Heparin and homogeneous model heparin oligosaccharides form distinct complexes with protamine: Light scattering and zeta potential analysis.
Heparin and homogeneous model heparin oligosaccharides form distinct complexes with protamine: Light scattering and zeta potential analysis.
复制标题
肝素和同质模型肝素寡糖与鱼精蛋白形成不同的复合物：光散射和 zeta 电位分析。
DOI：
10.1016/j.jpba.2017.03.010
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发表时间：
2017
影响因子：
3.4
通讯作者：
Keire,DavidA
中科院分区：
文献类型：
--
作者：
Sommers,CynthiaD;Ye,Hongping;Liu,Jian;Linhardt,RobertJ;Keire,DavidA
肝素与带正电荷的蛋白质（如血小板因子4（PF 4）或鱼精蛋白）的大的多分子复合物可引发患者使用肝素相关的免疫应答，包括最显著的不良事件肝素诱导的血小板减少症（HIT）。目前的证据表明，识别与肝素结合的PF 4的大的多分子复合物（300-700 kDa）的血小板活化抗体导致HIT [1]，并且在非常罕见的情况下，抗鱼精蛋白-肝素抗体可诱导血小板减少症[2]。肝素作为不同长度和硫酸化水平的硫酸化糖胺聚糖的混合物给药。迄今为止，由于缺乏用于检测目的的纯化、均质肝素链，尚未解决链长、硫酸化水平和杂质对肝素-鱼精蛋白复合物的形成、大小和免疫原性的潜在影响。在这里，一组充分表征的模型肝素寡糖与硫酸鱼精蛋白一起使用，以评估所得复合物的理化性质。肝素-鱼精蛋白复合物的流体动力学半径和zeta电位分布被观察到依赖于模型肝素寡糖的硫酸化位置、大小和浓度。在这项工作中分析的特征良好的寡糖-鱼精蛋白复合物将有助于建立肝素-鱼精蛋白复合物理化属性与其潜在的非法细胞免疫原性之间的联系。
Large multimolecular complexes of heparin with positively charged proteins such as platelet factor 4 (PF4) or protamine can initiate immune responses associated with heparin use in patients, including the most significant adverse event, heparin-induced thrombocytopenia (HIT). Current evidence suggests that platelet-activating antibodies that recognize large multi-molecular complexes (300–700 kDa) of PF4 bound to heparin cause HIT [1] and in very rare cases anti-protamine-heparin antibodies can induce thrombocytopenia [2]. Heparin is administered as a mixture of sulfated glycosaminoglycans of variable lengths and sulfation levels. To date the potential impact of chain length, sulfation level and impurities on the formation, size and immunogenicity of heparin-protamine complexes has not been addressed due to the lack of purified, homogenous heparin chains for testing purposes. Here, a set of well-characterized model heparin oligosaccharides was used with protamine sulfate to evaluate the physicochemical properties of the resulting complexes. Hydrodynamic radii and zeta potential profiles of heparin-protamine complexes were observed to be dependent upon the sulfation location, size and concentration of the model heparin oligosaccharides. The well-characterized oligosaccharide-protamine complexes analyzed in this work will be useful for establishing links between heparin-protamine complex physiochemical attributes to their potential to illicit cellular immunogenicity.