Is GPIbα really a master regulator of platelet activation?

We read with great interest the recent publication from Yan et al in Blood Advances entitled "Essential role of glycoprotein Ibα in platelet activation." 1 The study presents findings showing that the deletion of 10 amino acids (aa) from the cytoplasmic tail of glycoprotein Ibα (GPIbα) in mouse platelets results in defective platelet responses downstream of the von Willebrand factor (VWF)-GPIbα interaction but also all other major platelet receptors including GPVI, thromboxane receptor, P2Y12, and proteaseactivated receptor 4. Unsurprisingly, these mice exhibited impaired hemostasis and reduced thrombus formation after laser-or FeCl 3 -induced endothelial injury of arterioles and were protected in a model of pulmonary thromboembolism. 1 Mechanistically, this thromboprotective phenotype was linked to reduced protein kinase C (PKC) activity in 10aa -/-platelets.Complementary to these findings, the authors also show that a myristoylated peptide of GPIbα (MPαC), 2 previously shown to prevent the binding of 14-3-3ζ to GPIbα, is able to activate platelets via PKC in washed platelets but not in plateletrich plasma.Although the authors should be commended for the amount of data generated in this article, there are several crucial issues with the study that requires further consideration.