Increased galactose expression and enhanced clearance in patients with low von Willebrand factor
Increased galactose expression and enhanced clearance in patients with low von Willebrand factor
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DOI：
10.1182/blood-2018-09-874636
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发表时间：
2019-04-04
期刊：
影响因子：
20.3
通讯作者：
O'Donnell, James S.
中科院分区：
文献类型：
--
作者：
Aguila, Sonia;Lavin, Michelle;O'Donnell, James S.
血管性血友病因子（VWF）的聚糖决定簇在调节其对蛋白水解和清除的易感性方面发挥着关键作用。在许多不同的小鼠模型中，异常糖基化已被证明可引起血管性血友病（VWD）。然而，由于与准确评估VWF聚糖组成相关的重大技术挑战，碳水化合物在人VWD发病机制中的重要性在很大程度上仍未得到探索。为了解决这个问题，我们开发了一种新的凝集素结合面板，使人类VWF聚糖表征。然后使用该方法研究了110例低VWF患者与O血型匹配的健康对照组的聚糖表达。有趣的是，在健康对照人群中观察到VWF聚糖表达的显著个体间异质性。这种变异包括VWF上的末端唾液酸化和ABO（H）血型表达。重要的是，我们还观察到低VWF患者亚组中异常糖基化的证据。特别是，低VWF患者的末端α（2-6）-连接唾液酸化减少，半乳糖（Gal）暴露继发性增加。此外，在具有增强的VWF清除的那些患者中观察到半乳糖暴露和估计的VWF半衰期之间的负相关。总之，这些发现支持了这样的假设，即末端唾液酸化的丧失通过促进增强的清除而在至少一个亚组的患者中有助于支持低VWF的病理生理学。此外，VWF碳水化合物表达的改变可能导致正常人群中VWF水平的定量和定性变化。
Glycan determinants on von Willebrand factor (VWF) play critical roles in regulating its susceptibility to proteolysis and clearance. Abnormal glycosylation has been shown to cause von Willebrand disease (VWD) in a number of different mouse models. However, because of the significant technical challenges associated with accurate assessment of VWF glycan composition, the importance of carbohydrates in human VWD pathogenesis remains largely unexplored. To address this, we developed a novel lectin-binding panel to enable human VWF glycan characterization. This methodology was then used to study glycan expression in a cohort of 110 patients with low VWF compared with O blood group-matched healthy controls. Interestingly, significant interindividual heterogeneity in VWF glycan expression was seen in the healthy control population. This variation included terminal sialylation and ABO(H) blood group expression on VWF. Importantly, we also observed evidence of aberrant glycosylation in a subgroup of patients with low VWF. In particular, terminal alpha(2-6)-linked sialylation was reduced in patients with low VWF, with a secondary increase in galactose (Gal) exposure. Furthermore, an inverse correlation between Gal exposure and estimated VWF half-life was observed in those patients with enhanced VWF clearance. Together, these findings support the hypothesis that loss of terminal sialylation contributes to the pathophysiology underpinning low VWF in at least a subgroup of patients by promoting enhanced clearance. In addition, alterations in VWF carbohydrate expression are likely to contribute to quantitative and qualitative variations in VWF levels in the normal population.