PMID- 25150299
OWN - NLM
STAT- MEDLINE
DCOM- 20150303
LR  - 20210202
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Linking)
VI  - 124
IP  - 15
DP  - 2014 Oct 9
TI  - Binding of anti-platelet factor 4/heparin antibodies depends on the 
      thermodynamics of conformational changes in platelet factor 4.
PG  - 2442-9
LID - 10.1182/blood-2014-03-559518 [doi]
AB  - The chemokine platelet factor 4 (PF4) undergoes conformational changes when 
      complexing with polyanions. This can induce the antibody-mediated adverse drug 
      effect of heparin-induced thrombocytopenia (HIT). Understanding why the 
      endogenous protein PF4 becomes immunogenic when complexing with heparin is 
      important for the development of other negatively charged drugs and may also hint 
      toward more general mechanisms underlying the induction of autoantibodies to 
      other proteins. By circular dichroism spectroscopy, atomic force microscopy, and 
      isothermal titration calorimetry we characterized the interaction of PF4 with 
      unfractionated heparin (UFH), its 16-, 8-, and 6-mer subfractions, 
      low-molecular-weight heparin (LMWH), and the pentasaccharide fondaparinux. To 
      bind anti-PF4/heparin antibodies, PF4/heparin complexes require (1) an increase 
      in PF4 antiparallel beta-sheets exceeding  approximately 30% (achieved by UFH, LMWH, 16-, 8-, 
      6-mer), (2) formation of multimolecular complexes (UFH, 16-, 8-mer), and (3) 
      energy (needed for a conformational change), which is released by binding of 
      >/=11-mer heparins to PF4, but not by smaller heparins. These findings may help to 
      synthesize safer heparins. Beyond PF4 and HIT, the methods applied in the current 
      study may be relevant to unravel mechanisms making other endogenous proteins more 
      vulnerable to undergo conformational changes with little energy requirement (eg, 
      point mutations and post-translational modifications) and thereby predisposing 
      them to become immunogenic.
CI  - (c) 2014 by The American Society of Hematology.
FAU - Kreimann, Martin
AU  - Kreimann M
AD  - ZIK HIKE-Zentrum fur Innovationskompetenz, Humorale Immunreaktionen bei 
      Kardiovaskularen Erkrankungen, Greifswald, Germany;
FAU - Brandt, Sven
AU  - Brandt S
AD  - ZIK HIKE-Zentrum fur Innovationskompetenz, Humorale Immunreaktionen bei 
      Kardiovaskularen Erkrankungen, Greifswald, Germany;
FAU - Krauel, Krystin
AU  - Krauel K
AD  - Institut fur Immunologie und Transfusionsmedizin, Greifswald, Germany;
FAU - Block, Stephan
AU  - Block S
AD  - ZIK HIKE-Zentrum fur Innovationskompetenz, Humorale Immunreaktionen bei 
      Kardiovaskularen Erkrankungen, Greifswald, Germany;
FAU - Helm, Christiane A
AU  - Helm CA
AD  - Institut fur Physik, Greifswald, Germany; and.
FAU - Weitschies, Werner
AU  - Weitschies W
AD  - Institut fur Pharmazie, Greifswald, Germany.
FAU - Greinacher, Andreas
AU  - Greinacher A
AD  - Institut fur Immunologie und Transfusionsmedizin, Greifswald, Germany;
FAU - Delcea, Mihaela
AU  - Delcea M
AD  - ZIK HIKE-Zentrum fur Innovationskompetenz, Humorale Immunreaktionen bei 
      Kardiovaskularen Erkrankungen, Greifswald, Germany;
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140822
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antibodies)
RN  - 0 (Heparin, Low-Molecular-Weight)
RN  - 0 (Polysaccharides)
RN  - 37270-94-3 (Platelet Factor 4)
RN  - J177FOW5JL (Fondaparinux)
SB  - IM
MH  - Antibodies/*metabolism
MH  - Calorimetry
MH  - Circular Dichroism
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Fondaparinux
MH  - Heparin, Low-Molecular-Weight/chemistry
MH  - Humans
MH  - Microscopy, Atomic Force
MH  - Platelet Factor 4/*chemistry/*metabolism
MH  - Polysaccharides/metabolism
MH  - Protein Binding
MH  - Protein Structure, Secondary
MH  - Thermodynamics
EDAT- 2014/08/26 06:00
MHDA- 2015/03/04 06:00
CRDT- 2014/08/24 06:00
PHST- 2014/08/24 06:00 [entrez]
PHST- 2014/08/26 06:00 [pubmed]
PHST- 2015/03/04 06:00 [medline]
AID - S0006-4971(20)39718-4 [pii]
AID - 10.1182/blood-2014-03-559518 [doi]
PST - ppublish
SO  - Blood. 2014 Oct 9;124(15):2442-9. doi: 10.1182/blood-2014-03-559518. Epub 2014 
      Aug 22.