Journal of Thrombosis and Haemostasis最新文献_第7页

Thrombin generation profiling in rare coagulation factor deficiencies: associations with bleeding severity and potential for screening 罕见凝血因子缺乏的凝血酶生成分析：与出血严重程度和筛查潜力的关联。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-03-01 Epub Date: 2025-12-22 DOI: 10.1016/j.jtha.2025.11.025

Bauke Haisma , Sanna R. Rijpma , Marjon H. Cnossen , Paul L. den Exter , Ilmar C. Kruis , Karina Meijer , Laurens Nieuwenhuizen , Nick van Es , Joline L. Saes , Nicole M.A. Blijlevens , Waander L. van Heerde , Saskia E.M. Schols

Background

Rare coagulation factor deficiencies (RCFDs) can cause significant bleeding, but activated partial thromboplastin time (APTT) and prothrombin time (PT) may not detect abnormalities, and factor activity measurements do not predict bleeding severity. Thrombin generation assays may better reflect overall hemostatic capacity.

Objectives

This study investigated whether thrombin generation can detect RCFDs and correlate with bleeding severity in patients with congenital deficiencies of factor (F)II, FV, FV/FVIII, FVII, FX, and FXI.

Methods

Thrombin generation was measured using the Nijmegen hemostasis assay in patients from the cross-sectional Dutch Rare Bleeding disorders in the Netherlands (RBiN) study (2017-2019). Parameters analyzed included thrombin potential, lag time, and thrombin potential-to-lag time (TP/LT) ratio, normalized using pooled normal plasma and expressed as percentages of the mean from 37 healthy controls. Nijmegen hemostasis assay data were correlated with bleeding severity and compared with APTT and PT.

Results

We included 106 patients, mostly with mild deficiencies (median factor activity 5%-53%). Overall, thrombin generation in patients was significantly reduced compared with controls, with decreased thrombin potentials (median 58%) and prolonged lag times (150%), resulting in reduced TP/LT ratios (45%). These parameters correlated with bleeding severity; across RCFDs, median TP/LT ratios ranged from 30% to 104% in patients without spontaneous bleeding (bleeding severity grade 0-1), 26% to 49% in mild spontaneous bleeding (grade 2), and 0% to 22% in severe spontaneous bleeding (grade 3). At 95% specificity, TP/LT ratio showed 68% to 100% sensitivity, outperforming APTT and PT (14%-80%) in all RCFDs except FVII and FV/FVIII deficiency.

Conclusion

Thrombin generation profiling correlated with bleeding severity and showed higher sensitivity than conventional screening assays in detecting RCFDs, supporting its potential in screening and clinical evaluation of RFCDs.

简介：罕见凝血因子缺乏（rcfd）可引起严重出血，但APTT和PT可能无法检测异常，因子活性测量不能预测出血严重程度（BS）。凝血酶生成测定可以更好地反映整体止血能力。本研究探讨凝血酶生成是否可以检测rcfd，并与先天性II、V、V/VIII、VII、X和XI缺乏的患者出血严重程度相关。方法：采用荷兰RBiN横断面研究（2017-2019）患者的奈梅亨止血法（NHA）测量凝血酶生成。分析的参数包括凝血酶电位（TP）、滞后时间（LT）和TP/LT比值，使用合并的正常血浆归一化，并以37名健康对照者的平均值的百分比表示。NHA数据与BS相关，并与APTT和pt进行比较。结果：我们纳入106例患者，其中大多数患有轻度缺陷（中位因子活性为5-53%）。总体而言，与对照组相比，凝血酶生成显著减少，凝血酶电位降低（中位数为58%），延迟时间延长（150%），导致TP/LT比率降低（45%）。这些参数与BS相关；在rcfd中，无自发性出血患者的中位TP/LT比值为30-104% (bs0 -1)，轻度自发性出血患者为26-49% (bs2)，重度自发性出血患者为0-22% （bs3）。在95%的特异性下，TP/LT比值显示68-100%的敏感性，优于APTT和PT（14-80%）在所有rcfd中，除了FVII和FV/FVIII缺乏症。结论：凝血酶生成谱分析与BS相关，并且在检测rcfd方面比传统筛查方法具有更高的敏感性，支持其在筛查和临床评价rcfd方面的潜力。

{"title":"Thrombin generation profiling in rare coagulation factor deficiencies: associations with bleeding severity and potential for screening","authors":"Bauke Haisma , Sanna R. Rijpma , Marjon H. Cnossen , Paul L. den Exter , Ilmar C. Kruis , Karina Meijer , Laurens Nieuwenhuizen , Nick van Es , Joline L. Saes , Nicole M.A. Blijlevens , Waander L. van Heerde , Saskia E.M. Schols","doi":"10.1016/j.jtha.2025.11.025","DOIUrl":"10.1016/j.jtha.2025.11.025","url":null,"abstract":"<div><h3>Background</h3><div>Rare coagulation factor deficiencies (RCFDs) can cause significant bleeding, but activated partial thromboplastin time (APTT) and prothrombin time (PT) may not detect abnormalities, and factor activity measurements do not predict bleeding severity. Thrombin generation assays may better reflect overall hemostatic capacity.</div></div><div><h3>Objectives</h3><div>This study investigated whether thrombin generation can detect RCFDs and correlate with bleeding severity in patients with congenital deficiencies of factor (F)II, FV, FV/FVIII, FVII, FX, and FXI.</div></div><div><h3>Methods</h3><div>Thrombin generation was measured using the Nijmegen hemostasis assay in patients from the cross-sectional Dutch Rare Bleeding disorders in the Netherlands (RBiN) study (2017-2019). Parameters analyzed included thrombin potential, lag time, and thrombin potential-to-lag time (TP/LT) ratio, normalized using pooled normal plasma and expressed as percentages of the mean from 37 healthy controls. Nijmegen hemostasis assay data were correlated with bleeding severity and compared with APTT and PT.</div></div><div><h3>Results</h3><div>We included 106 patients, mostly with mild deficiencies (median factor activity 5%-53%). Overall, thrombin generation in patients was significantly reduced compared with controls, with decreased thrombin potentials (median 58%) and prolonged lag times (150%), resulting in reduced TP/LT ratios (45%). These parameters correlated with bleeding severity; across RCFDs, median TP/LT ratios ranged from 30% to 104% in patients without spontaneous bleeding (bleeding severity grade 0-1), 26% to 49% in mild spontaneous bleeding (grade 2), and 0% to 22% in severe spontaneous bleeding (grade 3). At 95% specificity, TP/LT ratio showed 68% to 100% sensitivity, outperforming APTT and PT (14%-80%) in all RCFDs except FVII and FV/FVIII deficiency.</div></div><div><h3>Conclusion</h3><div>Thrombin generation profiling correlated with bleeding severity and showed higher sensitivity than conventional screening assays in detecting RCFDs, supporting its potential in screening and clinical evaluation of RFCDs.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 3","pages":"Pages 913-925"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mechanisms of anticancer treatment-induced arterial and venous thrombosis 抗癌治疗诱导的动脉和静脉血栓形成机制。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-03-01 Epub Date: 2025-11-05 DOI: 10.1016/j.jtha.2025.10.028

