Differential inhibition of human atherosclerotic plaque-induced platelet activation by dimeric GPVI-Fc and anti-GPVI antibodies: functional and imaging studies
Authors
Jamasbi, Janina
Megens, Remco TA
Bianchini, Mariaelvy
Münch, Götz
Ungerer, Martin
Faussner, Alexander
Sherman, Shachar
Walker, Adam
Goyal, Pankaj
Jung, Stephanie
Brandl, Richard
Weber, Christian
Lorenz, Reinhard
Farndale, Richard
Elia, Natalie
Siess, Wolfgang
Publication Date
2015-06-01Journal Title
Journal of the American College of Cardiology
ISSN
0735-1097
Publisher
Jamasbi et al. Journal of the American College of Cardiology (2015)
Vol. 65, Issue 22, pp. 2404-2415. doi:10.1016/j.jacc.2015.03.573
Volume
65
Pages
2404-2415
Language
English
Type
Article
Metadata
Show full item recordCitation
Jamasbi, J., Megens, R. T., Bianchini, M., Münch, G., Ungerer, M., Faussner, A., Sherman, S., et al. (2015). Differential inhibition of human atherosclerotic plaque-induced platelet activation by dimeric GPVI-Fc and anti-GPVI antibodies: functional and imaging studies. Journal of the American College of Cardiology, 65 2404-2415. https://doi.org/10.1016/j.jacc.2015.03.573
Abstract
BACKGROUND
Glycoprotein VI (GPVI) is the essential platelet collagen receptor in atherothrombosis, but its inhibition causes only a mild bleeding tendency. Thus, targeting this receptor has selective antithrombotic potential.
OBJECTIVES
We compared compounds interfering with platelet PVI-atherosclerotic plaque interaction to improve current antiatherothrombotic therapy.
METHODS
Human atherosclerotic plaque-induced platelet aggregation was measured in anticoagulated blood under static and arterial flow conditions (550/s, 1,100/s, and 1,500/s). Inhibition by dimeric GPVI-Fc masking GPVI binding sites on collagen was compared with that of 3 anti-GPVI antibodies: BLO8-1, a human domain antibody; 5C4, a fragment antigen-binding (Fab fragment) of monoclonal rat immunoglobulin G; and m-Fab-F, a human recombinant sFab against GPVI dimers.
RESULTS
GPVI-Fc reduced plaque-triggered platelet aggregation in static blood by 51%, BLO8-1 by 88%, and 5C4 by 93%. Under arterial flow conditions BLO8-1 and 5C4 almost completely inhibited platelet aggregation, while preserving platelet adhesion on plaque. Inhibition by GPVI-Fc, even at high concentrations, was less marked but increased with shear rate. Advanced optical imaging revealed rapid persistent GPVI-Fc binding to collagen under low and high shear flow, upstream and downstream of plaque fragments. Particularly at low shear, platelets adhered in plaque flow niches to GPVI-Fc free segments of collagen fibers and recruited other platelets onto aggregates.
CONCLUSIONS
Anti-GPVI antibodies inhibit atherosclerotic plaque-induced platelet aggregation under static and flow conditions more effectively than GPVI-Fc. However, potent platelet inhibition by GPVI-Fc at higher shear (1,500/s) suggests localized antithrombotic efficacy at denuded or fissured stenotic high-risk lesions without systemic bleeding. The compound-specific differences have relevance for clinical trials targeting GPVI-collagen interaction on top of established antiplatelet therapies in patients with spontaneous plaque rupture or intervention-associated plaque injury.
Keywords
atherothrombosis, antithrombotic, glycoprotein VI, plaque rupture
Sponsorship
The study was supported by grants from advanceCOR GmbH (JJ), the August-Lenz foundation, the Deutsche Forschungsgemeinschaft SFB1123/Z01 (MB), and the British Heart Foundation (SMJ and RWF; grants RG/09/003/27122 and PG/10/011/28199). Two-photon laser scanning microscopy experiments have been supported by the Deutsche Forschungsgemeinschaft (INST 409/97-1) and the LMU.
Funder references
British Heart Foundation (RG/09/003/27122)
British Heart Foundation (RG/15/4/31268)
British Heart Foundation (PG/10/011/28199)
Identifiers
External DOI: https://doi.org/10.1016/j.jacc.2015.03.573
This record's URL: https://www.repository.cam.ac.uk/handle/1810/248138
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