The PI 3‐kinase PI 3 KC 2α regulates mouse platelet membrane structure and function independently of membrane lipid composition

PI 3 KC 2α is a phosphoinositide 3‐kinase with a recently reported function in platelets; PI 3 KC 2α‐deficient mouse platelets have altered membrane structure and impaired function. Yet, how these membrane changes cause platelet dysfunction remains unknown. Here, focused ion beam‐scanning electron microscopy of PI 3 KC 2α‐deficient platelet ultrastructure reveals a specific effect on the internal membrane structure, while liquid chromatography‐tandem mass spectrometry profiling of 294 lipid species shows unaltered lipid composition. Functionally, PI 3 KC 2α‐deficient platelets exhibit impaired thrombosis specifically under conditions involving membrane tethering. These studies indicate that the structural changes in PI 3 KC 2α‐deficient platelets are limited to the membrane, occur without major changes in lipid composition, and selectively impair cell function during thrombus formation. These findings illustrate a unique mechanism that may be targetable for anti‐thrombotic benefit.