Pablo Albasanz-García , Mark P. Ward , Lucy A. Norris

Recent advances in cancer treatment have improved outcomes for patients across a wide variety of cancers. However, despite the introduction of more targeted therapies, including those that harness the body’s natural immune system, cancer-associated thrombosis, particularly during therapy, is a significant clinical problem associated with poorer outcomes. Although venous thromboembolism is more common, arterial events cause significant morbidity and are frequently fatal. In addition to the well-established chemotherapeutic regimens, multiple therapies are now used in the first-line setting, including antibody-based treatments, immunotherapy, and hormone receptor modulators. Many cancers are now being managed as chronic diseases with long-term maintenance therapies in an increasingly older patient population with significant comorbidities. With this change in the treatment landscape, predictive biomarkers are needed to effectively identify patients and treatments associated with the highest risk of thrombosis in the current cancer population. Although cancer-associated thrombosis has been extensively studied, the specific mechanisms by which cancer therapy causes thrombosis remain poorly understood. The pathogenesis of immunothrombosis associated with cancer treatments in particular is poorly defined. Focusing on solid tumors, the aim of this narrative review is to explore our current understanding of the pathogenesis of thrombotic effects of systemic cancer treatment. These include coagulation activation, vascular endothelial damage, procoagulant effects of material from dead and dying tumor cells, as well as the role of inflammatory mediators. Greater understanding of pathogenesis of treatment-related cancer-associated thrombosis will lead to the identification of more effective biomarkers to guide thromboprophylaxis.

癌症治疗的最新进展改善了各种癌症患者的预后。然而，尽管引入了更有针对性的治疗方法，包括利用人体自然免疫系统的治疗方法，但癌症相关血栓形成，特别是在治疗期间，是一个与患者预后较差相关的重大临床问题。虽然静脉血栓栓塞更常见，但动脉血栓栓塞会引起严重的发病率，而且往往是致命的。除了完善的化疗方案外，目前在一线环境中使用的多种疗法包括基于抗体的治疗、免疫治疗和激素受体调节剂。许多癌症现在被作为慢性疾病进行管理，在越来越多的老年患者群体中进行长期维持治疗，并伴有显著的合并症。随着治疗领域的这种变化，需要预测性生物标志物来有效识别当前癌症人群中与血栓形成风险最高相关的患者和治疗。尽管癌症相关血栓形成已被广泛研究，但癌症治疗导致血栓形成的具体机制仍知之甚少。特别是与癌症治疗相关的免疫血栓形成的发病机制尚不明确。聚焦于实体肿瘤，这篇叙述性综述的目的是探讨我们目前对全身癌症治疗的血栓形成作用的发病机制的理解。这些包括凝血激活、血管内皮损伤、死亡和垂死肿瘤细胞物质的促凝作用以及炎症介质的作用。更好地了解治疗相关的癌症相关血栓形成的发病机制将导致鉴定更有效的生物标志物来指导血栓预防。

{"title":"Mechanisms of anticancer treatment-induced arterial and venous thrombosis","authors":"Pablo Albasanz-García , Mark P. Ward , Lucy A. Norris","doi":"10.1016/j.jtha.2025.10.028","DOIUrl":"10.1016/j.jtha.2025.10.028","url":null,"abstract":"<div><div>Recent advances in cancer treatment have improved outcomes for patients across a wide variety of cancers. However, despite the introduction of more targeted therapies, including those that harness the body’s natural immune system, cancer-associated thrombosis, particularly during therapy, is a significant clinical problem associated with poorer outcomes. Although venous thromboembolism is more common, arterial events cause significant morbidity and are frequently fatal. In addition to the well-established chemotherapeutic regimens, multiple therapies are now used in the first-line setting, including antibody-based treatments, immunotherapy, and hormone receptor modulators. Many cancers are now being managed as chronic diseases with long-term maintenance therapies in an increasingly older patient population with significant comorbidities. With this change in the treatment landscape, predictive biomarkers are needed to effectively identify patients and treatments associated with the highest risk of thrombosis in the current cancer population. Although cancer-associated thrombosis has been extensively studied, the specific mechanisms by which cancer therapy causes thrombosis remain poorly understood. The pathogenesis of immunothrombosis associated with cancer treatments in particular is poorly defined. Focusing on solid tumors, the aim of this narrative review is to explore our current understanding of the pathogenesis of thrombotic effects of systemic cancer treatment. These include coagulation activation, vascular endothelial damage, procoagulant effects of material from dead and dying tumor cells, as well as the role of inflammatory mediators. Greater understanding of pathogenesis of treatment-related cancer-associated thrombosis will lead to the identification of more effective biomarkers to guide thromboprophylaxis.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 3","pages":"Pages 789-803"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145471375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Endothelial protein C receptor–mediated endogenous and therapeutic transport of activated protein C across the blood–retina barrier protects the retina epcr介导的内源性和治疗性转运激活蛋白C通过血视网膜屏障保护视网膜。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-03-01 Epub Date: 2025-11-19 DOI: 10.1016/j.jtha.2025.10.033

Tami Livnat , Ivan Budnik , Yael Nisgav , Rima Dardik , Einat Avishai , Sheli Rose Gonen , Alon Zahavi , José A. Fernández , Valery Golderman , Zehavit Goldberg , Gili Kenet , John H. Griffin , Sarina Levy-Mendelovich

Background

Activated protein C (APC) is a serine protease known for its anticoagulant, anti-inflammatory, and cytoprotective properties. Although clinical evidence links protein C (PC) deficiency to various retinal pathologies, the physiological role of APC in the retina remains unexplored.

