Disruption of PF4/H multimolecular complex formation with a minimally anticoagulant heparin (ODSH).
Disruption of PF4/H multimolecular complex formation with a minimally anticoagulant heparin (ODSH).
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DOI：
10.1160/th11-11-0795
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发表时间：
2012-04
影响因子：
6.7
通讯作者：
Arepally GM
中科院分区：
文献类型：
--
作者：
Joglekar MV;Quintana Diez PM;Marcus S;Qi R;Espinasse B;Wiesner MR;Pempe E;Liu J;Monroe DM;Arepally GM
最近的研究表明，血小板因子4（PF 4）和肝素（H）的超大复合物（ULC）在肝素诱导的血小板减少症（HIT）的发病机制中起重要作用，HIT是由PF 4/H抗体引起的免疫介导的疾病。由于抗原性PF 4/H ULC通过非特异性静电相互作用组装，我们推断基于电荷的相互作用的破坏可以调节对抗原的免疫应答。我们测试了具有保留电荷的最低抗凝化合物（2-O，3-O-肝素化肝素或ODSH）以破坏PF 4/H复合物形成和免疫原性。我们表明，ODSH破坏复合物时，加入到预先形成的PF 4/H ULC和防止ULC形成时，同时与PF 4和UFH孵育。在其他研究中，我们表明，过量ODSH减少免疫测定中的HIT抗体（Ab）结合，PF 4/ODSH复合物不与HIT Ab交叉反应。当ODSH和UFH以等摩尔浓度混合时，我们表明，在ODSH存在下，肝素中和所需的鱼精蛋白量和PF 4/UFH的免疫原性降低的影响可以忽略不计。总之，这些研究表明，ODSH可以与UFH同时使用，以破坏PF 4/H电荷相互作用，并提供了一种新的策略，以减少抗体介导的并发症在HIT。
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 or 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 UFH are mixed at equimolar concentrations, we show that there is a negligible effect on amount of protamine required for heparin neutralization 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.