Blood Vessels, Thrombosis & Hemostasis最新文献

rFVIIIa-platelet binding enhances platelet procoagulant activity independently of thrombin generation rfviia -血小板结合增强血小板促凝活性独立于凝血酶的产生

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2026-02-01 DOI: 10.1016/j.bvth.2025.100132

Anja Strebel , Sebastian Lickert , Robert Klamroth , Viola Vogel , Fabrizio A. Pennacchio

Abstract

Platelets play a critical role in hemostasis. In addition to adhesion at the site of injury, phosphatidylserine (PS) exposing platelets (procoagulant) bind activated factor VIII (FVIIIa), facilitating coagulation. Effects of FVIIIa-platelet interactions on platelet activity are unclear. We explored how FVIIIa-platelet interactions affect their transition from a proaggregatory to procoagulant phenotype and how molecular modifications of recombinant FVIII (rFVIII) products might tune this phenotype shift. Platelets were collected from healthy donors and people with severe hemophilia A (HA) and were activated with thrombin and collagen-related peptide. Integrin αIIbβ3 activity and PS exposure were measured as markers of proaggregatory and procoagulant activities, respectively. Platelet phenotypes, rFVIIIa binding, and calcium influx were assessed by flow cytometry and confocal microscopy. rFVIIIa binding potentiated procoagulant activity while having no appreciable effect on percentage of platelets with activated integrin αIIbβ3. Potentiation of procoagulant activity was mediated by a thrombin-independent outside-in signaling cascade but involved integrin αIIbβ3. Similar trends were observed in platelets from healthy donors and patients with HA. A potential role of glycoprotein VI in rFVIIIa-platelet interactions was identified. rFVIIIa products with certain modifications to extend the circulation half-life of FVIII showed reduced binding to proaggregatory platelets compared to nonmodified rFVIIIa. Binding to procoagulant platelets was comparable across rFVIII products, except for rFVIII with site-specific PEGylation, which showed reduced binding. In conclusion, these results offer insights into FVIIIa-platelet interactions, and the potential impact of rFVIII modifications on platelet binding may inform clinical decision-making in HA.

血小板在止血中起着至关重要的作用。除了在损伤部位粘附外，暴露于血小板（促凝剂）的磷脂酰丝氨酸（PS）结合活化因子VIII (FVIIIa)，促进凝血。fviia -血小板相互作用对血小板活性的影响尚不清楚。我们探讨了FVIII -血小板相互作用如何影响它们从促聚集表型向促凝表型的转变，以及重组FVIII （rFVIII）产物的分子修饰如何调节这种表型转变。采集健康供体和严重血友病A （HA）患者的血小板，用凝血酶和胶原蛋白相关肽活化。整合素α ib β3活性和PS暴露分别作为促凝集和促凝活性的标志。通过流式细胞术和共聚焦显微镜评估血小板表型、rfviia结合和钙内流。rFVIIIa结合增强了促凝活性，但对活化整合素α ib β3的血小板百分比没有明显影响。促凝活性的增强是由一个不依赖凝血酶的外-内信号级联介导的，但与整合素α ib β3有关。在健康供体和HA患者的血小板中也观察到类似的趋势。鉴定了糖蛋白VI在rfviia -血小板相互作用中的潜在作用。与未修饰的rFVIIIa相比，经过一定修饰以延长FVIII循环半衰期的rFVIIIa产品与促聚集血小板的结合减少。所有rFVIII产品与促凝血小板的结合都是相似的，除了具有位点特异性PEGylation的rFVIII，其结合程度降低。总之，这些结果提供了对fviia -血小板相互作用的见解，并且rFVIII修饰对血小板结合的潜在影响可能为HA的临床决策提供信息。

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引用次数: 0

Diagnosis of platelet dysfunction in children: clinical predictors and test methods 儿童血小板功能障碍的诊断：临床预测因素和测试方法

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-12-15 DOI: 10.1016/j.bvth.2025.100135