Objectives

To determine whether PC and APC are synthesized locally in the healthy retina or are transported systemically across the blood–retina barrier (BRB) and to evaluate the contribution of the endothelial protein C receptor (EPCR) to APC transport and the therapeutic potential of APC in the retina following systemic administration.

Methods

We utilized a unique and viable severe protein C deficiency murine model developed in our laboratory. Reverse transcription polymerase chain reaction, immunostaining, and coagulation-based activity assays were used to determine the presence and distribution of PC, APC, and EPCR in the retina and after APC injection via the tail vein. EPCR blockage was performed using an EPCR-neutralizing antibody. The anti-inflammatory activity of the APC analog, 3K3A-APC, was assessed in a murine model of retinal pathologies.

Results

APC is not synthesized locally in the retina but originates from the systemic circulation, crosses the BRB, and accumulates in the retina. EPCR mediates the translocation of APC across the BRB. Systemically administered 3K3A-APC crosses the BRB and induces cytoprotective and anti-inflammatory effects in the retina comparable with intraocular treatment.

Conclusions

Our findings establish a fundamental step in investigating the concept of PC as a physiologically relevant, naturally protective protein in the eye. Our results support the feasibility of developing noninvasive, systemic APC-based therapies for retinal diseases.

背景：活化蛋白C （APC）是一种丝氨酸蛋白酶，以其抗凝血、抗炎和细胞保护特性而闻名。尽管临床证据将蛋白C （PC）缺乏与各种视网膜病变联系起来，但APC在视网膜中的生理作用仍未被探索。目的：确定PC和APC是在健康视网膜中局部合成的，还是通过血视网膜屏障（BRB）全身运输的。评估内皮蛋白C受体（EPCR）对APC转运的贡献以及APC在视网膜系统给药后的治疗潜力。方法：利用本实验室建立的一种独特的、有活力的严重蛋白C缺乏症（SPCD）小鼠模型。采用RT-PCR、免疫染色和基于凝固的活性测定来测定PC、APC和EPCR在视网膜和经尾静脉注射APC后的存在和分布。用EPCR中和抗体阻断EPCR。APC类似物3K3A-APC的抗炎活性在小鼠视网膜病变模型中进行了评估。结果：APC不是在视网膜局部合成，而是起源于体循环，穿过BRB，在视网膜内积累。EPCR介导APC在BRB上的易位。系统给药3K3A-APC穿过BRB，在视网膜中诱导细胞保护和抗炎作用，与眼内治疗相当。结论：我们的研究结果为研究PC作为眼部生理相关的天然保护蛋白的概念奠定了基础。我们的研究结果支持开发非侵入性、系统性apc治疗视网膜疾病的可行性。

{"title":"Endothelial protein C receptor–mediated endogenous and therapeutic transport of activated protein C across the blood–retina barrier protects the retina","authors":"Tami Livnat , Ivan Budnik , Yael Nisgav , Rima Dardik , Einat Avishai , Sheli Rose Gonen , Alon Zahavi , José A. Fernández , Valery Golderman , Zehavit Goldberg , Gili Kenet , John H. Griffin , Sarina Levy-Mendelovich","doi":"10.1016/j.jtha.2025.10.033","DOIUrl":"10.1016/j.jtha.2025.10.033","url":null,"abstract":"<div><h3>Background</h3><div>Activated protein C (APC) is a serine protease known for its anticoagulant, anti-inflammatory, and cytoprotective properties. Although clinical evidence links protein C (PC) deficiency to various retinal pathologies, the physiological role of APC in the retina remains unexplored.</div></div><div><h3>Objectives</h3><div>To determine whether PC and APC are synthesized locally in the healthy retina or are transported systemically across the blood–retina barrier (BRB) and to evaluate the contribution of the endothelial protein C receptor (EPCR) to APC transport and the therapeutic potential of APC in the retina following systemic administration.</div></div><div><h3>Methods</h3><div>We utilized a unique and viable severe protein C deficiency murine model developed in our laboratory. Reverse transcription polymerase chain reaction, immunostaining, and coagulation-based activity assays were used to determine the presence and distribution of PC, APC, and EPCR in the retina and after APC injection via the tail vein. EPCR blockage was performed using an EPCR-neutralizing antibody. The anti-inflammatory activity of the APC analog, 3K3A-APC, was assessed in a murine model of retinal pathologies.</div></div><div><h3>Results</h3><div>APC is not synthesized locally in the retina but originates from the systemic circulation, crosses the BRB, and accumulates in the retina. EPCR mediates the translocation of APC across the BRB. Systemically administered 3K3A-APC crosses the BRB and induces cytoprotective and anti-inflammatory effects in the retina comparable with intraocular treatment.</div></div><div><h3>Conclusions</h3><div>Our findings establish a fundamental step in investigating the concept of PC as a physiologically relevant, naturally protective protein in the eye. Our results support the feasibility of developing noninvasive, systemic APC-based therapies for retinal diseases.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 3","pages":"Pages 1141-1152"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

“Effect of direct oral anticoagulants in cirrhosis: an in vitro study”: comment by Elvers et al. “直接口服抗凝剂对肝硬化的影响：一项体外研究”：Elvers等人的评论。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-03-01 Epub Date: 2026-02-27 DOI: 10.1016/j.jtha.2025.07.043

Fynn L. Elvers, Jelle Adelmeijer, Ton Lisman

引用次数: 0

Antithrombosis stewardship across the care spectrum: optimizing transitions in venous thromboembolism 抗血栓管理在整个护理谱：优化过渡在静脉血栓栓塞。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-03-01 Epub Date: 2025-11-01 DOI: 10.1016/j.jtha.2025.09.043

Allison E. Burnett , Tara K. Lech , Suzanne McCarthy , Virginia Silvari

As global burden of venous thromboembolism (VTE) increases, clinicians are managing more patients across diverse and often fragmented care settings. VTE care transitions are more frequent and complex than those seen in stable anticoagulation conditions like atrial fibrillation. Each transition presents opportunity for optimizing antithrombotic therapies and mitigating associated risks. In this review, we use case-based scenarios to highlight common care transition challenges and offer evidence-based, stewardship-guided strategies to optimize antithrombotic use and outcomes throughout the VTE continuum.

