skip to main content

DOE PAGESDOE PAGES

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

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:
 [1] ;  [1] ;  [1] ;  [2] ;  [2] ;  [1] ;  [3] ;  [2] ;  [4] ;  [1] ;  [1]
  1. Univ. of Pennsylvania, Philadelphia, PA (United States)
  2. Children's Hospital of Pennsylvania, Philadelphia, PA (United States)
  3. Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source
  4. Duke Univ. School of Medicine, Durham, NC (United States)
Publication Date:
OSTI Identifier:
1258654
Grant/Contract Number:
P01HL110860
Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 6; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Research Org:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES