Impaired tolerance in the International Immune Tolerance Induction Study (I-ITI study) due to the presence of very low-titer inhibitors.

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis Pub Date : 2025-07-21 DOI:10.1016/j.jtha.2025.07.005

Lars L F G Valke, Charles R M Hay, Donna M DiMichele, Robert Polenewen, Marieke J A Verhagen, Daniëlle Meijer, Sanna R Rijpma, Nicole A M Blijlevens, Saskia E M Schols, Waander L van Heerde

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引用次数: 0

Abstract

Background: In persons with hemophilia A (pwHA), development of an inhibitor complicates treatment with factor VIII (FVIII) replacement therapy. Immune tolerance induction (ITI) is used to restore tolerance. However, some pwHA do not reach tolerance despite disappearance of the inhibitor detected with the Nijmegen Bethesda Assay (NBA), potentially due to persistent presence of very low-titer inhibitors.

Aim: We determined of presence of very low-titer inhibitors with the Nijmegen ultra-sensitive Bethesda Assay (NusBA) in the International-ITI study.

Methods: This study included 115 pwHA and inhibitors (pwHAI). In 53 of these participants both NBA and NusBA were determined from the same sample measured in 175 sample time points. Both FVIII half-life and recovery were correlated with NBA and NusBA results and used to plot ROC curves as 50 of these 175 concurrent measurements included a pharmacokinetic analysis.

Results: NusBA had a stronger correlation with FVIII half-life (r=-0.56, 95%-CI:-0.80--0.20, p=0.004) than NBA (r=-0.36, 95%-CI:-0.67--0.06, p=0.008). Also, the area under the curve (AUC) of the NusBA (0.79, 95%-CI:0.59-0.98) was higher than the AUC of the NBA (0.64, 95%-CI:0.40-0.87), with FVIII half-life ≥7 hours indicating tolerance. The NBA was unable to detect very low-titer inhibitor levels in pwHAI with a decreased FVIII half-life. Post-ITI, a positive NusBA was detected in 66% of all samples which is in contrast to the 42% NBA positive samples.

Conclusion: The NusBA can detect very low-titer inhibitors and correlates with FVIII half-life in the early post-ITI period. The NusBA has added value in pwHAI undergoing ITI to monitor tolerance.

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在国际免疫耐受诱导研究（I-ITI研究）中，由于极低滴度抑制剂的存在，耐受性受损。

背景：在血友病A （pwHA）患者中，抑制剂的开发使因子VIII （FVIII）替代疗法的治疗复杂化。免疫耐受诱导（ITI）用于恢复耐受性。然而，尽管Nijmegen Bethesda Assay （NBA）检测到抑制剂消失，一些pwHA仍未达到耐受性，这可能是由于非常低滴度抑制剂的持续存在。目的：在International-ITI研究中，我们用奈梅亨超灵敏贝塞斯达试验（NusBA）确定了极低效价抑制剂的存在。方法：本研究纳入115例pwHA及其抑制剂（pwHAI）。在这些参与者中，53人的NBA和NusBA都是从175个样本时间点测量的相同样本中确定的。FVIII半衰期和恢复与NBA和NusBA结果相关，并用于绘制ROC曲线，因为这175个并发测量中有50个包括药代动力学分析。结果：NusBA与FVIII半衰期的相关性（r=-0.56, 95%-CI:-0.80—0.20,p=0.004）高于NBA （r=-0.36, 95%-CI:-0.67—0.06,p=0.008）。NusBA的曲线下面积（AUC）（0.79, 95%-CI:0.59-0.98）高于NBA的AUC (0.64, 95%-CI:0.40-0.87)， FVIII半衰期≥7小时表明耐药。NBA无法在FVIII半衰期降低的pwHAI中检测到非常低滴度的抑制剂水平。在iti后，66%的样本中检测到NusBA阳性，而NBA样本中这一比例为42%。结论：NusBA可以检测到非常低效价的抑制剂，并与iti后早期FVIII半衰期相关。NusBA为pwHAI进行ITI监测耐受性增加了价值。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

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.