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【技术产业】《NEJM》：OSCS是污染肝素的罪魁祸首
ABSTRACT
Background
There is an urgent need to determine whether oversulfated chondroitin sulfate (OSCS), a compound contaminating heparin supplies worldwide, is the cause of the severe anaphylactoid reactions that have occurred after intravenous heparin administration in the United States and Germany.
Methods
Heparin procured from the Food and Drug Administration, consisting of suspect lots of heparin associated with the clinical events as well as control lots of heparin, were screened in a blinded fashion both for the presence of OSCS and for any biologic activity that could potentially link the contaminant to the observed clinical adverse events. In vitro assays for the activation of the contact system and the complement cascade were performed. In addition, the ability of OSCS to recapitulate key clinical manifestations in vivo was tested in swine.
Results
The OSCS found in contaminated lots of unfractionated heparin, as well as a synthetically generated OSCS reference standard, directly activated the kinin–kallikrein pathway in human plasma, which can lead to the generation of bradykinin, a potent vasoactive mediator. In addition, OSCS induced generation of C3a and C5a, potent anaphylatoxins derived from complement proteins. Activation of these two pathways was unexpectedly linked and dependent on fluid-phase activation of factor XII. Screening of plasma samples from various species indicated that swine and humans are sensitive to the effects of OSCS in a similar manner. OSCS-containing heparin and synthetically derived OSCS induced hypotension associated with kallikrein activation when administered by intravenous infusion in swine.
Conclusions
Our results provide a scientific rationale for a potential biologic link between the presence of OSCS in suspect lots of heparin and the observed clinical adverse events. An assay to assess the amidolytic activity of kallikrein can supplement analytic tests to protect the heparin supply chain by screening for OSCS and other highly sulfated polysaccharide contaminants of heparin that can activate the contact system.
http://content.nejm.org/cgi/content/full/NEJMoa0803200 本人已认领该文编译，48小时后若未提交译文，请其他战友自由认领。 Contaminated Heparin Associated with Adverse Clinical Events and Activation of the Contact System
污染肝素激活接触系统与临床不良反应有关
Background
There is an urgent need to determine whether oversulfated chondroitin sulfate (OSCS), a compound contaminating heparin supplies worldwide, is the cause of the severe anaphylactoid reactions that have occurred after intravenous heparin administration in the United States and Germany.
背景：
在美国和德国，在静脉用肝素后，出现了一种严重的类过敏性反应. (anaphylactoid reaction)，目前非常迫切需要确定是否是由其中的世界范围内的肝素污染物“超硫酸化硫酸软骨素”（oversulfated chondroitin sulfate）引起的。
Methods
方法
Heparin procured from the Food and Drug Administration, consisting of suspect lots of heparin associated with the clinical events as well as control lots of heparin, were screened in a blinded fashion both for the presence of OSCS and for any biologic activity that could potentially link the contaminant to the observed clinical adverse events. In vitro assays for the activation of the contact system and the complement cascade were performed. In addition, the ability of OSCS to recapitulate key clinical manifestations in vivo was tested in swine.
肝素来源于FDA，由怀疑与许多肝素相关的临床事件有关的肝素，和对照肝素组成，用盲法对OSCS存在和其生物功能与临床副反应之间的潜在联系进行筛选。在体外，对接触系统和补体级联反应的激活进行了检测。此外，在猪体内，对OSCS引起的临床关键现象进行检测。
Results
结果
The OSCS found in contaminated lots of unfractionated heparin, as well as a synthetically generated OSCS reference standard, directly activated the kinin–kallikrein pathway in human plasma, which can lead to the generation of bradykinin, a potent vasoactive mediator.
低分子肝素中污染物OSCS， 和以合成的OSCS作为标准参照，直接激活人类血浆中的激肽系统kinin–kallikrein ，能导致潜在血管活性介质缓激肽(bradykinin)产生。
In addition, OSCS induced generation of C3a and C5a, potent anaphylatoxins derived from complement proteins.
此外，OSCS也能诱导产生过敏反应毒素（Anaphylatoxins），补体蛋白C3a和.C5a的释出。
Activation of these two pathways was unexpectedly linked and dependent on fluid-phase activation of factor XII.
激活这两个通路意外地联系并依赖与 液相XII因子激活。
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作者:admin@医学,生命科学 2010-12-28 05:14
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