Pf4, also known as Platelet factor 4 or chemokine (C-X-C motif) ligand 4 (CXCL4), is a highly cationic tetrameric protein and an abundant chemokine released from platelet α -granules upon activation [1,2]. It is central to the pathophysiology of several thrombotic disorders. PF4 binds to polyanions, changing conformation to expose antigenic epitopes, and is involved in processes like promoting blood coagulation, and participating in innate and adaptive immunity when platelets are activated in response to infections [4,5].

PF4 is crucial in heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombotic thrombocytopenia (VITT). In HIT, PF4 combines with heparin to form an antigen that produces IgG antibodies [3]. In VITT, antibodies to PF4 form immune complexes with PF4, activating platelets and neutrophils through Fc receptors [2]. These antibodies can lead to Fcγ receptor-mediated pancellular activation and activation of hemostasis, increasing the risk of disseminated intravascular coagulation [1]. Additionally, PF4 binds and activates the thrombopoietin receptor, cellular myeloproliferative leukemia protein (c-Mpl), on platelets, activating Janus kinase 2 (JAK2) and phosphorylating signal transducer and activator of transcription (STAT) 3 and STAT5, leading to platelet aggregation [2].

In conclusion, Pf4 is a key protein in the context of thrombotic disorders such as HIT and VITT. Its role in forming immune complexes and activating platelets and related signaling pathways like c-Mpl-JAK2 is well-documented. Understanding Pf4 through these disease-related studies provides insights into the pathogenesis of thrombotic disorders and may guide the development of targeted therapies.