Characterization of Anticoagulant Heparin and Related Polysaccharides

描述(由申请人提供)： 肝素是一种硫酸盐多糖混合物，在许多临床情况下被广泛用作基础治疗，特别是用于预防血栓形成。虽然在过去的几十年里，肝素一直在临床上使用，但最近，有报道称，接受血液透析的患者在接受肝素治疗时发生了一系列严重的过敏性事件，导致了全球健康危机。在这场危机发生后的几周内，一个由学术界(包括该提案的联合PI)、FDA和工业界成员组成的多学科小组在与不良反应相关的肝素批次中发现了一种非自然污染物，即硫酸软骨素(OSCS)。尽管在过去20年里，许多科学研究确定了分析技术，这些技术确定了肝素的分子水平特征，包括成分和序列，但在这次肝素危机之前，这种关键的药剂主要是根据活性进行控制和剂量的。不幸的是，活性检测还不能区分其他能够“隐藏”肝素的硫酸盐多糖所产生的异质性。因此，这一危机的解决办法强调了纳入更详细的分析特征以监测和控制肝素的异质性的重要性，以避免未来出现如此严重的健康危机。在这项建议中，我们寻求使用一套发展良好和健壮的分析和结构-功能分析方法来从结构和功能上定义肝素。从这些检测中获得的有关肝素的信息将使我们能够构建用于监测和控制肝素质量的过滤器。最后，我们试图开发一个信息学平台来捕捉和传播捕捉肝素宏观和微观异质性的结构参数，以便将它们与明确定义的标准进行比较。信息学平台将对迅速传播这项提案的结果至关重要，以改进目前的肝素质量控制措施。 公共卫生相关性： 最近由于大量肝素污染引起的全球健康危机增加了测量和控制肝素等复杂多糖类药物结构异质性的重要性。在这项提案中，我们寻求利用我们的经验和专业知识，采用可靠的分析方法，从结构和功能上定义肝素。

DESCRIPTION (provided by applicant): Heparin is a suflated polysaccharide mixture that is widely used as baseline therapy in a number of clinical situations, especially for preventing thrombosis. While heparin has been administered in the clinic for the past several decades, recently, clusters of serious allergic-type events were reported in patients undergoing hemodialysis who were receiving heparin causing a global health crisis. Within a matter of weeks from the time of this crisis, a multidisciplinary team that comprised of members from academia (including co-PIs of this proposal), FDA and industry identified an unnatural contaminant, over sulfated chondroitin sulfate (OSCS), in the heparin lots associated with the adverse reactions. Despite the fact that, in the last 20 years, a number of scientific studies identified analytical techniques, which have defined molecular level characteristics of heparin, including composition and sequence, this critical pharmaceutical agent was primarily controlled and dosed on the basis of activity, prior to this heparin crisis. Unfortunately, the activity assays have not been able to distinguish the heterogeneity arising from other sulfated polysaccharides that have been able to "hide behind" heparin. The solution to this crisis, therefore emphasizes the importance of incorporating more detailed analytical characterization to monitor and control the heterogeneity in heparins to avoid such a serious health crisis in the future. In this proposal we seek to structurally and functionally define heparin using a set of well developed and robust analytical and structure-function assays. The information on heparin obtained from these assays would enable us to construct filters for monitoring and controlling the quality of heparin. Finally we seek to develop an informatics platform to capture and disseminate the structural parameters that capture the macro- and microheterogeneity of heparin to compare them against well defined standards. The informatics platform would be critical to rapidly disseminate the findings from this proposal to improve current quality control measures for heparin. PUBLIC HEALTH RELEVANCE: The recent global health crisis due to contaminated lots of heparin has elevated the importance of measuring and controlling the structural heterogenetiy of complex polysaccharide drugs like heparin. In this proposal we seek to build on our experience and expertise in employing robust analytical methods to structurally and functionally define heparin.