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DOI: 10.1160/TH11-11-0795
Disruption of PF4/H multimolecular complex formation with a minimally anticoagulant heparin (ODSH)
Publikationsverlauf
Received:
16. November 2011
Accepted after minor revision:
24. Februar 2011
Publikationsdatum:
29. November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201204/lookinside/thumbnails/10-1160-th11-11-0795-1.jpg)
Summary
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.
Presented in part at the 52nd American Society of Hematology Annual Meeting and Exposition, December 6th, 2010, Orlando, Florida, USA.
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