Disrupting the platelet internal membrane via PI3KC2α inhibition impairs thrombosis independently of canonical platelet activation

Maria V. Selvadurai, Mitchell J. Moon, Simon J. Mountford, Xiao Ma, Zhaohua Zheng, Ian G. Jennings, Natasha M. Setiabakti, Rizani P. Iman, Rose J. Brazilek, Nurul Aisha Z Abidin, Gaëtan Chicanne, Sonia Severin, Alyce J. Nicholls, Connie H.Y. Wong, Jean-Yves Rinckel, Anita Eckly, Christian Gachet, Warwick S. Nesbitt, Philip E. Thompson, Justin R. Hamilton

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Abstract

Arterial thrombosis causes heart attacks and most strokes and is the most common cause of death in the world. Platelets are the cells that form arterial thrombi, and antiplatelet drugs are the mainstay of heart attack and stroke prevention. Yet, current drugs have limited efficacy, preventing fewer than 25% of lethal cardiovascular events without clinically relevant effects on bleeding. The key limitation on the ability of all current drugs to impair thrombosis without causing bleeding is that they block global platelet activation, thereby indiscriminately preventing platelet function in hemostasis and thrombosis. Here, we identify an approach with the potential to overcome this limitation by preventing platelet function independently of canonical platelet activation and in a manner that appears specifically relevant in the setting of thrombosis. Genetic or pharmacological targeting of the class II phosphoinositide 3-kinase (PI3KC2α) dilates the internal membrane reserve of platelets but does not affect activation-dependent platelet function in standard tests. Despite this, inhibition of PI3KC2α is potently antithrombotic in human blood ex vivo and mice in vivo and does not affect hemostasis. Mechanistic studies reveal this antithrombotic effect to be the result of impaired platelet adhesion driven by pronounced hemodynamic shear stress gradients. These findings demonstrate an important role for PI3KC2α in regulating platelet structure and function via a membrane-dependent mechanism and suggest that drugs targeting the platelet internal membrane may be a suitable approach for antithrombotic therapies with an improved therapeutic window.

Original languageEnglish
Article numbereaar8430
Number of pages15
JournalScience Translational Medicine
Volume12
Issue number553
DOIs
Publication statusPublished - 22 Jul 2020

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