Bhavya S. Doshi , Eric N. Thompson , Walter Faig , Abigail Wax , Amrom E. Obstfeld , Michele P. Lambert

Abstract

Evaluation for platelet function disorders (PFD) in children is complicated by their limited exposure to hemostatic challenges, large volumes needed for light transmission aggregometry (LTA) testing, and limited data on the performance characteristics of whole-blood methods such as whole-blood impedance lumiaggregometry (WBILA). The objective of this study was to determine the clinical variables associated with the diagnosis of a PFD. A single-center, retrospective, cohort study of children evaluated for PFD was conducted. Medical charts were abstracted for demographics, medications, testing indications, bleeding sites and severity, and laboratory results. Univariate odds ratios (OR) and multivariable modeling were conducted for association of clinical variables with PFD diagnosis in children tested by LTA or WBILA. Of 667 patients, 20.5% were diagnosed with a PFD. The PFD cohort was more likely male (OR, 1.54; P = .025) and younger (8.8 vs 10.1 years; P = .026). Neither mucocutaneous bleeding (most common presenting indication) nor bleeding severity scores correlated with increased odds of PFD diagnosis. Both LTA and WBILA showed sensitivity of >91% and specificity of >84% for PFD diagnosis. A multivariable model identified younger age, male sex, thrombocytopenia, genetic disorders, and gastrointestinal bleeding with PFD diagnosis in the WBILA cohort. In conclusion, younger, male patients have a higher incidence of PFD. These data support that WBILA can effectively rule out PFD in a pediatric population.

儿童血小板功能障碍（PFD）的评估因其暴露于止血挑战有限，光透射聚集（LTA）测试需要大量数据，以及全血方法（如全血阻抗光聚集法（WBILA））的性能特征数据有限而变得复杂。本研究的目的是确定与PFD诊断相关的临床变量。对评估PFD的儿童进行了一项单中心、回顾性、队列研究。医学图表被抽象为人口统计、药物、检测指征、出血部位和严重程度以及实验室结果。采用单因素优势比（OR）和多变量模型分析临床变量与LTA或WBILA检测儿童PFD诊断的关系。在667名患者中，20.5%被诊断为PFD。PFD队列更可能是男性（OR, 1.54; P = 0.025）和年轻（8.8 vs 10.1岁；P = 0.026）。粘膜皮肤出血（最常见的表现）和出血严重程度评分均与PFD诊断几率增加无关。LTA和WBILA诊断PFD的敏感性为91%，特异性为84%。一个多变量模型确定了年龄较小、男性、血小板减少症、遗传疾病和胃肠道出血与WBILA队列中PFD的诊断。总之，年轻男性患者的PFD发病率较高。这些数据支持WBILA可以有效地排除儿科人群中的PFD。

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引用次数: 0

A novel transdermal curcumin gel shows potential in improving cardiac bioenergetic functions in Berkeley sickle cell mice 一种新的经皮姜黄素凝胶显示出改善伯克利镰状细胞小鼠心脏生物能量功能的潜力

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-11-26 DOI: 10.1016/j.bvth.2025.100131

Sirsendu Jana , Wayne Hicks , Haley Garbus-Grant , Yugal Goel , Richard Prince , Joel Friedman , Kalpna Gupta , Abdu I. Alayash

