Atomic description of the immune complex involved in heparin-induced thrombocytopenia

Cai, Zheng; Yarovoi, Serge V.; Zhu, Zhiqiang; Rauova, Lubica; Hayes, Vincent; Lebedeva, Tatiana; Liu, Qun; Poncz, Mortimer; Arepally, Gowthami; Cines, Douglas B.; Greene, Mark I.

doi:10.1038/ncomms9277

Atomic description of the immune complex involved in heparin-induced thrombocytopenia

Journal Article · Tue Sep 22 00:00:00 EDT 2015 · Nature Communications

DOI:https://doi.org/10.1038/ncomms9277· OSTI ID:1258654

Cai, Zheng ^[1]; Yarovoi, Serge V. ^[1]; Zhu, Zhiqiang ^[1]; Rauova, Lubica ^[2]; Hayes, Vincent ^[2]; Lebedeva, Tatiana ^[1]; Liu, Qun ^[3]; Poncz, Mortimer ^[2]; Arepally, Gowthami ^[4]; Cines, Douglas B. ^[1]; Greene, Mark I. ^[1]

Univ. of Pennsylvania, Philadelphia, PA (United States)
Children's Hospital of Pennsylvania, Philadelphia, PA (United States)
Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source
Duke Univ. School of Medicine, Durham, NC (United States)

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. Lastly, the atomic structures provide a basis to develop new diagnostics and non-anticoagulant therapeutics for HIT.

View Accepted Manuscript (DOE)

Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: USDOE

OSTI ID:: 1258654

Alternate ID(s):: OSTI ID: 1354271

Journal Information:: Nature Communications, Journal Name: Nature Communications Vol. 6; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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