抗组织因子途径抑制物诱导罕见性出血性疾病患者止血：一项基于体外凝血酶生成（TG）指导的初步研究。

Anti-TFPI for hemostasis induction in patients with rare bleeding disorders, an ex vivo thrombin generation (TG) guided pilot study.

机构信息

National Hemophilia Center, Sheba Medical Center, Tel Hashomer, Israel; Amalia Biron Research Institute of Thrombosis and Hemostasis, Sackler School of Medicine, Tel Aviv University, Israel.

Department of Pathophysiology, Sechenov First Moscow State Medical University (Sechenov University), Russia.

出版信息

Blood Cells Mol Dis. 2022 Jul;95:102663. doi: 10.1016/j.bcmd.2022.102663. Epub 2022 Apr 12.

DOI:10.1016/j.bcmd.2022.102663

PMID:35525014

Abstract

BACKGROUND

Rare bleeding disorders (RBD) are inherited coagulopathies, whose hemostatic control is based upon replacement therapy. Marstacimab (PF-06741086) is a human monoclonal IgG that targets the Kunitz2 domain of tissue factor pathway inhibitor [TFPI]. Marstacimab is currently in development for bleeding prophylaxis in patients with hemophilia.

OBJECTIVES

To assess the potential impact of Marstacimab upon thrombin generation (TG) in RBD patients' plasma samples.

RESULTS

Our cohort included 18 RBD patients, with severe deficiencies: 5 Von Willebrand Disease (VWD) type 3, 4 FVII, 3 FXI, 2 FXIII deficiency and 1 patient with: FX, FV + FVIII, Fibrinogen, combined vitamin K dependent factors' deficiency. Citrated samples from RBD patients were collected and spiked with Marstacimab, TG was measured by calibrated automated thrombogram. Among all patients a reduced baseline TG was observed as compared to controls. Improvement of median (lag time, peak and ETP was observed in Marstacimab spiked samples from 8 min, 99 nM, 1116 nMx min to 5.5 min, 194 nM,1614 nMx min, respectively. None of the values measured among RBD patients exceeded normal controls.

CONCLUSION

These in vitro data suggest that Marstacimab may serve as a promising approach for restoring the hemostatic balance in various RBD, though potential clinical implications should be further investigated.

摘要

背景

罕见出血性疾病（RBD）是遗传性凝血疾病，其止血控制基于替代疗法。Marstacimab（PF-06741086）是一种靶向组织因子途径抑制剂[TFPI]的 Kunitz2 结构域的人源单克隆 IgG。Marstacimab 目前正在开发用于血友病患者的出血预防。

目的

评估 Marstacimab 对 RBD 患者血浆样本中凝血酶生成（TG）的潜在影响。

结果

我们的队列包括 18 名 RBD 患者，存在严重缺陷：5 名血管性血友病（VWD）3 型，4 名 FVII，3 名 FXI，2 名 FXIII 缺乏症和 1 名患者存在：FX、FV+FVIII、纤维蛋白原、联合维生素 K 依赖性因子缺乏症。从 RBD 患者采集枸橼酸盐样本，并加入 Marstacimab，通过校准自动血栓图测量 TG。与对照组相比，所有患者的基线 TG 均降低。在 Marstacimab 加样样本中，中位（lag time，峰值和 ETP）分别从 8 分钟、99 nM、1116 nMx min 改善至 5.5 分钟、194 nM、1614 nMx min。在 RBD 患者中测量的所有值均未超过正常对照。