Abstract

Numerous studies have identified mitochondria as critical players in the pathophysiology of sickle cell disease (SCD). Here, we investigated the bioenergetic impairment in cardiac mitochondria as well as the putative benefits of a transdermal (TD) curcumin (VAS-101) treatment in a Berkeley SCD (BERK-SS) mouse model. Low oxygen consumption rate observed in cardiac mitochondria was indicative of impaired electron transport chain (ETC) activities in these animals. Furthermore, there was a loss of enzymatic activity primarily in complex I (reduced NAD dehydrogenase) and to a lesser degree in complex V (ATP synthase) observed in BERK-SS cardiac mitochondrial fractions. Proteomic analysis of cardiac mitochondria revealed changes in the relative abundance of proteins related to ETC complexes, especially in multiple subunits of complex I and complex V. Changes were also seen in proteins involved in several other pathways (eg, β-oxidation, glycolysis, mitochondrial protein transport, cytoskeleton, Ca⁺² regulation, and mitophagy). Moreover, TD curcumin treatment caused improvements in various oxidative stress parameters in heart tissues of BERK-SS mice. Together, our results suggest that novel TD curcumin may affect oxygen homeostasis at cellular and subcellular levels by improving mitochondrial respiration in the heart muscle of BERK-SS mice.

许多研究已经确定线粒体在镰状细胞病（SCD）的病理生理中起着关键作用。在这里，我们在伯克利SCD （BERK-SS）小鼠模型中研究了心脏线粒体的生物能损伤以及透皮姜黄素（VAS-101）治疗的可能益处。心肌线粒体的低耗氧率表明这些动物的电子传递链（ETC）活性受损。此外，在BERK-SS心脏线粒体中，酶活性主要丧失在复合体I（减少的NAD脱氢酶）和复合体V （ATP合酶）中，程度较轻。心肌线粒体的蛋白质组学分析显示，ETC复合物相关蛋白的相对丰度发生了变化，尤其是复合物I和复合物v的多个亚基。参与其他途径（如β-氧化、糖酵解、线粒体蛋白运输、细胞骨架、Ca+2调节和线粒体自噬）的蛋白也发生了变化。此外，姜黄素治疗可改善BERK-SS小鼠心脏组织的各种氧化应激参数。总之，我们的研究结果表明，新型TD姜黄素可能通过改善BERK-SS小鼠心肌的线粒体呼吸来影响细胞和亚细胞水平的氧稳态。

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引用次数: 0

Alpelisib, a PI3Kα inhibitor, effectively treats vascular anomalies with diverse genotypes and phenotypes Alpelisib是一种PI3Kα抑制剂，可有效治疗多种基因型和表型的血管异常

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-11-21 DOI: 10.1016/j.bvth.2025.100133

Deeti J. Pithadia ∗ , Marina J. Heskel ∗ , Arman Shotayev , Sunit Davda , Rachelle Durand , Daniel Cooke , Josephine Czechowicz , Mary Lesh , Patricia Cornett , Kristin A. Shimano , Erin F. Mathes , Ilona J. Frieden , Beth Apsel Winger

Abstract

Vascular anomalies (VAs) are complex, highly morbid conditions that are increasingly managed by hematologists with targeted therapies. They are often driven by activating mutations in the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. Alpelisib, a phosphoinositide 3-kinase-α (PI3Kα) inhibitor, is a key therapy for VAs; however, it is only approved for PIK3CA-related overgrowth spectrum (PROS), a VA diagnosis with multifaceted genotypic and phenotypic criteria, including a required PIK3CA mutation. Although there is a mechanistic rationale for alpelisib use in non-PROS VAs, published data supporting alpelisib use outside of PROS are limited. We conducted a single-center, retrospective study of 41 children and adults with VAs treated with alpelisib. Most patients failed prior therapies, including sirolimus. Alpelisib led to clinical improvement in 92% of the patients, 80% of whom did not meet PROS diagnostic criteria. There was no genetic testing in ∼50% of the responders, and ∼25% had mutations in non-PIK3CA genes in the PI3K/AKT/mTOR pathway (TEK, PIK3R1, and PTEN). Among patients with pre- and post-therapy imaging, 100% showed clinical improvement, but only 50% showed radiological improvement, highlighting discordance between imaging and clinical response. Our findings support expanding alpelisib use to VAs beyond PROS. In addition, they underscore the need for clinical trial end points based on clinical, not radiological, outcomes.