随着全球静脉血栓栓塞（VTE）负担的增加，临床医生正在管理更多的患者，这些患者来自不同且往往分散的护理环境。静脉血栓栓塞治疗的转变比房颤等稳定抗凝条件下更为频繁和复杂。每个转变都为优化抗血栓治疗和减轻相关风险提供了机会。在这篇综述中，我们使用基于案例的场景来强调常见的护理过渡挑战，并提供基于证据的、管理指导的策略，以优化静脉血栓栓塞连续体的抗血栓使用和结果。

引用次数: 0

Zinc finger CCCH-type containing 13–mediated N6-methyladenosine methylation mitigates endothelial injury in venous thrombosis by inhibiting elevated mitochondrial fission zc3h13介导的m6a甲基化通过抑制线粒体裂变升高来减轻静脉血栓形成中的内皮损伤。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-03-01 Epub Date: 2025-12-05 DOI: 10.1016/j.jtha.2025.11.007

Hui Lu , Yaohua Cai , Yanyi Tao , Yunqing Xia , Tingting Wu , Yu Hu , Liang V. Tang

Background

Endothelial injury is the core factor of venous thrombosis. N6-methyladenosine (m6A) plays a critical role in metabolism and cellular processes. Moreover, the balance of mitochondrial dynamics is essential in regulating cellular growth, apoptosis, and mobility. However, the roles of m6A modification and mitochondrial dynamics in regulating venous endothelial cells remains elusive.

Methods

Levels of m6A were evaluated by m6A dot blot and quantification analysis. Gain- and loss-of-function and rescue assays were performed to clarify gene functions. To investigate the mitochondrial dynamics in venous endothelium, mitochondrial morphology and function analysis were performed. The target gene of zinc finger CCCH-type containing 13 (ZC3H13) was identified through RNA-sequencing and methylated RNA immunoprecipitation sequencing. Mechanism of ZC3H13-mediated m6A modification was explored through methylated RNA immunoprecipitation quantitative polymerase chain reaction (qPCR), luciferase reporter assay, RNA stability assay, and RNA immunoprecipitation assay.

Results

Downregulated ZC3H13 expression and elevated mitochondrial fission were observed in injured venous endothelium. Functional verification has clarified ZC3H13 regulated endothelial cells by modulating mitochondrial fission. Furthermore, ZC3H13-mediated m6A modification profile was revealed, and DYRK1B was identified as its target in endothelial cells. Decreased m6A modification mediated by downregulation of ZC3H13 upregulated DYRK1B messenger RNA expression through inhibiting DYRK1B messenger RNA decay in an YTHDF-2-dependent manner. Functional verification also confirmed the functions of DYRK1B in regulating endothelial cells by modulating mitochondrial fission. Moreover, endothelial-targeted ZC3H13 overexpression attenuated venous endothelial injury, which contributed to the reduced thrombotic risk observed in mice.

Conclusion

The findings of the current study showed that ZC3H13 mitigates endothelial injury by inhibiting excessive mitochondrial fission through the m6A/YTHDF2/DYRK1B axis.

背景：血管内皮损伤是静脉血栓形成的核心因素。m6A在新陈代谢和细胞过程中起关键作用。此外，线粒体动力学的平衡在调节细胞生长、凋亡和移动方面是必不可少的。目前，m6A修饰和线粒体动力学在静脉内皮细胞调节中的作用尚不明确。方法：采用M6A点印迹法和定量分析法检测小鼠M6A水平。进行了功能获得和功能丧失以及修复试验以阐明基因功能。为观察大鼠静脉内皮细胞线粒体的动态变化，对其进行了线粒体形态和功能分析。通过RNA-seq和MeRIP-seq鉴定ZC3H13的靶基因。通过MeRIP-qPCR、荧光素酶报告基因实验、RNA稳定性实验和RNA免疫沉淀实验，探讨zc3h13介导m6A修饰的机制。结果：大鼠静脉内皮损伤后ZC3H13表达下调，线粒体分裂升高。功能验证表明ZC3H13通过调节线粒体裂变调节内皮细胞。此外，zc3h13介导的m6A修饰谱被揭示，DYRK1B被确定为内皮细胞中的靶点。ZC3H13下调介导的m6A修饰减少通过抑制DYRK1B mRNA的衰减以ythdf -2依赖的方式上调DYRK1B mRNA的表达。功能验证也证实了DYRK1B通过调节线粒体裂变调节内皮细胞的功能。此外，内皮靶向ZC3H13过表达可减轻静脉内皮损伤，从而降低小鼠血栓形成风险。结论：本研究结果表明，ZC3H13通过m6A/YTHDF2/DYRK1B轴抑制线粒体过度裂变，从而减轻内皮损伤。

{"title":"Zinc finger CCCH-type containing 13–mediated N6-methyladenosine methylation mitigates endothelial injury in venous thrombosis by inhibiting elevated mitochondrial fission","authors":"Hui Lu , Yaohua Cai , Yanyi Tao , Yunqing Xia , Tingting Wu , Yu Hu , Liang V. Tang","doi":"10.1016/j.jtha.2025.11.007","DOIUrl":"10.1016/j.jtha.2025.11.007","url":null,"abstract":"<div><h3>Background</h3><div>Endothelial injury is the core factor of venous thrombosis. N6-methyladenosine (m6A) plays a critical role in metabolism and cellular processes. Moreover, the balance of mitochondrial dynamics is essential in regulating cellular growth, apoptosis, and mobility. However, the roles of m6A modification and mitochondrial dynamics in regulating venous endothelial cells remains elusive.</div></div><div><h3>Methods</h3><div>Levels of m6A were evaluated by m6A dot blot and quantification analysis. Gain- and loss-of-function and rescue assays were performed to clarify gene functions. To investigate the mitochondrial dynamics in venous endothelium, mitochondrial morphology and function analysis were performed. The target gene of zinc finger CCCH-type containing 13 (ZC3H13) was identified through RNA-sequencing and methylated RNA immunoprecipitation sequencing. Mechanism of ZC3H13-mediated m6A modification was explored through methylated RNA immunoprecipitation quantitative polymerase chain reaction (qPCR), luciferase reporter assay, RNA stability assay, and RNA immunoprecipitation assay.</div></div><div><h3>Results</h3><div>Downregulated ZC3H13 expression and elevated mitochondrial fission were observed in injured venous endothelium. Functional verification has clarified ZC3H13 regulated endothelial cells by modulating mitochondrial fission. Furthermore, ZC3H13-mediated m6A modification profile was revealed, and DYRK1B was identified as its target in endothelial cells. Decreased m6A modification mediated by downregulation of ZC3H13 upregulated <em>DYRK1B</em> messenger RNA expression through inhibiting <em>DYRK1B</em> messenger RNA decay in an YTHDF-2-dependent manner. Functional verification also confirmed the functions of DYRK1B in regulating endothelial cells by modulating mitochondrial fission. Moreover, endothelial-targeted ZC3H13 overexpression attenuated venous endothelial injury, which contributed to the reduced thrombotic risk observed in mice.</div></div><div><h3>Conclusion</h3><div>The findings of the current study showed that ZC3H13 mitigates endothelial injury by inhibiting excessive mitochondrial fission through the m6A/YTHDF2/DYRK1B axis.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 3","pages":"Pages 1153-1170"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145701352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Safety and efficiency of D-dimer testing in combination with clinical decision rules to exclude pulmonary embolism in patients with cancer: individual patient data meta-analysis d -二聚体检测结合临床决策规则排除癌症患者肺栓塞的安全性和有效性：个体患者数据荟萃分析

