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dc.contributor.authorJamasbi, Janinaen
dc.contributor.authorMegens, Remco TAen
dc.contributor.authorBianchini, Mariaelvyen
dc.contributor.authorMünch, Götzen
dc.contributor.authorUngerer, Martinen
dc.contributor.authorFaussner, Alexanderen
dc.contributor.authorSherman, Shacharen
dc.contributor.authorWalker, Adamen
dc.contributor.authorGoyal, Pankajen
dc.contributor.authorJung, Stephanieen
dc.contributor.authorBrandl, Richarden
dc.contributor.authorWeber, Christianen
dc.contributor.authorLorenz, Reinharden
dc.contributor.authorFarndale, Richarden
dc.contributor.authorElia, Natalieen
dc.contributor.authorSiess, Wolfgangen
dc.date.accessioned2015-06-01T15:13:01Z
dc.date.available2015-06-01T15:13:01Z
dc.date.issued2015-06-01en
dc.identifier.issn0735-1097
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/248138
dc.description.abstractBACKGROUND 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.
dc.description.sponsorshipThe 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.
dc.languageEnglishen
dc.language.isoenen
dc.publisherJamasbi 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
dc.rightsCreative Commons Attribution 4.0*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectatherothrombosisen
dc.subjectantithromboticen
dc.subjectglycoprotein VIen
dc.subjectplaque ruptureen
dc.titleDifferential inhibition of human atherosclerotic plaque-induced platelet activation by dimeric GPVI-Fc and anti-GPVI antibodies: functional and imaging studiesen
dc.typeArticle
dc.description.versionThis is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.jacc.2015.03.573en
prism.endingPage2415
prism.publicationDate2015en
prism.publicationNameJournal of the American College of Cardiologyen
prism.startingPage2404
prism.volume65en
dc.rioxxterms.funderBHF
dc.rioxxterms.projectidRG/09/003/27122
dc.rioxxterms.projectidPG/10/011/28199
dcterms.dateAccepted2015-03-31en
rioxxterms.versionofrecord10.1016/j.jacc.2015.03.573en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-06-01en
dc.identifier.eissn1558-3597
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idBritish Heart Foundation (RG/09/003/27122)
pubs.funder-project-idBritish Heart Foundation (RG/15/4/31268)
pubs.funder-project-idBritish Heart Foundation (PG/10/011/28199)


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Creative Commons Attribution 4.0
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