Thromb Haemost 1994; 72(06): 843-847
DOI: 10.1055/s-0038-1648972
Original Article
Schattauer GmbH Stuttgart

α1-Antitrypsin Pittsburgh (Met358 → Arg) Inhibits the Contact Pathway of Intrinsic Coagulation and Alters the Release of Human Neutrophil Elastase during Simulated Extracorporeal Circulation

Yanina T Wachtfogel
1   Sol Sherry Thrombosis Research Center and the Hematology Division, Departments of Medicine and Physiology, Temple University School of Medicine, Philadelphia, PA, USA
,
Rainer Bischoff
2   Transgene SA, Strasbourg, France
,
Ross Bauer
3   Division of Cardiothoracic Surgery, Harrison Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
,
C Erik Hack
4   Central Laboratory of The Netherlands Red Cross, Blood Transfusion Service and Laboratory for Experimental and Clinical Immunology, University of Amsterdam, Amsterdam, The Netherlands
,
Jan H Nuijens
5   Gene Pharming Europe BV, Leiden, The Netherlands
,
Umberto Kucich
6   Research Division, Department of Medicine, The Graduate Hospital, Philadelphia, PA, USA
,
Stefan Niewiarowski
1   Sol Sherry Thrombosis Research Center and the Hematology Division, Departments of Medicine and Physiology, Temple University School of Medicine, Philadelphia, PA, USA
,
L Henry Edmunds Jr
3   Division of Cardiothoracic Surgery, Harrison Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
,
Robert W Colman
1   Sol Sherry Thrombosis Research Center and the Hematology Division, Departments of Medicine and Physiology, Temple University School of Medicine, Philadelphia, PA, USA
› Author Affiliations
Further Information

Publication History

Received 19 April 1994

Accepted after resubmission 19 August 1994

Publication Date:
26 July 2018 (online)

Summary

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, a j-antitrypsin Pittsburgh (Met358 → Arg), a mutant of α1-antitrypsin, is a potent inhibitor of plasma kalli-krein 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 α1-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 α 1.07 µg/ml (3-thromboglobulin at 120 min of recirculation suggesting that the inhibitor had little effect on platelet activation. However, Arg358 α1 arantitrypsin totally blocked kallikrein-Cl-in-hibitor complex formation but not Cl-Cl-inhibitor complex formation. Most importantly, Arg358 α1-antitrypsin decreased the release of 1.11 α 0.16 µg/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.

 
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