Disruption of PF4/H multimolecular complex formation with a minimally anticoagulant heparin (ODSH).

Published

Journal Article

Recent studies have shown that ultra-large complexes (ULCs) of platelet factor 4 (PF4) and heparin (H) play an essential role in the pathogenesis of heparin-induced thrombocytopenia (HIT), an immune-mediated disorder caused by PF4/H antibodies. Because antigenic PF4/H ULCs assemble through non-specific electrostatic interactions, we reasoned that disruption of charge-based interactions can modulate the immune response to antigen. We tested a minimally anticoagulant compound (2-O, 3-O desulfated heparin, ODSH) with preserved charge to disrupt PF4/H complex formation and immunogenicity. We show that ODSH disrupts complexes when added to pre-formed PF4/H ULCs and prevents ULC formation when incubated simultaneously with PF4 and UFH. In other studies, we show that excess ODSH reduces HIT antibody (Ab) binding in immunoassays and that PF4/ODSH complexes do not cross-react with HIT Abs. When ODSH and unfractionated heparin (UFH) are mixed at equimolar concentrations, we show that there is a negligible effect on amount of protamine required for heparin neutralisation and reduced immunogenicity of PF4/UFH in the presence of ODSH. Taken together, these studies suggest that ODSH can be used concurrently with UFH to disrupt PF4/H charge interactions and provides a novel strategy to reduce antibody mediated complications in HIT.

Full Text

Duke Authors

Cited Authors

  • Joglekar, MV; Quintana Diez, PM; Marcus, S; Qi, R; Espinasse, B; Wiesner, MR; Pempe, E; Liu, J; Monroe, DM; Arepally, GM

Published Date

  • April 2012

Published In

  • Thromb Haemost

Volume / Issue

  • 107 / 4

Start / End Page

  • 717 - 725

PubMed ID

  • 22318669

Pubmed Central ID

  • 22318669

Electronic International Standard Serial Number (EISSN)

  • 2567-689X

Digital Object Identifier (DOI)

  • 10.1160/TH11-11-0795

Language

  • eng

Conference Location

  • Germany