Plasma contact system is the initial part of both the intrinsic coagulation pathway and kallikrein–kinin pathway, which mainly involves three proteins: coagulation factor XII (FXII), prekallikrein (PK) and high-molecular weight kininogen. Fucosylated chondroitin sulfate (FCS) is a unique sulfated glycosaminoglycan (GAG) composed of a chondroitin sulfate-like backbone and sulfated fucose branches. The native FCS was preliminary found to cause undesired activation of the plasma contact system. How this unusual GAG functions in this process remains to be clarified. Herein, the relationship between its structure, plasma contact activation and its effects on the PK–FXII reciprocal activation loop were studied. The recalcification time assay indicated that the FCS at high concentration could be procoagulant which may be attributed to its contact activation activity. The structure–activity relationship study indicated that its high molecular weight and distinct fucose side chains are required for contact activation by FCS, although the sulfate substitution types of its side chains have less impact. In human plasma, the native FCSs potently induced FXII-dependent contact activation. However, in purified systems FCS did not significantly activate FXII per se or induce its autoactivation, whereas FCS significantly promoted the activation of PK by factor XIIa. Polysaccharide–protein interaction assays showed that FCS bound to PK with higher affinity than other contact system proteins. These data suggested that potent contact activation by FCS requires the positive feedback loop between PK and FXII. These findings contribute to better understanding of contact activation by complex GAG.

中文翻译：

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岩藻糖基化硫酸软骨素对血浆的接触活化及其构效关系研究

血浆接触系统是内在凝血途径和激肽释放酶-激肽途径的初始部分，主要涉及三种蛋白质：凝血因子XII（FXII），激肽释放酶（PK）和高分子量激肽原。岩藻糖基化硫酸软骨素（FCS）是一种独特的硫酸化糖胺聚糖（GAG），由硫酸软骨素样骨架和硫酸化岩藻糖分支组成。初步发现天然FCS会引起等离子体接触系统的意外激活。这种异常的GAG在此过程中如何发挥作用还有待阐明。在本文中，研究了其结构，等离子体接触活化及其对PK-FXII双向活化环的影响之间的关系。重新钙化时间测定表明，高浓度的FCS可能是促凝剂，这可能归因于其接触活化活性。结构-活性关系研究表明，尽管其侧链的硫酸盐取代类型影响较小，但通过FCS进行接触活化需要其高分子量和明显的岩藻糖侧链。在人血浆中，天然FCSs有效诱导FXII依赖的接触激活。但是，在纯化的系统中，FCS本身并未显着激活FXII或诱导其自动激活，而FCS显着促进了因子XIIa激活PK。多糖-蛋白质相互作用分析表明，FCS与PK的结合亲和力高于其他接触系统蛋白。这些数据表明，通过FCS进行有效的接触激活需要PK和FXII之间的正反馈回路。这些发现有助于更好地理解复杂GAG对接触的激活。