血管异常（VAs）是一种复杂的、高度病态的疾病，越来越多的血液学家使用靶向治疗来治疗。它们通常由磷酸肌肽3-激酶(PI3K)/AKT/哺乳动物雷帕霉素靶蛋白（mTOR）途径的激活突变驱动。Alpelisib是一种磷酸肌苷3-激酶α (PI3Kα)抑制剂，是治疗VAs的关键药物；然而，它仅被批准用于PIK3CA相关的过度生长谱（PROS），这是一种具有多方面基因型和表型标准的VA诊断，包括所需的PIK3CA突变。尽管在非PROS VAs中使用alpelisib有一个机制上的理由，但支持在PROS之外使用alpelisib的公开数据是有限的。我们进行了一项单中心、回顾性研究，对41名使用alpelisib治疗VAs的儿童和成人进行了研究。大多数患者先前的治疗失败，包括西罗莫司。Alpelisib使92%的患者临床改善，其中80%不符合PROS诊断标准。约50%的应答者没有进行基因检测，约25%的应答者在PI3K/AKT/mTOR通路（TEK、PIK3R1和PTEN）中存在非pik3ca基因突变。在治疗前和治疗后的患者中，100%的患者临床改善，但只有50%的患者放射学改善，突出了影像学与临床反应之间的不一致。我们的研究结果支持将alpelisib的使用范围扩大到VAs。此外，他们强调了临床试验终点基于临床而非放射学结果的必要性。

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引用次数: 0

Inflammatory cytokines, inflammasomes, and neutrophil extracellular traps in primary immune thrombocytopenia pathogenesis 原发性免疫性血小板减少发病机制中的炎性细胞因子、炎性小体和中性粒细胞胞外陷阱

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-11-18 DOI: 10.1016/j.bvth.2025.100129

Alessandro Lucchesi , Maria Belen Rodriguez , Matias Cordoba , Johnny Zhou , Otto Lam , Divya Pushkarna , Lora Benoit , Drew Provan

Abstract

Primary immune thrombocytopenia (ITP) is a disorder characterized by enhanced platelet clearance and impaired production due to immune dysregulation. Central to its pathogenesis are platelet autoantibodies, T-cell–mediated processes, and altered cytokine profiles, which exacerbate clearance and hinder production. These mechanisms mirror other immune-mediated diseases and contribute to symptoms such as fatigue and thromboembolism. Despite extensive research, the inflammatory role in ITP remains unclear, with variability across studies underscoring the need for further investigation to optimize therapies. This study aims to summarize the evidence on inflammatory cytokines, inflammasomes, and neutrophil extracellular traps (NET) in adult primary ITP. A systematic literature review was conducted using Embase and MEDLINE (search date 9 January 2024), covering publications from the past decade. Observational studies and clinical trials reporting inflammatory markers were included (79 studies). Most studies were case-control (69.7%) and conducted in China (77.2%). Activation of multiple immune and inflammatory pathways was observed. T helper 17 (Th17; n = 21) and T follicular helper cells (n = 4) demonstrated involvement, with Th17-derived interleukin-17 (IL-17) contributing prominently to the inflammatory milieu. NLRP3 inflammasome hyperactivity/increased expression (n = 6 studies) emerged as a significant pathway, and strongly associated markers (IL-18 [n = 4]) were elevated. Additionally, NET and neutrophil activation promoted inflammation and thrombosis (n = 2). In conclusion, immune dysregulation from Th17 cell pathways and NLRP3 inflammasome strongly contribute to inflammation in adults with primary ITP, with IL-18 and IL-17 linked to disease activity/progression. The findings suggest a need for novel therapies to target immune dysregulation and clarify their roles in ITP.

