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Impact of PI3K (Phosphoinositide 3-Kinase Alpha) Inhibition on Hemostasis and Thrombosis

Laurent, P-A; Hechler, B; Solinhac, R; Ragab, A; Cabou, C; Anquetil, T; Severin, S; ... Gratacap, M-P; + view all (2018) Impact of PI3K (Phosphoinositide 3-Kinase Alpha) Inhibition on Hemostasis and Thrombosis. Arteriosclerosis, Thrombosis, and Vascular Biology , 38 (9) pp. 2041-2053. 10.1161/ATVBAHA.118.311410. Green open access

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Abstract

Objective— PI3Kα (phosphoinositide 3-kinase alpha) is a therapeutic target in oncology, but its role in platelets and thrombosis remains ill characterized. In this study, we have analyzed the role of PI3Kα in vitro, ex vivo, and in vivo in 2 models of arterial thrombosis. Approach and Results— Using mice selectively deficient in p110α in the megakaryocyte lineage and isoform-selective inhibitors, we confirm that PI3Kα is not mandatory but participates to thrombus growth over a collagen matrix at arterial shear rate. Our data uncover a role for PI3Kα in low-level activation of the GP (glycoprotein) VI-collagen receptor by contributing to ADP secretion and in turn full activation of PI3Kβ and Akt/PKB (protein kinase B). This effect was no longer observed at high level of GP VI agonist concentration. Our study also reveals that over a vWF (von Willebrand factor) matrix, PI3Kα regulates platelet stationary adhesion contacts under arterial flow through its involvement in the outside-in signaling of vWF-engaged αIIbβ3 integrin. In vivo, absence or inhibition of PI3Kα resulted in a modest but significant decrease in thrombus size after superficial injuries of mouse mesenteric arteries and an increased time to arterial occlusion after carotid lesion, without modification in the tail bleeding time. Considering the more discrete and nonredundant role of PI3Kα compared with PI3Kβ, selective PI3Kα inhibitors are unlikely to increase the bleeding risk at least in the absence of combination with antiplatelet drugs or thrombopenia. Conclusions— This study provides mechanistic insight into the role of PI3Kα in platelet activation and arterial thrombosis.

Type: Article
Title: Impact of PI3K (Phosphoinositide 3-Kinase Alpha) Inhibition on Hemostasis and Thrombosis
Open access status: An open access version is available from UCL Discovery
DOI: 10.1161/ATVBAHA.118.311410
Publisher version: http://doi.org/10.1161/ATVBAHA.118.311410
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
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/10057003
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