From unfractionated heparin to pentasaccharide: Paradigm of rigorous science growing in the understanding of the in vivo thrombin generation.
从普通肝素到五糖: 严格的科学范式在体内凝血酶生成的理解中成长。
Anticoagulation Clinical trials Deep venous thrombosis Heparin history Laboratory monitoring Mechanism of action Natural polysaccharides New scheme of coagulation Pentasaccharide Translational medicine
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摘要

Following a chance discovery made by a medical student who was searching for a clot-promoting activity in tissue extracts, it took 15-20 years to attain the therapeutic use of standard unfractionated heparin (UFH), due to problems with the purification and extraction of the active material. Soon it was found that: 1) thrombin inactivation by UFH was associated with the formation of molecular complexes between antithrombin and the activated forms of factor X (FXa) and thrombin, 2) low-molecular-weight fractions of UFH lose their antithrombin activity while still interacting with FXa, 3) a pentasaccharide sequence of UHF increases FXa (but not thrombin) inactivation by antithrombin. Low-molecular-weight heparins (LMWHs) with little effect on thrombin and strongly active versus FXa were then developed. In patients, LMWHs (and the pentasaccharide sequence) came up as a useful class of drugs to prevent and treat thrombosis, their greatest advantage over UFH being the convenience of the once/twice daily subcutaneous injections at a fixed dose without any laboratory monitoring. In addition to providing major information on in vivo modulation of thrombin generation, the heparin saga served as a paradigm to support an alternative coagulation scheme that includes platelets and tissue factor as integral parts of the model. Forthcoming work with this scheme - also supported by studies in hemophilia and rare bleeding disorders - is expected to provide major hints for understanding why some patients benefit more than others from the small amount of thrombin they form and directions to tailor prevention and treatment of thromboembolic disorders.

译文

一名在组织提取物中寻找促进凝块活性的医科学生偶然发现后,花了 15-20 年才获得标准普通肝素 (UFH) 的治疗用途, 由于活性物质的纯化和提取存在问题。很快发现: 1) 由 UFH 引起的凝血酶失活与抗凝血酶和活化形式的因子 X (FXa) 和凝血酶之间分子复合物的形成有关,2) UFH 的低分子量部分失去抗凝血酶活性,同时仍与 FXa 相互作用,3)UHF 的五糖序列通过抗凝血酶增加 FXa (但不是凝血酶) 失活。然后开发了对凝血酶影响较小且对 FXa 有强烈活性的低分子量肝素 (LMWHs)。在病人身上,LMWHs (和五糖序列) 是预防和治疗血栓形成的一类有用的药物, 与 UFH 相比,它们最大的优势是在没有任何实验室监测的情况下,以固定剂量每天一次/两次皮下注射的便利性。除了提供关于凝血酶生成的体内调节的主要信息,肝素 saga 作为支持替代凝血方案的范例,包括血小板和组织因子作为模型的组成部分。这项计划即将开展的工作 -- 也得到血友病和罕见出血性疾病研究的支持 -- 有望为理解为什么一些患者比其他患者从他们形成的少量凝血酶中获益更多提供主要线索以及定制血栓栓塞性疾病预防和治疗的方向。

Thrombin

神经 凝血因子 临床研究术语
概述  :  

凝血酶也称为凝血因子IIa(FIIa),由其无活性前体凝血酶原转化而成,是丝氨酸蛋白酶和维生素K依赖性凝血因子家族的成员,参与凝血过程的各个环节,在凝血级联中起关键作用。在凝血反应中,凝血酶通过正负反馈,发挥着促凝和抗凝双重调节作用,维持机体凝血系统的平衡。近年来发现,凝血酶除了在凝血级联中发挥重要作用外,与炎症及炎症相关的多种疾病也关联密切,累及神经、消化、心血管、运动、呼吸、内分泌等多个系统。结构凝血酶来源于其无活性的酶原形式-凝血酶原,一种在肝脏中合成并分泌到血液中的70KD糖蛋白。在

thrombin    英 ['θrɒmbɪn]  美 ['θrɑmbɪn] 

释    义   n. [生化] 凝血酶

例    句   The ultimate result is the formation of the thrombin and fibrin clot, and each enzymolysisaccompaniment magnify effective. 最终结果是凝血酶和纤维蛋白凝块的形成,而且每步酶解反应均有放大效应。

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