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-03-01 Epub Date: 2025-12-05 DOI: 10.1016/j.jtha.2025.10.035

Kristina Vrotniakaite-Bajerciene , Ranjeeta Mallick , Toshihiko Takada , Noemie Kraaijpoel , Maarten van Smeden , Karel G.M. Moons , Jeffrey A. Kline , Menno V. Huisman , Emily Martens , Marc Righini , Nick van Es , Frederikus A. Klok , Harry R. Büller , Arnaud Perrier , Kerstin de Wit , Philip S. Wells , Javier Galipienzo , Waleed Ghanima , Pierre-Marie Roy , Marc Carrier , Grégoire Le Gal

Background

Failure rates of clinical decision rules (CDRs) combined with D-dimer to exclude pulmonary embolism (PE) are higher in patients with cancer compared with noncancer patients, raising concerns about their use in this patient group.

Objectives

To compare the failure rates of the Wells score, revised Geneva score, and YEARS algorithm in patients with cancer who underwent standard imaging with those in whom imaging was withheld, and report the diagnostic yield of these algorithms.

Methods

We used data from an individual-patient level meta-analysis of prospective diagnostic management studies of patients with suspected PE. The primary outcome was the 3-month incidence of venous thromboembolism, excluding PE (failure), using fixed and age-adjusted D-dimer results across different patient management categories for all investigated CDRs. The secondary outcome included the proportion of patients for whom PE could be ruled out without further imaging (diagnostic yield).

Results

A total of 2258 (7.6%) patients with cancer from 17 studies were included in the analysis. The 3-month incidence of venous thromboembolism in patients after excluding PE ranged from 0.52% (95% CI, 0.06%-4.35%) to 2.83% (95% CI, 0.96%-8.34%) and was comparable across all management categories. The highest diagnostic yield of 26% was found for the revised Geneva score, with an age-adjusted D-dimer cutoff, and the YEARS algorithm.

Conclusion

The failure rates of patients with cancer for whom PE was excluded using CDRs and withholding imaging were similar to those observed after standard imaging. Current diagnostic algorithms for suspected PE are applicable to patients with cancer.

背景：临床决策规则（cdr）联合d -二聚体排除肺栓塞（PE）的失败率在癌症患者中高于非癌症患者，这引起了对其在该患者组中使用的担忧。目的：比较Wells评分、修订Geneva评分和YEARS算法在接受标准影像学检查的癌症患者与未接受影像学检查的癌症患者中的失败率，并报告这些算法的诊断结果。方法：我们使用来自疑似PE患者前瞻性诊断管理研究的个体患者水平荟萃分析的数据。主要结局是在排除PE（失败）后，使用固定和年龄调整（AA） d -二聚体结果在所有调查cdr的不同患者管理类别中的3个月VTE发生率。次要结局包括无需进一步影像学检查即可排除PE的患者比例（诊断率）。结果：来自17项研究的2258例（7.6%）癌症患者被纳入分析。排除PE的患者的3个月VTE发生率从0.52% （95% CI 0.06 - 4.35）到2.83% （95% CI 0.96 - 8.34）不等，并且在所有管理类别中具有可比性。采用AA d -二聚体截止值和YEARS算法的修订Geneva评分的最高诊断率为26%。结论：使用cdr预持成像排除PE的癌症患者的失败率与标准成像后观察到的失败率相似。目前疑似PE的诊断算法适用于癌症患者。

{"title":"Safety and efficiency of D-dimer testing in combination with clinical decision rules to exclude pulmonary embolism in patients with cancer: individual patient data meta-analysis","authors":"Kristina Vrotniakaite-Bajerciene , Ranjeeta Mallick , Toshihiko Takada , Noemie Kraaijpoel , Maarten van Smeden , Karel G.M. Moons , Jeffrey A. Kline , Menno V. Huisman , Emily Martens , Marc Righini , Nick van Es , Frederikus A. Klok , Harry R. Büller , Arnaud Perrier , Kerstin de Wit , Philip S. Wells , Javier Galipienzo , Waleed Ghanima , Pierre-Marie Roy , Marc Carrier , Grégoire Le Gal","doi":"10.1016/j.jtha.2025.10.035","DOIUrl":"10.1016/j.jtha.2025.10.035","url":null,"abstract":"<div><h3>Background</h3><div>Failure rates of clinical decision rules (CDRs) combined with D-dimer to exclude pulmonary embolism (PE) are higher in patients with cancer compared with noncancer patients, raising concerns about their use in this patient group.</div></div><div><h3>Objectives</h3><div>To compare the failure rates of the Wells score, revised Geneva score, and YEARS algorithm in patients with cancer who underwent standard imaging with those in whom imaging was withheld, and report the diagnostic yield of these algorithms.</div></div><div><h3>Methods</h3><div>We used data from an individual-patient level meta-analysis of prospective diagnostic management studies of patients with suspected PE. The primary outcome was the 3-month incidence of venous thromboembolism, excluding PE (failure), using fixed and age-adjusted D-dimer results across different patient management categories for all investigated CDRs. The secondary outcome included the proportion of patients for whom PE could be ruled out without further imaging (diagnostic yield).</div></div><div><h3>Results</h3><div>A total of 2258 (7.6%) patients with cancer from 17 studies were included in the analysis. The 3-month incidence of venous thromboembolism in patients after excluding PE ranged from 0.52% (95% CI, 0.06%-4.35%) to 2.83% (95% CI, 0.96%-8.34%) and was comparable across all management categories. The highest diagnostic yield of 26% was found for the revised Geneva score, with an age-adjusted D-dimer cutoff, and the YEARS algorithm.</div></div><div><h3>Conclusion</h3><div>The failure rates of patients with cancer for whom PE was excluded using CDRs and withholding imaging were similar to those observed after standard imaging. Current diagnostic algorithms for suspected PE are applicable to patients with cancer.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 3","pages":"Pages 971-984"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145701367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The win ratio for evaluating edoxaban vs dalteparin for cancer-associated venous thromboembolism: an analysis of the randomized Hokusai Venous Thromboembolism Cancer trial 评价依多沙班与达特帕林治疗癌症相关静脉血栓栓塞的胜比：一项随机的Hokusai静脉血栓栓塞癌症试验分析

