• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文学位 >A new mechanism-driven bypassing strategy for direct factor Xa inhibitors reveals an unexpected property of target specific anticoagulants.
【24h】

A new mechanism-driven bypassing strategy for direct factor Xa inhibitors reveals an unexpected property of target specific anticoagulants.

机译：直接因子Xa抑制剂的新机制驱动旁路策略揭示了靶标特异性抗凝剂的出乎意料的特性。

获取原文
获取原文并翻译 | 示例
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Hemostasis is a crucial component of vascular homeostasis that prevents blood loss while also maintaining vascular patency. Hemostasis is achieved, in part, through a cascade of serine proteases that are sequentially activated, culminating in formation of the effector protease, thrombin. Normally, this process is tightly regulated, but loss of regulation can lead to bleeding or excessive clot formation (thrombosis). In the event of thrombosis, anticoagulation is the mainstay of care. Numerous pharmacokinetic problems with the oral anticoagulant warfarin prompted the development of new oral agents that directly inhibit the serine proteases of coagulation. In particular, several active site inhibitors of coagulation factor Xa (FXa) have recently been approved and are at least as effective as warfarin for the prevention of thrombosis. However, they, like warfarin, increase the risk of bleeding, and there are no approved countermeasures to treat or prevent bleeding with these direct FXa inhibitors. We evaluated whether a variant of FXa (FXaI[16]L) could reverse the effects of the direct FXa inhibitor rivaroxaban. FXaI[16]L has poor active site function and a long plasma half-life but has high catalytic activity at the site of vascular injury, making it an effective pro-hemostatic agent. FXaI[16]L potently reversed the effects of rivaroxaban in in vitro studies and animal models of coagulation. Kinetic studies revealed that both FXaI[16]L and wt-FXa are highly inhibited by rivaroxaban at therapeutic concentrations when bound to the cofactor FVa. Despite this high level of inhibition with rivaroxaban, both FXaI[16]L and wt-FXa support thrombin generation. To explain this discrepancy, we measured the kinetics of FXa inhibition by antithrombin III (ATIII), a key regulator of FXa activity in plasma. Rivaroxaban impaired ATIII-dependent FXa inhibition by creating a pool of reversibly-inhibited FXa, and kinetic simulations indicated that, under these conditions, a steady-state of free, uninhibited FXa is established. Thus, there is a paradoxical increase in the level of free FXa which explains how FXaI[16]L can generate thrombin in the presence of rivaroxaban. These results reveal a previously unreported, unintended consequence of direct FXa inhibitors that may have important implications. Further, FXaI[16]L may be able to fill the unmet clinical need for a rapid, hemostatic reversal agent for these new anticoagulants.
机译：止血是血管动态平衡的重要组成部分，它可以防止失血并保持血管通畅。止血部分地通过级联的丝氨酸蛋白酶实现的，所述丝氨酸蛋白酶被顺序激活，最终形成效应蛋白酶凝血酶。通常，该过程受到严格的调节，但是调节的丧失会导致出血或血栓形成过多（血栓形成）。发生血栓形成时，抗凝是主要的治疗手段。口服抗凝剂华法林存在许多药代动力学问题，促使人们开发出直接抑制丝氨酸蛋白酶凝结的新型口服剂。特别地，最近已经批准了几种凝血因子Xa（FXa）的活性部位抑制剂，它们在预防血栓形成方面至少与华法林一样有效。但是，它们像华法令一样，会增加出血的风险，并且尚无批准的使用这些直接FXa抑制剂治疗或预防出血的对策。我们评估了FXa的变体（FXaI [16] L）是否可以逆转直接FXa抑制剂利伐沙班的作用。 FXaI [16] L具有较差的活性位点功能和较长的血浆半衰期，但在血管损伤位点具有较高的催化活性，使其成为有效的止血剂。 FXaI [16] L在体外研究和凝血动物模型中有效逆转了利伐沙班的作用。动力学研究表明，当与辅因子FVa结合时，利伐沙班在治疗浓度下都高度抑制FXaI [16] L和wt-FXa。尽管利伐沙班具有如此高的抑制水平，FXaI [16] L和wt-FXa均支持凝血酶生成。为了解释这种差异，我们测量了抗凝血酶III（ATIII）抑制FXa的动力学，抗凝血酶III是血浆中FXa活性的关键调节剂。利伐沙班通过产生可逆抑制的FXa池削弱了ATIII依赖性FXa的抑制作用，动力学模拟表明，在这些条件下，可以建立稳定的游离，未抑制的FXa。因此，游离FXa含量反常增加，这解释了FXaI [16] L在利伐沙班存在下如何产生凝血酶。这些结果揭示了直接FXa抑制剂以前未曾报道过的意外结果，可能具有重要意义。此外，FXaI [16] L可能能够满足这些新抗凝剂对快速止血逆转剂的临床需求。

著录项

  • 作者

    Thalji, Nabil K.;

  • 作者单位

    University of Pennsylvania.;

  • 授予单位 University of Pennsylvania.;
  • 学科 Pharmacology.;Medicine.;Biochemistry.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 153 p.
  • 总页数 153
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号