Abstract Number: OC 02.1
Meeting: ISTH 2022 Congress
Background: Heparin-induced thrombocytopenia (HIT) is a thrombotic disorder caused by antibodies to platelet factor 4 (PF4)/heparin complexes that activate white blood cells (WBCs) via Fcγ receptors (FcγRs). Complement activation by HIT antibodies plays an important role in HIT immune complex (IC) binding to WBCs. However, the effect of complement and complement receptors (CRs) on IC binding to WBC FcγRs is not known.
Aims: Examine the contributions of CR1 (CD35), CR3 (CD18/CD11b), CR4 (CD18/CD11c), C1qR (CD93), FcγRI (CD64), and FcγRIIA (CD32) in HIT IC binding to WBCs.
Methods: THP-1 cells, a monocytic cell line expressing FcγRI/IIA but lacking CRs, were incubated with PF4, heparin, and IgG monoclonal HIT-like antibody KKO (KKO ICs) with or without FcγRIIA blocking antibody (IV.3) in plasma or media. Whole blood was pre-incubated with blocking antibodies to CR1/2/3/4 or FcγRI/II, followed by incubation with KKO ICs. Cell surface binding of C3c and KKO was measured by flow cytometry.
Results: THP-1 cells incubated with KKO ICs in plasma caused substantial complement deposition that was unaccompanied by IgG binding (Figure 1A). In media without a source of complement, KKO ICs showed robust binding in a FcγRII dependent manner (70% reduction in binding by IV.3; Figure 1B). In whole blood, IC binding to neutrophils (Figure 2A) and monocytes (Figure 2B) was significantly diminished by anti-CR1 (70-85%), anti-CR3 (20-70%), or combined CR1/CR3 blockade (85-95%), but unaffected by Fc γR blockade.
Conclusion(s): These studies suggest that in plasma and whole blood: 1) complement masks Fc regions on HIT ICs and thereby limits their binding to FcγRIIA, and 2) binding of KKO ICs to monocytes and neutrophils is initiated primarily through CR1 and CR3, not directly to FcγRs. These data demonstrate that CR inhibition could serve as a potential therapeutic strategy to prevent thrombosis in HIT.
Funding: NIH Grant HL151730 (GMA/DBC/LR), ASH Medical Student Physician-Scientist Award (HMH)
To cite this abstract in AMA style:Harris H, Khandelwal S, Rauova L, Cines D, Arepally G. Complement Receptors Mediate Binding of Heparin-Induced Thrombocytopenia Immune Complexes to Fc Receptor Bearing Cells [abstract]. https://abstracts.isth.org/abstract/complement-receptors-mediate-binding-of-heparin-induced-thrombocytopenia-immune-complexes-to-fc-receptor-bearing-cells/. Accessed October 2, 2023.
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