{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T10:27:02Z","timestamp":1787740022293,"version":"build-2784847793"},"reference-count":0,"publisher":"Georg Thieme Verlag KG","issue":"06","license":[{"start":{"date-parts":[[2018,4,25]],"date-time":"2018-04-25T00:00:00Z","timestamp":1524614400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Thromb Haemost"],"published-print":{"date-parts":[[2018,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Neonatal platelets are hypo-reactive to the tyrosine kinase-linked receptor agonist collagen. Here, we have investigated whether the hypo-responsiveness is related to altered levels of glycoprotein VI (GPVI) and integrin \u03b12\u03b21, or to defects in downstream signalling events by comparison to platelet activation by C-type lectin-like receptor 2 (CLEC-2). GPVI and CLEC-2 activate a Src- and Syk-dependent signalling pathway upstream of phospholipase C (PLC) \u03b32. Phosphorylation of a conserved YxxL sequence known as a (hemi) immunotyrosine-based-activation-motif (ITAM) in both receptors is critical for Syk activation. Platelets from human pre-term and full-term neonates display mildly reduced expression of GPVI and CLEC-2, as well as integrin \u03b1IIb\u03b23, accounted for at the transcriptional level. They are also hypo-responsive to the two ITAM receptors, as shown by measurement of integrin \u03b1IIb\u03b23 activation, P-selectin expression and Syk and PLC\u03b32 phosphorylation. Mouse platelets are also hypo-responsive to GPVI and CLEC-2 from late gestation to 2 weeks of age, as determined by measurement of integrin \u03b1IIb\u03b23 activation. In contrast, the response to G protein-coupled receptor agonists was only mildly reduced and in some cases not altered in neonatal platelets of both species. A reduction in response to GPVI and CLEC-2, but not protease-activated receptor 4 (PAR-4) peptide, was also observed in adult mouse platelets following immune thrombocytopenia, whereas receptor expression was not impaired. Our results demonstrate developmental differences in platelet responsiveness to GPVI and CLEC-2, and also following immune platelet depletion leading to reduced Syk activation. The rapid generation of platelets during development or following platelet depletion is achieved at the expense of signalling by ITAM-coupled receptors.<\/jats:p>","DOI":"10.1055\/s-0038-1646924","type":"journal-article","created":{"date-parts":[[2018,4,25]],"date-time":"2018-04-25T23:22:02Z","timestamp":1524698522000},"page":"1009-1020","source":"Crossref","is-referenced-by-count":37,"title":["Significant Hypo-Responsiveness to GPVI and CLEC-2 Agonists in Pre-Term and Full-Term Neonatal Platelets and following Immune Thrombocytopenia"],"prefix":"10.1055","volume":"118","author":[{"given":"Alexander","family":"Hardy","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Science, IBR Building, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ver\u00f3nica","family":"Palma-Barqueros","sequence":"additional","affiliation":[{"name":"Servicio de Hematolog\u00eda y Oncolog\u00eda M\u00e9dica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonaci\u00f3n, Universidad de Murcia, IMIB-Arrixaca, U765-CIBERER, Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Watson","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Science, IBR Building, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Daniel","family":"Malcor","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Cambridge, Downing Site, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Eble","sequence":"additional","affiliation":[{"name":"Institute of Physiological Chemistry and Pathobiochemistry, University of M\u00fcnster, M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Gardiner","sequence":"additional","affiliation":[{"name":"ACRF Department of Cancer Biology and Therapeutics, John Curtin School of Medical Research, Australian National University, Canberra, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Blanco","sequence":"additional","affiliation":[{"name":"Departamento de Ginecolog\u00eda y Obstetricia, Hospital Cl\u00ednico Universitario Virgen de la Arrixaca. IMIB-Arrixaca, Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Guijarro-Campillo","sequence":"additional","affiliation":[{"name":"Departamento de Ginecolog\u00eda y Obstetricia, Hospital Cl\u00ednico Universitario Virgen de la Arrixaca. IMIB-Arrixaca, Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Delgado","sequence":"additional","affiliation":[{"name":"Departamento de Ginecolog\u00eda y Obstetricia, Hospital Cl\u00ednico Universitario Virgen de la Arrixaca. IMIB-Arrixaca, Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Lozano","sequence":"additional","affiliation":[{"name":"Servicio de Hematolog\u00eda y Oncolog\u00eda M\u00e9dica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonaci\u00f3n, Universidad de Murcia, IMIB-Arrixaca, U765-CIBERER, Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ra\u00fal","family":"Teruel-Montoya","sequence":"additional","affiliation":[{"name":"Servicio de Hematolog\u00eda y Oncolog\u00eda M\u00e9dica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonaci\u00f3n, Universidad de Murcia, IMIB-Arrixaca, U765-CIBERER, Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicente","family":"Vicente","sequence":"additional","affiliation":[{"name":"Servicio de Hematolog\u00eda y Oncolog\u00eda M\u00e9dica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonaci\u00f3n, Universidad de Murcia, IMIB-Arrixaca, U765-CIBERER, Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Watson","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Science, IBR Building, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom"},{"name":"Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, Midlands, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Rivera","sequence":"additional","affiliation":[{"name":"Servicio de Hematolog\u00eda y Oncolog\u00eda M\u00e9dica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonaci\u00f3n, Universidad de Murcia, IMIB-Arrixaca, U765-CIBERER, Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisca","family":"Ferrer-Mar\u00edn","sequence":"additional","affiliation":[{"name":"Servicio de Hematolog\u00eda y Oncolog\u00eda M\u00e9dica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonaci\u00f3n, Universidad de Murcia, IMIB-Arrixaca, U765-CIBERER, Murcia, Spain"},{"name":"Grado de Medicina, Universidad Cat\u00f3lica San Antonio de Murcia, Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2018,4,25]]},"container-title":["Thrombosis and Haemostasis"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/s-0038-1646924.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,5,6]],"date-time":"2019-05-06T20:38:35Z","timestamp":1557175115000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/s-0038-1646924"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,25]]},"references-count":0,"journal-issue":{"issue":"06","published-online":{"date-parts":[[2018,5,30]]},"published-print":{"date-parts":[[2018,6]]}},"URL":"https:\/\/doi.org\/10.1055\/s-0038-1646924","relation":{},"ISSN":["0340-6245","2567-689X"],"issn-type":[{"value":"0340-6245","type":"print"},{"value":"2567-689X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,25]]}}}