Thrombin and Human Plasma Kallikrein Inhibition during Simulated Extracorporeal Circulation Block Platelet and Neutrophil Activation

Yanina T. Wachtfogel; Charles Kettner; C. Erik Hack; Jan H. Nuijens; Thomas M. Reilly; Robert M. Knabb; Umberto Kucich; Stefan Niewiarowski; L. Henry Edmunds Jr.; Robert W. Colman

doi:10.1055/s-0037-1615442

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 1998; 80(04): 686-691
DOI: 10.1055/s-0037-1615442

Rapid Communication

Schattauer GmbH

Thrombin and Human Plasma Kallikrein Inhibition during Simulated Extracorporeal Circulation Block Platelet and Neutrophil Activation

Yanina T. Wachtfogel

¹From the Sol Sherry Thrombosis Research Center and the Hematology Division, Department of Medicine, Temple University School of Medicine, Philadelphia, PA, USA

,

Charles Kettner

²Du Pont Merck Pharmaceutical Company, Wilmington, DE, USA

,

C. Erik Hack

³Central 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

⁴Gene Pharming Europe BV, Leiden, The Netherlands

,

Thomas M. Reilly

²Du Pont Merck Pharmaceutical Company, Wilmington, DE, USA

,

Robert M. Knabb

²Du Pont Merck Pharmaceutical Company, Wilmington, DE, USA

,

Umberto Kucich

⁵Research Division, Department of Medicine, The Graduate Hospital, Philadelphia, PA, USA

,

Stefan Niewiarowski

¹From the Sol Sherry Thrombosis Research Center and the Hematology Division, Department of Medicine, Temple University School of Medicine, Philadelphia, PA, USA

,

L. Henry Edmunds Jr.

⁶Division of Cardiothoracic Surgery, Harrison Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

,

Robert W. Colman

¹From the Sol Sherry Thrombosis Research Center and the Hematology Division, Department of Medicine, Temple University School of Medicine, Philadelphia, PA, USA

› Institutsangaben

Abstract

Summary

Cardiopulmonary bypass causes hemorrhagic complications, and initiates a chemical and cellular inflammatory response. Contact of blood with synthetic surfaces leads to qualitative and quantitative alterations in platelets, neutrophils, complement, and contact systems. Despite the fact that cardiopulmonary bypass is carried out in the presence of high doses of heparin, there is significant activation of both platelets and neutrophils. Thrombin is protected on cell and fibrin surfaces from antithrombin, even in the presence of high doses of heparin (~ 5 U/ml). We therefore studied the effect of a small (Mr = 497), highly effective (Ki = 41 pM), reversible tripeptide inhibitor of thrombin, DUP 714 (1 μM), in a well characterized model of simulated extracorporeal circulation. In the absence of DUP 714, platelet counts decreased by 75% 5 min after the start of extra-corporeal bypass and increased to 48% at 120 min of recirculation. DUP 714 significantly preserved platelet counts, decreased plasma levels of platelet β-thromboglobulin levels, but did not prevent a decrease in sensitivity of platelets to adenosine diphosphate. Kallikrein-C1-inhibitor and C1-C1-inhibitor complexes increased progressively from 0.32 U/ml to 0.67 U/ml and from 4.45 U/ml to 7.25 U/ml, respectively, during 120 min of recirculation without DUP 714. Addition of DUP 714 significantly inhibited kallikrein-C1-inhibitor complex formation but did not affect C1-C1-inhibitor complexes. In the absence of DUP 714, human neutrophil elastase levels rose from a baseline of 0.01 ± 0.00 μg/ml to 1.18 ± 0.21 μg/ml during 120 min of recirculation. Human neutrophil elastase release at 120 min was significantly inhibited in the presence of DUP 714 to 37% of the value with heparin alone. These results indicated that addition of this novel thrombin (and kallikrein) inhibitor to heparin preserved platelet counts, decreased platelet secretion, and provided the additional benefit of partially blocking neutrophil activation during simulated extra-corporeal circulation.

This work was presented in part at the American Society of Hematology Meetings, Nashville, TN, December 2-6, 1994 and published in abstract form in Blood 84: 72a, 1994.

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Referenzen

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