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-03-01 Epub Date: 2025-12-19 DOI: 10.1016/j.jtha.2025.11.024

Nick van Es , Luuk J.J. Scheres , Kristen M. Sanfilippo , Harry Büller , Marc Carrier , Marcello Di Nisio , Michael Grosso , Renato D. Lopes , William F. McIntyre , Bjorn Redfors , Annelise Segers , Peter Verhamme , Jeffrey I. Weitz , Patrick M. Bossuyt , Deborah M. Siegal

Background

The Hokusai Venous Thromboembolism (VTE) Cancer trial demonstrated that edoxaban was noninferior to dalteparin for the treatment of cancer-associated venous VTE.

Objectives

We reanalyzed the trial using the win ratio, an approach that evaluates a composite of outcomes in a hierarchical order.

Methods

Forty-nine thrombosis experts ranked 10 outcomes in order of clinical importance from all-cause death (most important) to clinically relevant nonmajor bleeding (least important). We performed unmatched pairwise comparisons between participants on edoxaban and those on dalteparin at 6- and 12-month follow-up. Within each pair, edoxaban was assigned a win, loss, or tie according to the hierarchy of outcomes. We calculated the win ratio (total wins divided by total losses among edoxaban patients), with more wins than losses indicating the benefit of edoxaban, and the win difference (total wins minus total losses).

Results

Among 273 528 pairs (522 × 524 participants), edoxaban was associated with a win in 34.9%, a loss in 38.5%, and a tie in 26.6%. The win ratio was 0.91 (95% CI, 0.76-1.08), with a win difference of −3.55% (95% CI, −9.9% to 2.9%) at 12 months. The win ratio remained unchanged at 6 months (0.91; 95% CI, 0.75-1.11). The findings were consistent with a hierarchy of only death, recurrent VTE, and major bleeding (win ratio, 0.92; 95% CI, 0.76-1.11), or when replacing all-cause death with VTE-related death or fatal bleeding (win ratio, 0.83; 95% CI, 0.65-1.06).

Conclusion

We observed no significant difference between edoxaban and dalteparin for the treatment of cancer-associated VTE when using the win ratio approach with a hierarchy of 10 prioritized outcomes.

背景：Hokusai静脉血栓栓塞癌症试验表明，在治疗癌症相关静脉血栓栓塞（VTE）方面，依多沙班不逊于达特帕林。我们使用胜率（win-ratio）重新分析了该试验，胜率是一种按等级顺序评估综合结果的方法。方法：49名血栓专家根据临床重要性对10个结局进行排序，从全因死亡（最重要）到临床相关的非大出血（最不重要）。在6个月和12个月的随访期间，我们对使用依多沙班和达特帕林的参与者进行了无与伦比的两两比较。在每一对中，依多沙班根据结果的等级被分配为赢、输或平。我们计算了赢比（伊多沙班患者的总胜利除以总损失），赢比输表明伊多沙班的益处，以及赢差（总胜利减去总损失）。结果：在273,528对（522x524名参与者）中，依多沙班与34.9%的患者相关，38.5%的患者相关，26.6%的患者相关。12个月的胜率为0.91 (95%-CI, 0.76 ~ 1.08)，胜率差为-3.55% （95%-CI, -9.9 ~ 2.9）。6个月时胜率保持不变（0.91,95% ci; 0.75-1.11）。研究结果与仅死亡、静脉血栓栓塞复发和大出血的分级一致（胜比，0.92；95%可信区间，0.76 - 1.11），或将全因死亡替换为静脉血栓栓塞相关死亡或致命出血时（胜比，0.83；95%可信区间，0.65 - 1.06）。结论：当使用10个优先结果的win-ratio方法时，我们观察到edoxaban和dalteparin在治疗癌症相关性静脉血栓栓塞方面没有显著差异。

{"title":"The win ratio for evaluating edoxaban vs dalteparin for cancer-associated venous thromboembolism: an analysis of the randomized Hokusai Venous Thromboembolism Cancer trial","authors":"Nick van Es , Luuk J.J. Scheres , Kristen M. Sanfilippo , Harry Büller , Marc Carrier , Marcello Di Nisio , Michael Grosso , Renato D. Lopes , William F. McIntyre , Bjorn Redfors , Annelise Segers , Peter Verhamme , Jeffrey I. Weitz , Patrick M. Bossuyt , Deborah M. Siegal","doi":"10.1016/j.jtha.2025.11.024","DOIUrl":"10.1016/j.jtha.2025.11.024","url":null,"abstract":"<div><h3>Background</h3><div>The Hokusai Venous Thromboembolism (VTE) Cancer trial demonstrated that edoxaban was noninferior to dalteparin for the treatment of cancer-associated venous VTE.</div></div><div><h3>Objectives</h3><div>We reanalyzed the trial using the win ratio, an approach that evaluates a composite of outcomes in a hierarchical order.</div></div><div><h3>Methods</h3><div>Forty-nine thrombosis experts ranked 10 outcomes in order of clinical importance from all-cause death (most important) to clinically relevant nonmajor bleeding (least important). We performed unmatched pairwise comparisons between participants on edoxaban and those on dalteparin at 6- and 12-month follow-up. Within each pair, edoxaban was assigned a win, loss, or tie according to the hierarchy of outcomes. We calculated the win ratio (total wins divided by total losses among edoxaban patients), with more wins than losses indicating the benefit of edoxaban, and the win difference (total wins minus total losses).</div></div><div><h3>Results</h3><div>Among 273 528 pairs (522 × 524 participants), edoxaban was associated with a win in 34.9%, a loss in 38.5%, and a tie in 26.6%. The win ratio was 0.91 (95% CI, 0.76-1.08), with a win difference of −3.55% (95% CI, −9.9% to 2.9%) at 12 months. The win ratio remained unchanged at 6 months (0.91; 95% CI, 0.75-1.11). The findings were consistent with a hierarchy of only death, recurrent VTE, and major bleeding (win ratio, 0.92; 95% CI, 0.76-1.11), or when replacing all-cause death with VTE-related death or fatal bleeding (win ratio, 0.83; 95% CI, 0.65-1.06).</div></div><div><h3>Conclusion</h3><div>We observed no significant difference between edoxaban and dalteparin for the treatment of cancer-associated VTE when using the win ratio approach with a hierarchy of 10 prioritized outcomes.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 3","pages":"Pages 1032-1041"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145804953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

