Selective inhibition of the platelet phosphoinositide 3-kinase p110β as promising new strategy for platelet protection during extracorporeal circulation

Andreas Straub; Hans Peter Wendel; Klaus Dietz; Daniela Schiebold; Karlheinz Peter; Simone M. Schoenwaelder; Gerhard Ziemer

doi:10.1160/TH07-07-0452

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2008; 99(03): 609-615
DOI: 10.1160/TH07-07-0452

New Technologies, Diagnostic Tools and Drugs

Schattauer GmbH

Selective inhibition of the platelet phosphoinositide 3-kinase p110β as promising new strategy for platelet protection during extracorporeal circulation

Andreas Straub

¹Dept. of Thoracic, Cardiac and Vascular Surgery, University of Tübingen, Germany

³Baker Heart Research Institute, Melbourne, Australia

,

Hans Peter Wendel

¹Dept. of Thoracic, Cardiac and Vascular Surgery, University of Tübingen, Germany

,

Klaus Dietz

²Dept. of Medical Biometry, University of Tübingen, Germany

,

Daniela Schiebold

¹Dept. of Thoracic, Cardiac and Vascular Surgery, University of Tübingen, Germany

,

Karlheinz Peter

³Baker Heart Research Institute, Melbourne, Australia

,

Simone M. Schoenwaelder

⁴Australian Centre for Blood Diseases, Monash University, Melbourne, Australia

,

Gerhard Ziemer

¹Dept. of Thoracic, Cardiac and Vascular Surgery, University of Tübingen, Germany

› Institutsangaben

Abstract

Summary

Extracorporeal circulation (ECC) is used in cardiac surgery for cardiopulmonary bypass as well as in ventricular assist devices and for extracorporeal membrane oxygenation. Blood contact with the artificial surface and shear stress of ECC activates platelets and leukocytes resulting in a coagulopathy and proinflammatory events. Blockers of the platelet glycoprotein (GP) IIb/IIIa (CD41/CD61) can protect platelet function during ECC, a phenomenon called “platelet anaesthesia”, but may be involved in post-ECC bleeding. We hypothesized that the new selective phosphoinositide 3-kinase p110β inhibitor TGX-221 that inhibits shear-induced platelet activation without prolonging the bleeding time in vivo may also protect platelet function during ECC. Heparinized blood of healthy volunteers (n=6) was treated in vitro with either the GP IIb/IIIa blocker tirofiban, TGX-221 or as control and circulated in an ECC moand after 30 minutes circulation CD41 expression on the ECCtubing as measure for platelet-ECC binding and generation of the platelet activation marker β-thromboglobulin were determined using ELISA. Platelet aggregation and platelet-granulocyte binding were analysed in flow cytometry. After log-transforming the data statistical evaluation was performed using multifactor ANOVA in combination with Tukey’s HSD test (global alpha = 5%).Tirofiban and TGX-221 inhibited platelet-ECC interaction, platelet aggregation and platelet-granulocyte binding. Tirofiban also inhibited ECC-induced β-thromboglobulin release.The observed inhibition of platelet-ECC interaction and platelet activation by tirofiban contributes to explain the mechanism of“platelet anaesthesia”.TGX-221 represents a promising alternative to GP IIb/IIIa blockade and should be further investigated for use during ECC in vivo.

Keywords

GP IIb/IIIa - platelet pharmacology - surgery

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Referenzen

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