抗组织因子途径抑制物在血友病临床应用中的研究进展

doi:10.16150/j.1671-2870.2025.02.015

摘要/Abstract

摘要：

近年来，针对血友病治疗中未满足的需求，已有较多研究取得了前所未有的药物治疗进展，包括数种创新机制疗法的开发，在伴或不伴抑制物的血友病患者中通过调节凝血酶生成来重新平衡止血。其中，涉及止血再平衡机制的非因子治疗取得了显著进展，临床研发聚焦点之一在抗组织因子途径抑制物（tissue factor pathway inhibitor， TFPI）疗法。TFPI是凝血途径中的关键抗凝蛋白，能够抑制组织因子（tissue factor， TF）介导的凝血启动，阻断TFPI活性，可以增强凝血酶生成，为血友病治疗提供了一种新的方法，且该机制同时适用于血友病A或血友病B患者，理论上对伴或不伴抑制物的患者均有效。至2025年6月，进入临床研发阶段或在国外上市的抗TFPI药物包括康赛珠单抗（concizumab）、马塔西单抗（marstacimab）、贝伐昔单抗（befovacimab）、KN057和MG1113。这些药物通过不同的抗体类型，以不同的结合力或靶向TFPI的不同结构域来抑制其活性。不同临床试验阶段的研究显示，这些药物在降低年出血率和改善患者预后方面具有良好的效果。此外，抗TFPI药品为皮下注射及给药间隔可长达1周，均为患者带来了便利。抗TFPI疗法代表了血友病治疗领域的一个重要转变。然而，抗TFPI疗法也面临一些挑战，如可能导致潜在的血栓风险，目前尚无适的实验室检测方法来监测治疗效果。

关键词: 血友病, 抗组织因子途径抑制物, 血栓

Abstract:

In recent years， to address the unmet needs in hemophilia treatment， significant research has led to unprecedented advances in pharmacotherapy， including the development of several innovative mechanism-based therapies that restore hemostatic balance by modulating thrombin generation in hemophilia patients with or without inhibitors. Among them， non-factor therapies involving hemostatic rebalancing mechanisms have achieved remarkable progress， with one of the key focuses in clinical development being anti-tissue factor pathway inhibitor （TFPI） therapy. TFPI is a key anticoagulant protein in the coagulation pathway that inhibits tissue factor （TF）-mediated initiation of coagulation. Blocking TFPI activity can enhance thrombin generation， providing a novel approach for hemophilia treatment. Notably， this mechanism applies to patients with hemophilia A or B and is theoretically effective for patients with or without inhibitors. As of June 2025， anti-TFPI agents that have entered clinical development or been approved for marketing internationally include concizumab， marstacimab， befovacimab， KN057， and MG1113. These agents inhibit TFPI activity through different antibody types， employing varying binding affinities or targeting distinct domains of TFPI. Studies on clinical trials across various phases have demonstrated that these drugs have good efficacy in reducing annual bleeding rates and improving patient prognosis. In addition， anti-TFPI drugs are administered subcutaneously， with dosing intervals up to one week， providing convenience for patients. Anti-TFPI therapy represents an important shift in the field of hemophilia management. However， it faces some challenges， including potential thrombotic risks and the current absence of suitable laboratory assays to monitor treatment efficacy.

Key words: Hemophilia, Anti-tissue factor pathway inhibitor, Thrombosis

中图分类号:

R554⁺.1

肖剑文, 易维佳. 抗组织因子途径抑制物在血友病临床应用中的研究进展[J]. 诊断学理论与实践, 2025, 24(02): 226-232.

XIAO Jianwen, YI Weijia. Research progress on clinical application of anti-tissue factor pathway inhibitor in hemophilia[J]. Journal of Diagnostics Concepts & Practice, 2025, 24(02): 226-232.

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抗TFPI单克隆抗体	单克隆抗体特性	TFPI结合位点	最新临床开发阶段		全球上市情况
抗TFPI单克隆抗体	单克隆抗体特性	TFPI结合位点	NCT编号	受试者形态	全球上市情况
concizumab	人源化IgG 4	K2结构域	NCT04083781 (explorer 7)	12岁及以上患有血友病A或血友病B并伴有抑制物的患者（任何严重程度）	加拿大 (2023)^* 瑞士 (2023)^* 澳洲 (2023)^* 日本 (2023)^† 美国 (2024)^¶
			NCT04082429 (explorer8)	12岁及以上患有血友病A或血友病B未伴有抑制物的患者
			NCT05135559 进行中 (explorer10)	12岁以下A型或B型血友病患者，伴有或不伴有抑制物
marstacimab	全人源IgG1	K2结构域	NCT03938792 (BASIS)	12岁及以上A型（重型）或B型（中重型至重型）血友病患者，伴有或不伴有抑制物	美国 (2024)^‡ 欧盟 (2024)^§ 2024年8月13日在中国申报上市并获得受理。
marstacimab	全人源IgG1	K2结构域	NCT05611801 (BASIS KIDS)	12岁以下A型（重型）或B型（中重型至重型）血友病患者，伴有或不伴有抑制物	美国 (2024)^‡ 欧盟 (2024)^§ 2024年8月13日在中国申报上市并获得受理。
befovacimab	人源化IgG2	K1和K2结构域	Ⅱ期 NCT03597022 终止	18岁及以上A型或B型血友病患者，伴有或不伴有抑制物
KN057	人源化		Ⅲ期 NCT06312475进行中	12岁及以上患有血友病A或血友病B并伴有抑制物的患者
MG1113	人源化IgG4	K2结构域	Ⅰb期 NCT05493631进行中	19岁及以上重型血友病A或血友病B患者，伴有或不伴有抑制物