原发性免疫性血小板减少症（ITP）是一种以免疫失调导致的血小板清除增强和生成受损为特征的疾病。其发病机制的核心是血小板自身抗体、t细胞介导的过程和细胞因子谱的改变，它们加剧了清除并阻碍了生产。这些机制反映了其他免疫介导的疾病，并导致疲劳和血栓栓塞等症状。尽管进行了广泛的研究，炎症在ITP中的作用仍不清楚，研究之间的差异强调了进一步研究以优化治疗的必要性。本研究旨在总结炎症因子、炎症小体和中性粒细胞胞外陷阱（NET）在成人原发性ITP中的证据。使用Embase和MEDLINE（检索日期为2024年1月9日）进行了系统的文献综述，涵盖了过去十年的出版物。报告炎症标志物的观察性研究和临床试验被纳入（79项研究）。大多数研究为病例对照（69.7%），在中国进行（77.2%）。观察到多种免疫和炎症途径的激活。T辅助17 （Th17, n = 21）和T滤泡辅助细胞（n = 4）参与其中，Th17衍生的白细胞介素-17 （IL-17）在炎症环境中起着重要作用。NLRP3炎性小体过度活跃/表达增加（n = 6项研究）成为重要途径，且强相关标志物（IL-18 [n = 4]）升高。此外，NET和中性粒细胞活化促进炎症和血栓形成（n = 2）。总之，来自Th17细胞通路和NLRP3炎性体的免疫失调强烈促进了原发性ITP成人的炎症，IL-18和IL-17与疾病活动/进展有关。研究结果表明，需要针对免疫失调的新疗法，并阐明其在ITP中的作用。

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引用次数: 0

Distinct endothelial cell toxicities of Abl tyrosine kinase inhibitors lead to arterial thrombosis 不同的内皮细胞毒性的Abl酪氨酸激酶抑制剂导致动脉血栓形成

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-11-17 DOI: 10.1016/j.bvth.2025.100127

Richard Travers , Alec Stepanian , Sebastiana Redford , Gregory Martin , Nicole L. Svedberg , Kun Xu , Glenn Merrill-Skoloff , Christopher Chen , Robert Flaumenhaft , Iris Z. Jaffe

Abstract

Inhibitors targeting Abl kinase have dramatically improved survival in Philadelphia chromosome–positive leukemias. First-generation imatinib has minimal cardiovascular side effects, whereas newer agents such as dasatinib, ponatinib, and nilotinib are more effective cancer treatments but carry a high risk of arterial thrombosis. The allosteric Abl kinase inhibitor asciminib was recently approved without long-term cardiovascular follow-up. Previous studies reveal disparate effects of dasatinib, ponatinib, and nilotinib on platelets with consistent evidence of endothelial cell (EC) toxicity. Here, we explore prothrombotic endothelial toxicity mechanisms by comparing exposure to vehicle vs clinically relevant concentrations of imatinib, dasatinib, ponatinib, nilotinib, and asciminib on primary human coronary artery ECs (HCAEC) and mouse models of endothelial injury and vascular thrombosis. Dasatinib and ponatinib increased adhesion of human platelets to HCAEC, specifically when ECs, but not platelets, were exposed to drugs. Dasatinib, ponatinib, and nilotinib impaired HCAEC healing in vitro, whereas only nilotinib impaired healing in vivo and increased von Willebrand factor levels in mice. Dasatinib and ponatinib increased early platelet but not fibrin accumulation in the mouse cremaster arteriole laser injury–induced thrombosis model, and only ponatinib increased platelet-leukocyte aggregate formation. Asciminib had no toxic effect in any of these assays, similar to imatinib. These studies reveal novel and distinct mechanisms by which EC damage induced by dasatinib, ponatinib, and nilotinib contributes to a prothrombogenic EC state. The findings suggest the need for distinct side effect prevention strategies and provide preclinical data supporting vascular safety of asciminib, while awaiting long-term vascular safety follow-up results.

