PF4 activates the thrombopoietin receptor c-Mpl in platelets resulting in JAK2-STAT3/5 signaling.
Inhibition of the c-Mpl-JAK2 pathway abrogates PF4-induced platelet aggregation.
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) and phosphorylation of signal transducer and activator of transcription (STAT) 3 and STAT5, leading to platelet aggregation. Inhibition of the c-Mpl-JAK2 pathway inhibits platelet aggregation to PF4, VITT serum, and to the combination of PF4 and IgG isolated from VITT patient plasma. The results support a model in which PF4-based immune complexes activate platelets through binding of the Fc domain to FcγRIIA and PF4 to c-Mpl.