title: Alpha 1-antitrypsin Pittsburgh (Met358-->Arg) inhibits the contact pathway of intrinsic coagulation and alters the release of human neutrophil elastase during simulated extracorporeal circulation.
abstract: Cardiopulmonary bypass prolongs bleeding time, increases postoperative blood loss, and triggers activation of plasma proteolytic enzyme systems and blood cells referred to as the "whole body inflammatory response". Contact of blood with synthetic surfaces leads to qualitative and quantitative alterations in platelets, neutrophils, contact and complement systems. Contact and complement pathway proteins both induce neutrophil activation. alpha 1-antitrypsin Pittsburgh (Met358-->Arg), a mutant of alpha 1-antitrypsin, is a potent inhibitor of plasma kallikrein and thrombin. We investigated whether this recombinant mutant protein inhibited platelet activation, as well as contact and/or complement-induced neutrophil activation during simulated extracorporeal circulation. Arg358 alpha 1-antitrypsin did not prevent the 34% drop in platelet count at 5 min of recirculation, did not block the 50% decrease in ADP-induced platelet aggregation at 120 min of recirculation, nor inhibit the release of 6.06 +/- 1.07 micrograms/ml beta-thromboglobulin at 120 min of recirculation suggesting that the inhibitor had little effect on platelet activation. However, Arg358 alpha 1-antitrypsin totally blocked kallikrein-C1-inhibitor complex formation but not C1-C1-inhibitor complex formation. Most importantly, Arg358 alpha 1-antitrypsin decreased the release of 1.11 +/- 0.16 micrograms/ml human neutrophil elastase by 43%. The attenuation of neutrophil activation in the absence of an effect on complement activation via the classical pathway, supports the concept that kallikrein is a major mediator of neutrophil degranulation during cardiopulmonary bypass.
authors.affiliation: Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA 19140.
authors.forename: Y T
authors.initials: YT
authors.lastname: Wachtfogel
authors.forename: R
authors.initials: R
authors.lastname: Bischoff
authors.forename: R
authors.initials: R
authors.lastname: Bauer
authors.forename: C E
authors.initials: CE
authors.lastname: Hack
authors.forename: J H
authors.initials: JH
authors.lastname: Nuijens
authors.forename: U
authors.initials: U
authors.lastname: Kucich
authors.forename: S
authors.initials: S
authors.lastname: Niewiarowski
authors.forename: L H
authors.initials: LH
authors.lastname: Edmunds
authors.forename: R W
authors.initials: RW
authors.lastname: Colman
mesh_terms: D001120:Arginine; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D003171:Complement Pathway, Classical / Q000187:drug effects; D005112:Extracorporeal Circulation; D006801:Humans; D007958:Leukocyte Count / Q000187:drug effects; D019272:Leukocyte Elastase; D008715:Methionine; D008955:Models, Cardiovascular; D010196:Pancreatic Elastase / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D000515:alpha 1-Antitrypsin / Q000494:pharmacology*
chemical_list: D011994:Recombinant Proteins; D000515:alpha 1-Antitrypsin; C038915:alpha 1-antitrypsin Pittsburgh; D001120:Arginine; D008715:Methionine; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase