Platelet factor 4 (PF4) is an abundant chemokine that is released from platelet α-granules upon activation. PF4 is central to the pathophysiology of vaccine-induced immune thrombocytopenia and thrombosis (VITT) in which antibodies to PF4 form immune complexes with PF4, which activate platelets and neutrophils through Fc receptors. In this study, we show that PF4 binds and activates the thrombopoietin (TPO) receptor, c-Mpl on platelets. This leads to the activation of Janus kinase 2 (JAK2) …