基于质谱的精准诊断技术为抗凝血酶缺乏症提供了新见解。

IF 5.5 2区 医学 Q1 HEMATOLOGY Journal of Thrombosis and Haemostasis Pub Date : 2024-10-17 DOI:10.1016/j.jtha.2024.10.005
Mirjam Kruijt, Maria Eugenia de la Morena-Barrio, Javier Corral, Christa M Cobbaert, L Renee Ruhaak
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引用次数: 0

摘要

背景:尽管五常法(预防性、个性化、预测性、参与性、心理认知)医学和以患者为中心的医疗保健在各个医疗保健领域日益普及,但抗凝血酶缺乏症(ATD)的诊断仍以粗略的诊断测试为基础,将患者分为临床异质性亚组,相关的血栓性表型可能因此而被忽视。临床路径和大多数证据都以这些测试为基础,因此普通治疗仍是常态:为了揭示 ATD 的异质性,我们开发了一种基于质谱(LC-MRM-MS)的抗凝血酶检测方法,可对患者血浆中的抗凝血酶蛋白形式进行分子鉴定。本研究首次揭示了该检测方法的临床性能:方法:91 名无血缘关系的 ATD 患者和 41 名患有影响抗凝血酶糖基化的先天性糖基化紊乱的患者的血浆进行了功能和基因表征,并通过 LC-MRM-MS 进行了分析。采用既定的数据分析策略对抗凝血酶蛋白形式进行定量和分子鉴定:结果:该检测能识别存在定量缺陷的患者,区分 I 型和 II 型 ATD,并识别出变异蛋白形式。总体而言,LC-MRM-MS 对 ATD 的诊断灵敏度为 100%,而功能测试的灵敏度为 81.1%。II 型 ATD 是一种容易误诊的亚型,LC-MRM-MS 与功能测试的识别率差异更大,前者为 100%,后者为 56.8%:基于 MS 的定性和定量 AT 测试可作为研究 ATD 临床异质性分子基础的平台。这种针对 ATD 的精准诊断方法可以降低诊断的不确定性,并使 ATD 诊断和临床路径现代化。
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Novel insights into antithrombin deficiency enabled by mass spectrometry-based precision diagnostics.

Background: Although P5 (preventive, personalized, predictive, participatory, psychocognitive) medicine and patient-focused healthcare are gaining ground in various healthcare areas, the diagnosis of antithrombin deficiency (ATD) is still based on crude diagnostic tests, clustering patients into clinically heterogeneous subgroups whereby relevant thrombophilia phenotypes may go unnoticed. Clinical pathways and the majority of evidence are based on these tests; therefore, generic treatment is still the norm.

Objectives: To unravel the heterogeneity of ATD, a mass spectrometry (liquid chromatography coupled to multiple-reaction-monitoring mass spectrometry [LC-MRM-MS])-based test for antithrombin was developed allowing molecular characterization of the antithrombin proteoforms in patient plasma. This study provides the first insight into the tests' clinical performance.

Methods: Plasma from 91 unrelated ATD patients and 41 patients with a congenital disorder of glycosylation affecting antithrombin glycosylation were characterized functionally, genetically, and analyzed by LC-MRM-MS. An established data analysis strategy was applied for quantitation and molecular characterization of antithrombin proteoforms.

Results: The test recognized patients with a quantitative defect, discriminated between type I and type II ATD, and identified variant proteoforms. Overall, the diagnostic sensitivity for ATD was 100% for LC-MRM-MS compared with 81.1% by the functional test. Type II ATD, a subtype prone to misdiagnosis, revealed an even larger difference of 100% identification by LC-MRM-MS vs 56.8% by functional test.

Conclusion: The qualitative and quantitative mass spectrometry-based AT-test can serve as a platform for investigating the molecular basis of the clinical heterogeneity of ATD. This "precision diagnostics" approach for ATD can lower diagnostic uncertainty and modernize the ATD diagnostic and clinical pathways.

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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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