulin; D007611:Aprotinin; D007610:Kallikreins; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase