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

被引：96

作者：

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
]}

机构：

[1] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[2] Childrens Hosp Philadelphia, Div Hematol, Philadelphia, PA 19104 USA

[3] Brookhaven Natl Lab, NSLS X4, New York Struct Biol Ctr, Upton, NY 11973 USA

[4] Duke Univ, Sch Med, Dept Med, Div Hematol, Durham, NC 27710 USA

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

关键词：

PLATELET FACTOR-IV; FACTOR 4/HEPARIN ANTIBODIES; HUMAN PLATELET-FACTOR-4; VENOUS THROMBOEMBOLISM; CONFORMATIONAL-CHANGES; MONOCLONAL-ANTIBODY; CRYSTAL-STRUCTURE; FONDAPARINUX; PATHOGENESIS; BINDING;

D O I：

10.1038/ncomms9277

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：10

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