针对Abl激酶的抑制剂显著提高了费城染色体阳性白血病患者的生存率。第一代伊马替尼对心血管的副作用很小，而较新的药物如达沙替尼、波纳替尼和尼洛替尼是更有效的癌症治疗药物，但有动脉血栓形成的高风险。变构Abl激酶抑制剂阿西米尼最近被批准，没有长期心血管随访。先前的研究表明，达沙替尼、波纳替尼和尼洛替尼对血小板的不同影响与内皮细胞（EC）毒性一致。在这里，我们通过比较暴露于载体与临床相关浓度的伊马替尼、达沙替尼、波纳替尼、尼洛替尼和阿西米尼对原发性人冠状动脉内皮细胞（HCAEC）和内皮损伤和血管血栓形成小鼠模型的毒性机制，探讨血栓形成前内皮毒性机制。达沙替尼和波纳替尼增加了人血小板对HCAEC的粘附，特别是当ECs而不是血小板暴露于药物中时。达沙替尼、波纳替尼和尼洛替尼在体外损伤HCAEC的愈合，而只有尼洛替尼在体内损伤愈合，并增加小鼠的血管性血癌因子水平。达沙替尼和波纳替尼在小鼠微动脉激光损伤致血栓模型中增加了早期血小板积累，但没有增加纤维蛋白积累，只有波纳替尼增加了血小板-白细胞聚集的形成。与伊马替尼类似，阿西米尼在这些试验中没有毒性作用。这些研究揭示了由达沙替尼、波纳替尼和尼洛替尼诱导的EC损伤导致血栓形成前EC状态的新颖和独特的机制。研究结果提示需要明确的副作用预防策略，并提供支持阿西米尼血管安全性的临床前数据，同时等待长期血管安全性随访结果。

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引用次数: 0

Abnormal von Willebrand factor multimer pattern without VWF variants in autosomal-recessive cutis laxa type IIA 常染色体隐性皮肤松弛症IIA型中无VWF变异的异常血管性血友病因子多模式

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-11-17 DOI: 10.1016/j.bvth.2025.100130

Jeremy W. Jacobs , Lorin A. Bibb , Nadia Syed , Rosemary Demet , Garrett S. Booth , David Gailani

引用次数: 0

Uniaxial cyclic stretch regulates the expression of thrombomodulin and von Willebrand factor on endothelial cells 单轴循环拉伸调节内皮细胞血栓调节素和血管性血友病因子的表达

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-11-01 DOI: 10.1016/j.bvth.2025.100103

Arianna Giannetti , Elisabeth Génot , Antonia Perez-Martin , Elsa Faure , Jean-Christophe Gris , Maïda Cardoso , Christophe Goze-Bac , Christine Benistant , Manouk Abkarian

Abstract

Deep vein thrombosis (DVT) is the formation of a thrombus in the valvular sinuses of the veins in the lower limbs. It is often associated with blood stasis during prolonged immobilization, however, the triggers for DVT are not well understood. Venous valvular sinuses experience unique blood flow patterns due to the cyclic opening and closing of the valve. We hypothesize that stretching helps maintain vein antithrombotic properties, and its absence could contribute to the onset of DVT. To test this idea, confluent human endothelial cells are cultured on hydrogel-coated elastic membranes subjected to uniaxial cyclic stretching at rates of 60 cycles per minute. We study how different levels and duration of stretching influence the expression of 2 important proteins of the hemostatic system, thrombomodulin (TM) and von Willebrand factor (VWF). Our results show that the cells elongate and align orthogonal to the stretch direction. Stretch amplitude of 10% increases TM levels by 75% within 6 hours and remains high up to 24 hours. Interestingly, no significant change occurred at the 5% stretch even after 24 hours. When 10% stretching is interrupted after 24 hours, VWF levels measured 6 hours after interruption increase significantly. Additionally, we show that stretching flattens the nuclei and aligns them orthogonal to the stretching direction. Notably, the epigenetic acetylation mark histone H3 lysine 27 acetylation, which regulates TM gene expression, increases by 1.6-fold. Taken together, our findings suggest that cyclic stretch contributes to the regulation of endothelium thromboresistance and might prevent thrombosis.

