title: Atomic description of the immune complex involved in heparin-induced thrombocytopenia.
abstract: Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by immune complexes containing platelet factor 4 (PF4), antibodies to PF4 and heparin or cellular glycosaminoglycans (GAGs). Here we solve the crystal structures of the: (1) PF4 tetramer/fondaparinux complex, (2) PF4 tetramer/KKO-Fab complex (a murine monoclonal HIT-like antibody) and (3) PF4 monomer/RTO-Fab complex (a non-HIT anti-PF4 monoclonal antibody). Fondaparinux binds to the 'closed' end of the PF4 tetramer and stabilizes its conformation. This interaction in turn stabilizes the epitope for KKO on the 'open' end of the tetramer. Fondaparinux and KKO thereby collaborate to 'stabilize' the ternary pathogenic immune complex. Binding of RTO to PF4 monomers prevents PF4 tetramerization and inhibits KKO and human HIT IgG-induced platelet activation and platelet aggregation in vitro, and thrombus progression in vivo. The atomic structures provide a basis to develop new diagnostics and non-anticoagulant therapeutics for HIT.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Serge V
authors.initials: SV
authors.lastname: Yarovoi
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Lubica
authors.initials: L
authors.lastname: Rauova
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Hayes
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Lebedeva
authors.affiliation: New York Structural Biology Center, National Synchrotron Light Source (NSLS) X4, Brookhaven National Laboratory, Upton, New York 11973, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Mortimer
authors.initials: M
authors.lastname: Poncz
authors.affiliation: Division of Hematology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina 27710, USA.
authors.forename: Gowthami
authors.initials: G
authors.lastname: Arepally
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Mark I
authors.initials: MI
authors.lastname: Greene
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D000925:Anticoagulants / Q000009:adverse effects*; D000936:Antigen-Antibody Complex; D001327:Autoimmune Diseases / Q000139:chemically induced*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D006025:Glycosaminoglycans / Q000276:immunology / Q000378:metabolism; D006493:Heparin / Q000009:adverse effects* / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008958:Models, Molecular; D015539:Platelet Activation; D010978:Platelet Factor 4 / Q000276:immunology / Q000378:metabolism; D011487:Protein Conformation; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology
chemical_list: D000906:Antibodies; D000925:Anticoagulants; D000936:Antigen-Antibody Complex; D006025:Glycosaminoglycans; D007074:Immunoglobulin G; D010978:Platelet Factor 4; D006493:Heparin