Blocking endothelial protein C receptor (EPCR) accelerates thrombus development in vivo

Miguel N. Centelles; Cristina Puy; Jacinto Lopez-Sagaseta; Kenji Fukudome; Ramón Montes; José Hermida

doi:10.1160/TH09-11-0750

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2010; 103(06): 1239-1244
DOI: 10.1160/TH09-11-0750

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Blocking endothelial protein C receptor (EPCR) accelerates thrombus development in vivo

Miguel N. Centelles

¹Division of Cardiovascular Sciences, Laboratory of Thrombosis and Haemostasis, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain

,

Cristina Puy

¹Division of Cardiovascular Sciences, Laboratory of Thrombosis and Haemostasis, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain

,

Jacinto Lopez-Sagaseta

¹Division of Cardiovascular Sciences, Laboratory of Thrombosis and Haemostasis, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain

,

Kenji Fukudome

²Department of Immunology, Saga Medical School, Saga, Japan

,

Ramón Montes

¹Division of Cardiovascular Sciences, Laboratory of Thrombosis and Haemostasis, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain

,

José Hermida

¹Division of Cardiovascular Sciences, Laboratory of Thrombosis and Haemostasis, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain

› Institutsangaben

Abstract

Summary

The endothelial protein C receptor (EPCR) plays an anticoagulant role by improving protein C activation. Although low levels of activated protein C (APC) constitute a thrombosis risk factor, the relationship between modulating EPCR function and thrombosis has not been addressed so far. Monoclonal antibodies (mAb) against murine EPCR were raised, and their ability to block protein C/APC binding was tested. The ferric chloride carotid artery injury model in mice was chosen to test the effect of anti-EPCR mAb on thrombus formation. The time to total occlusion of the vessel was analysed in three groups, given an isotype control mAb (IC), a blocking (RCR-16) or a non-blocking (RCR-20) anti-EPCR mAb. RCR-16 prevented the interaction between protein C/APC and EPCR as demonstrated by surface plasmon resonance and flow cytometry, and inhibited the activation of protein C on the endothelium. IC and RCR-20 were unable to induce such effects. In vivo, RCR-16 shortened the time to total vessel occlusion with respect to IC [13.4 ± 1.0 (mean ± SD) and 17.8 ± 3.2 minutes, respectively, p<0.001]. Occlusive thrombi lasting for more than one hour were observed in all RCR-16-treated animals, but only in 43% of IC-treated ones. Results with RCR-20 were indistinguishable from those observed with IC. For the first time, a direct relationship between blocking EPCR and thrombosis is demonstrated. Blocking anti-EPCR autoantibodies can predispose to thrombosis episodes and may constitute a new therapeutic target.

Keywords

Endothelial cell protein C receptor - protein C - thrombosis - monoclonal antibodies - animal thrombosis models

Volltext

Referenzen

References
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