Complex formation with nucleic acids and aptamers alters the antigenic properties of platelet factor 4

Blood. 2013 Jul 11;122(2):272-81. doi: 10.1182/blood-2013-01-478966. Epub 2013 May 14.


The tight electrostatic binding of the chemokine platelet factor 4 (PF4) to polyanions induces heparin-induced thrombocytopenia, a prothrombotic adverse drug reaction caused by immunoglobulin G directed against PF4/polyanion complexes. This study demonstrates that nucleic acids, including aptamers, also bind to PF4 and enhance PF4 binding to platelets. Systematic assessment of RNA and DNA constructs, as well as 4 aptamers of different lengths and secondary structures, revealed that increasing length and double-stranded segments of nucleic acids augment complex formation with PF4, while single nucleotides or single-stranded polyA or polyC constructs do not. Aptamers were shown by circular dichroism spectroscopy to induce structural changes in PF4 that resemble those induced by heparin. Moreover, heparin-induced anti-human-PF4/heparin antibodies cross-reacted with human PF4/nucleic acid and PF4/aptamer complexes, as shown by an enzyme immunoassay and a functional platelet activation assay. Finally, administration of PF4/44mer-DNA protein C aptamer complexes in mice induced anti-PF4/aptamer antibodies, which cross-reacted with murine PF4/heparin complexes. These data indicate that the formation of anti-PF4/heparin antibodies in postoperative patients may be augmented by PF4/nucleic acid complexes. Moreover, administration of therapeutic aptamers has the potential to induce anti-PF4/polyanion antibodies and a prothrombotic diathesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / immunology
  • Antibodies / metabolism
  • Aptamers, Nucleotide / chemistry
  • Aptamers, Nucleotide / metabolism*
  • Base Pairing
  • Base Sequence
  • Blood Platelets / metabolism
  • DNA / chemistry
  • DNA / metabolism
  • Heparin / pharmacology
  • Humans
  • Macromolecular Substances / metabolism
  • Mice
  • Molecular Sequence Data
  • Nucleic Acid Conformation
  • Nucleic Acids / chemistry
  • Nucleic Acids / metabolism*
  • Platelet Activation / immunology
  • Platelet Factor 4 / immunology*
  • Platelet Factor 4 / metabolism*
  • Polyelectrolytes
  • Polymers
  • Protein Binding / drug effects
  • RNA / chemistry
  • RNA / metabolism


  • Antibodies
  • Aptamers, Nucleotide
  • Macromolecular Substances
  • Nucleic Acids
  • Polyelectrolytes
  • Polymers
  • polyanions
  • Platelet Factor 4
  • RNA
  • Heparin
  • DNA