摘要深静脉血栓（deep vein thrombosis， DVT）是指下肢静脉瓣膜窦内形成血栓。它通常与长时间固定期间的血瘀有关，然而，深静脉血栓的触发因素尚不清楚。由于瓣膜的循环打开和关闭，静脉瓣膜窦经历了独特的血流模式。我们假设拉伸有助于维持静脉抗血栓特性，而拉伸的缺失可能导致深静脉血栓的发生。为了验证这一想法，将融合的人内皮细胞培养在水凝胶涂覆的弹性膜上，并以每分钟60次的速率进行单轴循环拉伸。我们研究了不同程度和持续时间的拉伸对止血系统中2种重要蛋白血栓调节蛋白（thrombomodulin， TM）和血管性血液病因子（von Willebrand factor， VWF）表达的影响。我们的结果表明，细胞伸长并与拉伸方向正交。10%的拉伸幅度使TM水平在6小时内增加75%，并在24小时内保持高水平。有趣的是，即使在24小时后，5%的拉伸也没有明显的变化。当10%的拉伸在24小时后中断时，中断6小时后测量的VWF水平显着增加。此外，我们发现拉伸使原子核变平，并使它们与拉伸方向正交。值得注意的是，调控TM基因表达的表观遗传乙酰化标记组蛋白H3赖氨酸27乙酰化增加了1.6倍。综上所述，我们的研究结果表明，循环拉伸有助于调节内皮细胞血栓抵抗，并可能预防血栓形成。

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引用次数: 0

Ubiquitous dysregulation of the Wnt pathway in immune thrombocytopenia genetic susceptibility Wnt通路在免疫性血小板减少遗传易感性中的普遍失调

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-11-01 DOI: 10.1016/j.bvth.2025.100107

Estelle Lecluze , Stennio Da Silva Faria , Manon Saby , Jason Yu , Véronique Lisi , Vincent-Philippe Lavallée , Taylor Olmsted Kim , Michael E. Scheurer , Amanda B. Grimes , Thomas Pincez

Abstract

The pathogenesis of immune thrombocytopenia (ITP) is complex and incompletely understood. Multiple cell types have been implicated, and their respective contribution is unclear. A recent genome-wide association study identified single-nucleotide polymorphisms (SNPs) associated with pediatric ITP within or near 5 genes in the canonical Wnt signaling pathway. To investigate whether this pathway was dysregulated in ITP and identify which cell types were involved, we leveraged extensive functional genomics and single-cell RNA sequencing (scRNA-seq) data. By linking the identified SNPs to likely regulated genes, we showed an enrichment in the Wnt pathway and identified 2 additional genes in this pathway involved in ITP. The SNPs affected regulation of the Wnt pathway genes in multiple cell types. Indeed, scRNA-seq showed some of these genes were expressed in lymphocytes, whereas others were expressed in platelets or megakaryocytes. By comparing the cell-specific expression of these genes between individuals with ITP and healthy controls, we demonstrated that several genes in the Wnt pathway were differentially expressed between these 2 groups. Some genes were upregulated, whereas other were downregulated in ITP. In sum, the Wnt signaling pathway is broadly dysregulated in ITP, with a complex pattern that varies across genes and cell types.

摘要免疫性血小板减少症（ITP）的发病机制复杂且不完全清楚。涉及多种细胞类型，它们各自的作用尚不清楚。最近的一项全基因组关联研究发现，在典型Wnt信号通路的5个基因内或附近存在与儿童ITP相关的单核苷酸多态性（snp）。为了研究该通路是否在ITP中失调并确定哪些细胞类型参与其中，我们利用了广泛的功能基因组学和单细胞RNA测序（scRNA-seq）数据。通过将鉴定的snp与可能的调控基因连接起来，我们发现Wnt通路中有富集，并鉴定了该通路中参与ITP的另外2个基因。SNPs影响多种细胞类型中Wnt通路基因的调控。事实上，scRNA-seq显示其中一些基因在淋巴细胞中表达，而其他基因在血小板或巨核细胞中表达。通过比较这些基因在ITP个体和健康对照组之间的细胞特异性表达，我们证明了Wnt通路中的几个基因在这两组之间存在差异表达。在ITP中，一些基因表达上调，而另一些基因表达下调。总之，Wnt信号通路在ITP中广泛失调，具有复杂的模式，因基因和细胞类型而异。

