ArticleJournal of thrombosis and haemostasis : JTH2025
Glycoprotein VI is a receptor for the PF4/anti-PF4 IgG complex and contributes to platelet activation in heparin-induced thrombocytopenia (HIT).
Article in Journal of thrombosis and haemostasis : JTH, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundPlatelet factor 4 (PF4) plays a central role in heparin-induced thrombocytopenia (HIT). PF4 is a positively charged tetramer that forms immune complexes with anti-PF4 immunoglobulin G, activating platelets via FcγRIIA. Despite extensive study, a platelet receptor for PF4 within these complexes has not been clearly defined.
objectiveWe hypothesized that glycoprotein VI (GPVI), a collagen receptor known to interact with multiple ligands, binds PF4 and contributes to platelet activation in HIT.
methodsWe used platelet aggregation assays, surface plasmon resonance, and AlphaFold 3 modeling to investigate interactions between PF4, the HIT-mimicking monoclonal antibody KKO, and GPVI.
resultsPlatelet aggregation triggered by PF4/KKO or HIT patient sera was reduced by anti-GPVI antibodies or the anti-GPVI Fab fragment ACT017. Surface plasmon resonance showed that PF4 binds GPVI with a dissociation constant of Kd approximately equal to 1 μM, but PF4/KKO complexes exhibited enhanced binding, with a 5 to 17-fold reduction in dissociation rate and Kd approximately equal to 30 to 100 nM. This interaction was blocked by heparin. In contrast, the nonpathogenic anti-PF4 antibody RTO had no effect. AlphaFold 3 modeling predicted electrostatic interactions between anionic GPVI surfaces and the PF4/KKO complex, with PF4 tetramers contacting both the GPVI D2 domain and KKO Fab.
conclusionGPVI functions as a receptor for PF4/HIT antibody complex, engaging FcγRIIA and contributing to platelet activation in HIT.
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