NRF2/miR-17-5p/TMEM16F axis regulates the crosstalk of inflammation and thrombosis in sepsis NRF2/miR-17-5p/TMEM16F轴调控脓毒症炎症和血栓形成的串扰。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-03-01 Epub Date: 2025-12-23 DOI: 10.1016/j.jtha.2025.11.027

Meishan Yan , Qi Liu , Yao An , Haoran Dong , Xu Han , Zimeng Li , Siqi Li , Li Chen , Tingting Li , Minghui Xu , Xijuan Zhao , Xiushuai Dong , Chunyan Gao

Background

Sepsis is characterized by the simultaneous activation of inflammation and coagulation in response to systemic infection, leading to microvascular dysfunction and consequential multiorgan failure. Previous studies have revealed that TMEM16F is involved in blood coagulation and inflammatory response. However, its detailed regulatory molecular mechanisms and functions in sepsis remain unknown.

Objectives

In this study, we aim to investigate the regulatory effects and the underlying mechanism of TMEM16F in sepsis-induced microvascular thrombosis and inflammation.

Methods

We used septic patients, lipopolysaccharide (LPS)-induced septic mouse models, and in vitro cellular experiments with LPS-stimulated endothelial cells. Bioinformatical analysis and molecular biological techniques were performed to identify the target genes of TMEM16F.

Results and Conclusions

We found that TMEM16F was highly expressed in vivo and in vitro septic model, and its deletion decreased mortality, inflammation, and the microthrombi formations in LPS-induced septic mice. Additionally, silencing NRF2 not only inhibited TMEM16F expression but also improved LPS-induced thrombosis, inflammation, and organ injury, which could be reversed by inhibition of miR-17-5p. By bioinformatics analysis with subsequent chromatin immunoprecipitation-polymerase chain reaction and luciferase activity experiments, we revealed that the transcription factor NRF2 drove TMEM16F transcription through promoter binding while suppressing miR-17-5p, thereby increasing TMEM16F expression in endothelial cells. Furthermore, plasma concentrations of TMEM16F and miR-17-5p were correlated with coagulation activation, inflammation, and disseminated intravascular coagulation scores in septic patients. Overall, these findings identify the NRF2/miR-17-5p/TMEM16F axis may be a potential therapeutic target for sepsis.

背景：脓毒症的特点是炎症和凝血同时激活，以应对全身感染，导致微血管功能障碍和随之而来的多器官功能衰竭。已有研究表明，TMEM16F参与血液凝固和炎症反应。然而，其在脓毒症中的具体调控分子机制和功能尚不清楚。目的：本研究旨在探讨TMEM16F在败血症诱导的微血管血栓形成和炎症中的调控作用及其机制。方法：采用脓毒症患者、脂多糖（LPS）诱导的脓毒症小鼠模型，以及LPS刺激内皮细胞（ECs）的体外细胞实验。利用生物信息学分析和分子生物学技术鉴定TMEM16F的靶基因。结果和结论：我们发现TMEM16F在体内和体外脓毒症模型中高表达，其缺失降低了lps诱导的脓毒症小鼠的死亡率、炎症和微血栓形成。此外，沉默NRF2不仅可以抑制TMEM16F的表达，还可以改善LPS诱导的血栓形成、炎症和器官损伤，这些可以通过抑制miR-17-5p来逆转。通过随后的染色质免疫沉淀-聚合酶链反应（CHIP）和荧光素酶活性实验的生物信息学分析，我们发现转录因子NRF2通过启动子结合驱动TMEM16F转录，同时抑制miR-17-5p，从而增加ECs中TMEM16F的表达。此外，TMEM16F和miR-17-5p的血浆浓度与脓毒症患者的凝血激活、炎症和DIC评分相关。总的来说，这些发现表明NRF2/miR-17-5p/TMEM16F轴可能是脓毒症的潜在治疗靶点。

{"title":"NRF2/miR-17-5p/TMEM16F axis regulates the crosstalk of inflammation and thrombosis in sepsis","authors":"Meishan Yan , Qi Liu , Yao An , Haoran Dong , Xu Han , Zimeng Li , Siqi Li , Li Chen , Tingting Li , Minghui Xu , Xijuan Zhao , Xiushuai Dong , Chunyan Gao","doi":"10.1016/j.jtha.2025.11.027","DOIUrl":"10.1016/j.jtha.2025.11.027","url":null,"abstract":"<div><h3>Background</h3><div>Sepsis is characterized by the simultaneous activation of inflammation and coagulation in response to systemic infection, leading to microvascular dysfunction and consequential multiorgan failure. Previous studies have revealed that TMEM16F is involved in blood coagulation and inflammatory response. However, its detailed regulatory molecular mechanisms and functions in sepsis remain unknown.</div></div><div><h3>Objectives</h3><div>In this study, we aim to investigate the regulatory effects and the underlying mechanism of TMEM16F in sepsis-induced microvascular thrombosis and inflammation.</div></div><div><h3>Methods</h3><div>We used septic patients, lipopolysaccharide (LPS)-induced septic mouse models, and <em>in vitro</em> cellular experiments with LPS-stimulated endothelial cells. Bioinformatical analysis and molecular biological techniques were performed to identify the target genes of TMEM16F.</div></div><div><h3>Results and Conclusions</h3><div>We found that TMEM16F was highly expressed <em>in vivo</em> and <em>in vitro</em> septic model, and its deletion decreased mortality, inflammation, and the microthrombi formations in LPS-induced septic mice. Additionally, silencing NRF2 not only inhibited TMEM16F expression but also improved LPS-induced thrombosis, inflammation, and organ injury, which could be reversed by inhibition of miR-17-5p. By bioinformatics analysis with subsequent chromatin immunoprecipitation-polymerase chain reaction and luciferase activity experiments, we revealed that the transcription factor NRF2 drove TMEM16F transcription through promoter binding while suppressing miR-17-5p, thereby increasing TMEM16F expression in endothelial cells. Furthermore, plasma concentrations of TMEM16F and miR-17-5p were correlated with coagulation activation, inflammation, and disseminated intravascular coagulation scores in septic patients. Overall, these findings identify the NRF2/miR-17-5p/TMEM16F axis may be a potential therapeutic target for sepsis.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 3","pages":"Pages 1089-1103"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sex differences in outcomes of vitamin K antagonist treatment in patients with a mechanical heart valve: a Dutch population-based cohort study 机械心脏瓣膜患者维生素K拮抗剂治疗结果的性别差异：荷兰基于人群的队列研究

