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	Zheng Cai, Serge V Yarovoi, Zhiqiang Zhu, Lubica Rauova, Vincent Hayes, Tatiana Lebedeva, Qun Liu, Mortimer Poncz, Gowthami Arepally, Douglas B Cines, Mark I Greene
Journal	Nature communications (Nat Commun) Vol. 6 Pg. 8277 (Sep 22 2015) ISSN: 2041-1723 [Electronic] England
PMID	26391892 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References	Antibodies Anticoagulants Antigen-Antibody Complex Glycosaminoglycans Immunoglobulin G Platelet Factor 4 Heparin
Topics	Animals Antibodies (immunology) Anticoagulants (adverse effects) Antigen-Antibody Complex Autoimmune Diseases (chemically induced) Enzyme-Linked Immunosorbent Assay Gene Expression Regulation Glycosaminoglycans (immunology, metabolism) Heparin (adverse effects, immunology) Humans Immunoglobulin G (immunology) Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Models, Molecular Platelet Activation Platelet Factor 4 (immunology, metabolism) Protein Conformation Thrombocytopenia (chemically induced, immunology, pathology)

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