用数学建模方法研究康舒单抗对血友病 A 的下游影响。

IF 5.5 2区 医学 Q1 HEMATOLOGY
Kenji Miyazawa, Alan E Mast, Adam R Wufsus, Michael Dockal, Marianne Kjalke, Karin Leiderman
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引用次数: 0

摘要

背景:组织因子途径抑制剂(TFPI)是一种抗凝血蛋白,可抑制FXa、TF-FVIIa-FXa复合物以及凝血酶原酶复合物的早期形式。康妥珠单抗是一种单克隆抗体,可阻断 TFPI 对 FXa 的抑制,减少血友病患者的出血:利用数学模型研究康妥珠单抗如何影响 TFPI 的各种反应以恢复血友病 A 的凝血酶生成:方法:采用分区模型估算游离康珠单抗及其与 TFPIα 和 TFPIβ 复合物的血浆浓度。在血友病 A 的条件下,将康珠单抗整合到一个流动介导的凝血数学模型中,并模拟了一个小的损伤。然后对模拟结果进行分析,以确定康利珠单抗如何阻断 TFPI 抗凝活性,特别是如何抑制血浆中和血小板上的 FXa、抑制内皮下的 TF:VIIa 以及血浆 TFPIα 通过 TFPIβ 事先螯合到内皮,从而改变凝血酶的生成:结果:Concizumab通过同时改变TFPI抗凝阻断的三种机制,改善了血友病A的模拟凝血酶生成。通过形成三元 TFPIα-concizumab-TFPIβ 复合物,康舒单抗能封存血浆中 75% 的 TFPIα。在所有TF水平中,降低TFPIα血浆浓度对滞后时间的影响最大,其次是阻断TFPIα对TF:VIIa:FXa的抑制,随后是阻断TFPIα对血浆中和血小板表面FXa的抑制:结论:康居单抗的有效性是通过阻断血浆中和多个生理表面上的TFPI抗凝活性来实现的。康利珠单抗的一个以前未被认识到的重要功能是将血浆中的 TFPIα 封闭在血管内皮中。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Examining downstream effects of concizumab in hemophilia A with a mathematical modeling approach.

Background: Tissue factor (TF) pathway inhibitor (TFPI) is an anticoagulant protein that inhibits factor (F)Xa, the TF-FVIIa-FXa complex, and early forms of the prothrombinase complex. Concizumab is a monoclonal antibody that blocks FXa inhibition by TFPI and reduces bleeding in hemophilia.

Objectives: To examine how concizumab impacts various reactions of TFPI to restore thrombin generation in hemophilia A using mathematical models.

Methods: A compartment model was used to estimate plasma concentrations of free concizumab and its complexes with TFPIα and TFPIβ. Concizumab was integrated into a flow-mediated mathematical model of coagulation, and a small injury was simulated under hemophilia A conditions. Simulations were then analyzed to determine how concizumab's blockade of TFPI anticoagulant activities, specifically the inhibition of FXa in plasma and on platelets, inhibition of TF:FVIIa at the subendothelium, and prior sequestration of plasma TFPIα to the endothelium via TFPIβ, altered thrombin generation.

Results: Concizumab improved simulated thrombin generation in hemophilia A by simultaneously altering all 3 mechanisms of the TFPI anticoagulant blockade examined. Concizumab sequestered ∼75% of plasma TFPIα through the formation of ternary TFPIα-concizumab-TFPIβ-complexes. For all TF levels, reducing the TFPIα plasma concentration had the largest impact on the lag time, followed by blocking TFPIα inhibition of TF:FVIIa:FXa and subsequently by blocking TFPIα inhibition of FXa in plasma and on the platelet surface.

Conclusion: The effectiveness of concizumab is mediated through the blockade of TFPI anticoagulant activities in plasma and on multiple physiological surfaces. An important and previously unrecognized function of concizumab was the sequestration of plasma TFPIα to the endothelium.

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来源期刊
Journal of Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis 医学-外周血管病
CiteScore
24.30
自引率
3.80%
发文量
321
审稿时长
1 months
期刊介绍: The Journal of Thrombosis and Haemostasis (JTH) serves as the official journal of the International Society on Thrombosis and Haemostasis. It is dedicated to advancing science related to thrombosis, bleeding disorders, and vascular biology through the dissemination and exchange of information and ideas within the global research community. Types of Publications: The journal publishes a variety of content, including: Original research reports State-of-the-art reviews Brief reports Case reports Invited commentaries on publications in the Journal Forum articles Correspondence Announcements Scope of Contributions: Editors invite contributions from both fundamental and clinical domains. These include: Basic manuscripts on blood coagulation and fibrinolysis Studies on proteins and reactions related to thrombosis and haemostasis Research on blood platelets and their interactions with other biological systems, such as the vessel wall, blood cells, and invading organisms Clinical manuscripts covering various topics including venous thrombosis, arterial disease, hemophilia, bleeding disorders, and platelet diseases Clinical manuscripts may encompass etiology, diagnostics, prognosis, prevention, and treatment strategies.
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