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引用次数: 0

Low-molecular-weight heparin vs aspirin postpartum (LEAP): a single-center pilot randomized control trial 低分子肝素与产后阿司匹林（LEAP）：一项单中心随机对照试验

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-11-01 DOI: 10.1016/j.bvth.2025.100106

Evangelia Vlachodimitropoulou , Kinga Malinowski , Eric Kaplovitch , Marc Carrier , Nadine Shehata

Abstract

Low-molecular-weight heparin (LMWH) for 6 weeks postpartum for prophylaxis of venous thromboembolism (VTE) is suggested for patients with previous VTE or high-risk thrombophilia, yet evidence supporting this duration is limited. This study assesses the feasibility of a randomized controlled trial (RCT) comparing a shorter duration of LMWH postpartum. In a single-center pilot feasibility study, patients with previous VTE or high-risk thrombophilia were randomized to receive either 6 weeks of LMWH or a 3-week course of LMWH followed by 3 weeks of low-dose aspirin. We evaluated enrollment, adherence rates, and retention. Secondary outcomes included objectively confirmed VTE, bleeding events using the International Society on Thrombosis and Haemostasis criteria, and patient satisfaction via the Perception of Anti-Coagulant Treatment Questionnaire at 3 and 6 weeks postpartum. From October 2021 to July 2023, 67 individuals were screened, yielding a consent rate of 55%, with 30 participants enrolled. Fourteen patients were randomized to the LMWH group and 13 to the LMWH-aspirin group. Adherence was achieved in both groups (96.5% for LMWH, 93.9% for LMWH-aspirin, P = .027). Missing data were minimal. No VTE or maternal deaths occurred. One participant in the LMWH arm had delayed postpartum hemorrhage. Quality of life was improved in the combined treatment group at 6 weeks (P < .001). This single-center pilot study indicates that a larger RCT to evaluate a mixed regimen of LMWH and aspirin against traditional LMWH therapy is feasible. Enrollment and adherence rates were achieved, and quality of life may be improved. This trial was registered at www.ClinicalTrials.gov as #NCT05058924.

摘要建议产后6周应用低分子肝素（LMWH）预防静脉血栓栓塞（VTE），但目前尚无证据支持这一疗程。本研究评估一项比较产后低分子肝素持续时间较短的随机对照试验（RCT）的可行性。在一项单中心试点可行性研究中，既往有静脉血栓栓塞或高危血栓形成的患者被随机分为两组，一组接受6周低分子肝素治疗，另一组接受3周低分子肝素治疗，然后服用3周低剂量阿司匹林。我们评估了入组、依从率和保留率。次要结局包括客观确认的静脉血栓栓塞、国际血栓和止血学会标准的出血事件，以及产后3周和6周通过抗凝治疗问卷的患者满意度。从2021年10月到2023年7月，对67人进行了筛查，同意率为55%，共有30名参与者参加。14例患者随机分为低分子肝素组和13例低分子肝素-阿司匹林组。两组患者均达到依从性（低分子肝素组96.5%，低分子肝素-阿司匹林组93.9%,P = 0.027）。数据缺失极少。未发生静脉血栓栓塞或产妇死亡。低分子肝素组有一名参与者延迟了产后出血。联合治疗组患者6周生活质量明显改善（P < .001）。这项单中心试点研究表明，更大的随机对照试验评估低分子肝素和阿司匹林混合方案对传统低分子肝素治疗的影响是可行的。登记和依从率达到了，生活质量可能得到改善。该试验在www.ClinicalTrials.gov注册为#NCT05058924。

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