PF4 activates the c-Mpl–Jak2 pathway in platelets

Author:

Buka Richard J.1ORCID,Montague Samantha J.12ORCID,Moran Luis A.1ORCID,Martin Eleyna M.12ORCID,Slater Alexandre12ORCID,Watson Steve P.12ORCID,Nicolson Phillip L. R.13ORCID

Affiliation:

1. 1Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

2. 2Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, Birmingham and Nottingham, United Kingdom

3. 3Department of Haematology, University Hospitals Birmingham National Health Service Foundation Trust, Birmingham, United Kingdom

Abstract

Abstract Platelet factor 4 (PF4) is an abundant chemokine that is released from platelet α-granules on 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 receptor, cellular myeloproliferative leukemia protein (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 sera, and 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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