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-03-01 Epub Date: 2025-10-08 DOI: 10.1016/j.jtha.2025.09.010

Eva K. Kempers , Chantal Visser , Jaap Seelig , Qingui Chen , Henk J. Adriaansen , Maarten J. Beinema , Arina J. ten Cate-Hoek , Laura M. Faber , Charlotte E.A. Dronkers , Melchior C. Nierman , Roger K. Schindhelm , Nynke M. Wiersma , Alexander D.M. Stork , Frederikus A. Klok , Frank W.G. Leebeek , Ron Pisters , Suzanne C. Cannegieter , Raffaele De Caterina , Martin E.W. Hemels , Hugo ten Cate , Marieke J.H.A. Kruip

Background

Patients with a mechanical heart valve (MHV) require vitamin K antagonist (VKA) treatment to prevent thromboembolism.

Objectives

To examine the quality of VKA treatment and clinical outcomes, including all-cause mortality, bleeding, and thromboembolism, by sex and age in patients with an MHV.

Methods

Data from 17 Dutch anticoagulation clinics were linked to Statistics Netherlands. Patients with an MHV receiving VKAs between 2013 and 2019 were included and followed from the first MHV hospitalization discharge until death, VKA discontinuation, or December 31, 2019. Quality of treatment was assessed by the time in therapeutic range (TTR) and international normalized ratio variability (variance growth rate). Clinical outcomes were identified by first in-hospital diagnoses and primary causes of death and expressed as incidence rates (IR) per 100 person-years, stratified by sex and age.

Results

In total, 3527 MHV patients (38% women, median age 67 years) had a median follow-up of 3.0 years. Women <55 years (n = 228) had lower TTR compared with the other sex and age groups. All-cause mortality rates were similar across the sexes in both age groups. Women aged <55 years had a higher IR (95% CI) of both bleeding (2.52 [1.49-3.98] vs 1.03 [0.51-1.84]) and thromboembolism (2.83 [1.73-4.38] vs 1.70 [1.01-2.69]) than similarly aged men (n = 395). However, treatment quality and IR were similar for women and men aged ≥55 years.

Conclusion

Women with MHVs aged <55 years exhibited poorer quality of VKA treatment and higher rates of complications than similarly aged men. These findings highlight the need for tailored anticoagulation strategies in younger female MHV patients.

背景：机械心脏瓣膜（MHV）患者需要维生素K拮抗剂（VKA）治疗来预防血栓栓塞。目的：研究MHV患者性别和年龄的VKA治疗质量和临床结果，包括全因死亡率、出血和血栓栓塞。方法：来自17个荷兰抗凝诊所的数据与荷兰统计局相关联。纳入2013年至2019年期间接受VKA治疗的MHV患者，并从首次MHV住院出院至死亡、VKA停止或2019年12月31日进行随访。通过治疗范围内时间（TTR）和INR变异性（VGR）评估治疗质量。临床结果通过首次住院诊断和主要死亡原因确定，并以每100人年（PYs）的发病率（IR）表示，按性别和年龄分层。结果：共有3527例MHV患者（38%为女性，中位年龄67岁），中位随访时间为3.0年。结论：mhv患者年龄增大

{"title":"Sex differences in outcomes of vitamin K antagonist treatment in patients with a mechanical heart valve: a Dutch population-based cohort study","authors":"Eva K. Kempers , Chantal Visser , Jaap Seelig , Qingui Chen , Henk J. Adriaansen , Maarten J. Beinema , Arina J. ten Cate-Hoek , Laura M. Faber , Charlotte E.A. Dronkers , Melchior C. Nierman , Roger K. Schindhelm , Nynke M. Wiersma , Alexander D.M. Stork , Frederikus A. Klok , Frank W.G. Leebeek , Ron Pisters , Suzanne C. Cannegieter , Raffaele De Caterina , Martin E.W. Hemels , Hugo ten Cate , Marieke J.H.A. Kruip","doi":"10.1016/j.jtha.2025.09.010","DOIUrl":"10.1016/j.jtha.2025.09.010","url":null,"abstract":"<div><h3>Background</h3><div>Patients with a mechanical heart valve (MHV) require vitamin K antagonist (VKA) treatment to prevent thromboembolism.</div></div><div><h3>Objectives</h3><div>To examine the quality of VKA treatment and clinical outcomes, including all-cause mortality, bleeding, and thromboembolism, by sex and age in patients with an MHV.</div></div><div><h3>Methods</h3><div>Data from 17 Dutch anticoagulation clinics were linked to Statistics Netherlands. Patients with an MHV receiving VKAs between 2013 and 2019 were included and followed from the first MHV hospitalization discharge until death, VKA discontinuation, or December 31, 2019. Quality of treatment was assessed by the time in therapeutic range (TTR) and international normalized ratio variability (variance growth rate). Clinical outcomes were identified by first in-hospital diagnoses and primary causes of death and expressed as incidence rates (IR) per 100 person-years, stratified by sex and age.</div></div><div><h3>Results</h3><div>In total, 3527 MHV patients (38% women, median age 67 years) had a median follow-up of 3.0 years. Women <55 years (<em>n</em> = 228) had lower TTR compared with the other sex and age groups. All-cause mortality rates were similar across the sexes in both age groups. Women aged <55 years had a higher IR (95% CI) of both bleeding (2.52 [1.49-3.98] vs 1.03 [0.51-1.84]) and thromboembolism (2.83 [1.73-4.38] vs 1.70 [1.01-2.69]) than similarly aged men (<em>n</em> = 395). However, treatment quality and IR were similar for women and men aged ≥55 years.</div></div><div><h3>Conclusion</h3><div>Women with MHVs aged <55 years exhibited poorer quality of VKA treatment and higher rates of complications than similarly aged men. These findings highlight the need for tailored anticoagulation strategies in younger female MHV patients.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 3","pages":"Pages 955-970"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0