The role of fluid-phase immune complexes in the pathogenesis of heparin-induced thrombocytopenia. Issue 194 (October 2020)

• Record Type: Journal Article
• Authors: Huynh, Angela; Arnold, Donald M.; Smith, James W.; Elliott, Taylor D.; Ivetic, Nikola; Kelton, John G.; Nazy, Ishac
• Is Part Of: Thrombosis research. Issue 194(2020)
• Page Start: 135
• Page End: 141
• Publication Date: 2020-10
• Subjects: Thrombosis -- Periodicals; 616.135
• DOI: 10.1016/j.thromres.2020.06.012
• Languages: English
• ISSNs: 0049-3848

Abstract

Abstract: Immune complexes assemble on the platelet surface and cause Fc-mediated platelet activation in heparin-induced thrombocytopenia (HIT); however, it is not known if fluid-phase immune complexes contribute to HIT. The objective of this study was to understand the role of fluid-phase immune complexes in platelet activation and HIT. Binding of wild-type and 15 platelet factor 4 (PF4) mutants to platelets was measured using flow cytometry. Platelet activation was measured using the PF4-dependent 1 4 C-serotonin release assay (PF4-SRA) with KKO and a HIT-patient plasma in the presence of wild-type or PF4 mutants. To activate platelets, we found that a minimal level of wild-type PF4 is required to bind the platelet surface in the presence of KKO (2.67 relative MFI) or HIT-patient plasma (1.71 relative MFI). Only a subset of PF4 mutants was able to support platelet activation, despite having lower surface binding than the minimum binding required of wild-type PF4 (9 mutants with KKO and 2 mutants with HIT-patient plasma). Using individual PF4 mutants, we identified that HIT immune complexes can be formed in fluid-phase and induce platelet activation. Further studies are required to investigate the role of fluid-phase HIT immune complexes in the development of thrombocytopenia and thrombosis associated with clinical HIT. Highlights: PF4 forms fluid-phase HIT immune complexes without binding platelets or heparin. Fluid-phase HIT immune complexes can cause platelet activation without heparin. Fluid-phase HIT immune complexes could play a role in the pathogenesis of HIT.