Anti-tissue factor pathway inhibitor ( TFPI) therapy: a novel approach to the treatment of haemophilia
Anti-tissue factor pathway inhibitor ( TFPI) therapy: a novel approach to the treatment of haemophilia
复制标题
DOI：
10.1007/s12185-018-2548-6
复制
发表时间：
2020-01-01
影响因子：
2.1
通讯作者：
Chowdary, Pratima
中科院分区：
文献类型：
--
作者：
Chowdary, Pratima
由于目前的护理标准，因子替代疗法的局限性，需要新的方法来治疗血友病。期望包括减轻治疗负担和有效预防关节损伤。通过恢复凝血酶的生成来治疗血友病可能是一种有效的方法。恢复凝血酶生成的一个有希望的靶点是组织因子途径抑制剂（TFPI），这是一种多价kuniz型丝氨酸蛋白酶抑制剂，通过对组织因子-因子VIIa复合物的xa依赖性反馈抑制来调节组织因子诱导的凝血。TFPI的抑制使凝血过程在进化上恢复到更原始的状态，而其他天然抑制剂的调节作用则得以保留。一种适体和三种针对TFPI的单克隆抗体已在临床试验中进行了研究。除了改善与轻度血友病相关的凝血酶生成外，抗tfpi疗法具有皮下给药的优势。然而，由于新的作用机制，需要确定治疗窗口以及潜在的并发症。本文综述了TFPI、其在正常凝血中的作用、抑制TFPI的原理，并总结了以前或目前正在开发的抗TFPI治疗方法。
Novel approaches to the treatment of haemophilia are needed due to the limitations of the current standard of care, factor replacement therapy. Aspirations include lessening the treatment burden and effectively preventing joint damage. Treating haemophilia by restoring thrombin generation may be an effective approach. A promising target for restoring thrombin generation is tissue factor pathway inhibitor (TFPI), a multivalent Kunitz-type serine protease inhibitor that regulates tissue factor-induced coagulation via factor Xa-dependent feedback inhibition of the tissue factor-factor VIIa complex. Inhibition of TFPI reverts the coagulation process to a more primitive state evolutionarily, whilst regulation by other natural inhibitors is preserved. An aptamer and three monoclonal antibodies directed against TFPI have been investigated in clinical trials. As well as improving thrombin generation in the range associated with mild haemophilia, anti-TFPI therapies have the advantage of subcutaneous administration. However, the therapeutic window needs to be defined along with the potential for complications due to the novel mechanism of action. This review provides an overview of TFPI, its role in normal coagulation, the rationale for TFPI inhibition, and a summary of anti-TFPI therapies, previously or currently in development.