Bioengineering factor Xa to treat bleeding
Bioengineering factor Xa to treat bleeding
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DOI：
10.1016/s0049-3848(16)30360-7
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发表时间：
2016-05-01
影响因子：
7.5
通讯作者：
Camire, Rodney M.
中科院分区：
文献类型：
--
作者：
Camire, Rodney M.
临床上需要开发安全和快速的治疗策略来控制由大量紧急情况引起的出血。在过去的几年里，我们的实验室已经开发了新的类似酶原的FXA变体，并以血友病为模型系统测试了它们的安全性和有效性。这些变异体具有一系列性质，这些性质是由重链N端的氨基酸变化引起的，该变化改变了关键的构象变化。这些特性包括对血浆蛋白酶抑制剂的抵抗力，在没有FVA的情况下活性低，以及加入凝血酶原酶后挽救低活性，产生非常有效的促止血剂。依赖FVA的活性恢复是其疗效的关键方面，也有助于将变异定位到血管损伤的位置。虽然临床前数据支持它们用于血友病的治疗，但它们有可能作为快速止血剂用于治疗一系列出血情况。本文将讨论这些FXA类酶原变异体的生化性质及其在体内的特性。(C)2016爱思唯尔有限公司。保留所有权利。
There is a clinical need to develop safe and rapid therapeutic strategies to control bleeding arising from a host of emergent situations. Over the past several years our laboratory has developed novel zymogen-like FXa variants and tested their safety and efficacy using hemophilia as a model system. The variants have a spectrum of properties resulting from an amino acid change at the N-terminus of the heavy chain that alters a critical conformational change. These properties, which include resistance to plasma protease inhibitors, low activity in the absence of FVa, and rescue of low activity upon incorporation in prothrombinase, yield remarkably effective pro-hemostatic agents. The FVa-dependent restoration of activity is a key aspect to their efficacy and also contributes to localizing the variants to the site of vascular injury. While pre-clinical data support their use in the setting of hemophilia, they have the potential to act as rapid pro-hemostatic agents for the treatment of a range of bleeding conditions. This review will discuss the biochemical properties of these FXa zymogen-like variants and their in vivo characterization. (C) 2016 Elsevier Ltd. All rights reserved.