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. Lastly, the atomic structures provide a basis to develop new diagnostics and non-anticoagulant therapeutics for HIT.
- Authors:
-
- 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)
- Publication Date:
- Research Org.:
- Brookhaven National Laboratory (BNL), Upton, NY (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1258654
- Grant/Contract Number:
- P01HL110860
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Volume: 6; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES
Citation Formats
Cai, Zheng, Yarovoi, Serge V., Zhu, Zhiqiang, Rauova, Lubica, Hayes, Vincent, Lebedeva, Tatiana, Liu, Qun, Poncz, Mortimer, Arepally, Gowthami, Cines, Douglas B., and Greene, Mark I. Atomic description of the immune complex involved in heparin-induced thrombocytopenia. United States: N. p., 2015.
Web. doi:10.1038/ncomms9277.
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. Atomic description of the immune complex involved in heparin-induced thrombocytopenia. United States. https://doi.org/10.1038/ncomms9277
Cai, Zheng, Yarovoi, Serge V., Zhu, Zhiqiang, Rauova, Lubica, Hayes, Vincent, Lebedeva, Tatiana, Liu, Qun, Poncz, Mortimer, Arepally, Gowthami, Cines, Douglas B., and Greene, Mark I. Tue .
"Atomic description of the immune complex involved in heparin-induced thrombocytopenia". United States. https://doi.org/10.1038/ncomms9277. https://www.osti.gov/servlets/purl/1258654.
@article{osti_1258654,
title = {Atomic description of the immune complex involved in heparin-induced thrombocytopenia},
author = {Cai, Zheng and Yarovoi, Serge V. and Zhu, Zhiqiang and Rauova, Lubica and Hayes, Vincent and Lebedeva, Tatiana and Liu, Qun and Poncz, Mortimer and Arepally, Gowthami and Cines, Douglas B. and Greene, Mark I.},
abstractNote = {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.},
doi = {10.1038/ncomms9277},
journal = {Nature Communications},
number = ,
volume = 6,
place = {United States},
year = {Tue Sep 22 00:00:00 EDT 2015},
month = {Tue Sep 22 00:00:00 EDT 2015}
}
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