Novel alternate hemostatic agents for patients with inhibitors: beyond bypass therapy
Novel alternate hemostatic agents for patients with inhibitors: beyond bypass therapy
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DOI：
10.1182/asheducation-2017.1.605
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发表时间：
2017-12-01
影响因子：
3
通讯作者：
Ragni, Margaret V.
中科院分区：
文献类型：
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作者：
Ragni, Margaret V.
抑制剂的形成是血友病治疗最严重的并发症之一。抑制剂是由针对输注凝血因子的 T 细胞反应引起的，严重 A 型血友病患者的累积发病率为 30%，严重 B 型血友病患者的累积发病率为 3%。这些抑制剂中和因子 VIII 或 IX 活性并破坏正常的血液停滞。抑制剂患者对标准因子治疗变得无反应，并且作为替代，使用旁路治疗(例如，重组因子VIIa或因子VIII抑制剂旁路活性)。然而，与非抑制剂患者相比，对旁路药物的反应较差，疾病负担较高，发病率、住院率、费用和死亡率更高。此外，抑制剂的形成会干扰预防出血事件，并且是基因治疗的禁忌症。因此，非常需要针对抑制剂患者的更有效的治疗。在过去的几年中，针对有或没有抑制剂的血友病患者出现了新型替代止血剂的激增。这些药物利用凝血因子和天然抗凝剂的技术操作来促进止血。这些方法包括：（1）凝血因子的突变体或模拟物，使其对天然抗凝血剂具有抵抗力； (2) 敲低或破坏天然抗凝剂，防止凝血因子降解。本文的目的是回顾这些新型替代止血剂及其作用机制，以及早期临床试验中获得的初步药代动力学、安全性和有效性数据。
Inhibitor formation is among the most severe complications of hemophilia treatment. With a cumulative lincidence of 30% in those with severe hemophilia A and 3% in those with severe hemophilia B, inhibitors are caused by a T-cell response directed against infused coagulation factor; these inhibitors neutralize factor VIII or IX activity and disrupt normal hernostasis. Inhibitor patients become unresponsive to standard factor treatment and, as an alternative, use bypass treatment (eg, recombinant factor Vila or factor VIII inhibitor bypass activity). However, response to bypass agents is poorer and the burden of disease is higher, with greater morbidity, hospitalization, cost, and mortality, than in noninhibitor patients. Furthermore, inhibitor formation interferes with prophylaxis to prevent bleeding episodes and is a contraindication to gene therapy. Thus, more effective therapies for inhibitor patients are greatly needed. In the last several years, there has been an explosion of novel alternative hemostatic agents for hemophilia patients with and without inhibitors. These agents take advantage of technologic manipulation of coagulation factors and natural anticoagulants to promote hemostasis. The approaches include the following: (1) mutants or mimics of coagulation factors, rendering them resistant to natural anticoagulants; or (2) knock-down or disruption of natural anticoagulants, preventing degradation of coagulation factors. The purpose of this article was to review these novel alternative hemostatic agents and their mechanisms of action, as well as the preliminary pharmacokinetic, safety, and efficacy data available from early-phase clinical trials.