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The class I phosphoinositide 3-kinases α and β control antiphospholipid antibodies-induced platelet activation

Terrisse, AD; Laurent, PA; Garcia, C; Gratacap, MP; Vanhaesebroeck, B; Sié, P; Payrastre, B; (2016) The class I phosphoinositide 3-kinases α and β control antiphospholipid antibodies-induced platelet activation. Thrombosis and Haemostasis 10.1160/TH15-08-0661. Green open access

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Abstract

Antiphospholipid syndrome (APS) is an autoimmune disease characterised by the presence of antiphospholipid antibodies (aPL) associated with increased thrombotic risk and pregnancy morbidity. Although aPL are heterogeneous auto-antibodies, the major pathogenic target is the plasma protein β2-glycoprotein 1. The molecular mechanisms of platelet activation by aPL remain poorly understood. Here, we explored the role of the class IA phosphoinositide 3-kinase (PI3K) α and β isoforms in platelet activation by aPL. Compared to control IgG from healthy individuals, the IgG fraction isolated from patients with APS potentiates platelet aggregation induced by low dose of thrombin in vitro and increases platelet adhesion and thrombus growth on a collagen matrix under arterial shear rate through a mechanism involving glycoprotein Ib (GPIb) and Toll Like Receptor 2 (TLR-2). Using isoforms-selective pharmacological PI3K inhibitors and mice with megakaryocyte/platelet lineage-specific inactivation of class IA PI3K isoforms, we demonstrate a critical role of the PI3Kβ and PI3Kα isoforms in platelet activation induced by aPL. Our data show that aPL potentiate platelet activation through GPIbα and TLR-2 via a mechanism involving the class IA PI3Kα and β isoforms, which represent new potential therapeutic targets in the prevention or treatment of thrombotic events in patients with APS.

Type: Article
Title: The class I phosphoinositide 3-kinases α and β control antiphospholipid antibodies-induced platelet activation
Open access status: An open access version is available from UCL Discovery
DOI: 10.1160/TH15-08-0661
Publisher version: http://dx.doi.org/10.1160/TH15-08-0661
Language: English
Additional information: This article is not an exact copy of the original published article in Thrombosis and Haemostasis. The definitive publisher-authenticated version of Terrisse, AD; Laurent, PA; Garcia, C; Gratacap, MP; Vanhaesebroeck, B; Sié, P; Payrastre, B; (2016) The class I phosphoinositide 3-kinases α and β control antiphospholipid antibodies-induced platelet activation. Thrombosis and Haemostasis is available online at: http://dx.doi.org/10.1160/TH15-08-0661.
Keywords: Antiphospholipid antibodies, blood platelets, phosphoinositide 3-kinases, thrombosis
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/1492748
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