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Response to: “DOACs for Left Ventricular Thrombus: Persistent Equipoise Despite New Observational and Randomized Data” 对《左室血栓DOACs:尽管有新的观察和随机数据,但仍保持平衡》的回应
IF 3.4 3区 医学 Q2 HEMATOLOGY Pub Date : 2026-01-01 DOI: 10.1016/j.rpth.2025.103340
Hossam Elbenawi , Kirsten Lipps , Samuel Heller Jr. , David A. Liedl , Raymond C. Shields , Ana I. Casanegra , Stanislav Henkin , Thom W. Rooke , Paul W. Wennberg , Waldemar E. Wysokinski , Robert D. McBane , Damon E. Houghton
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引用次数: 0
Comparing survival with vitamin K antagonists, low-molecular-weight heparin, and direct oral anticoagulants in patients with cancer—a systematic review and meta-analysis 比较维生素K拮抗剂、低分子肝素和直接口服抗凝剂在癌症患者中的生存——系统回顾和荟萃分析
IF 3.4 3区 医学 Q2 HEMATOLOGY Pub Date : 2026-01-01 DOI: 10.1016/j.rpth.2025.103268
Vasiliki Xirou , Anika Patel , Maria Fernanda Albuja Altamirano , Rishabh Singh , Jason Gusdorf , Kevin Barnum , Megan McNichol , Justine Ryu , Jeffrey I. Zwicker , Thita Chiasakul , Rushad Patell

Background

Venous thromboembolism (VTE) is a frequent complication in malignancy. Low-molecular-weight heparins and direct oral anticoagulants have replaced vitamin K antagonists (VKAs) as the standard of care for cancer-associated VTE. Nonetheless, clinical trials have not established a survival benefit of these agents compared with VKA.

Objectives

We conducted a systematic review and meta-analysis to compare survival in cancer patients receiving VKA vs other anticoagulants.

Methods

We searched Embase, Web of Science, PubMed, ClinicalTrials.gov, and Cochrane from inception until April 10, 2025, focusing on the use of VKA and non-VKA in cancer patients. Primary outcome was mortality and secondary outcomes included thromboembolism and bleeding.

Results

Of 11,198 studies screened, 14 studies (70,025 patients) were included. VKA were associated with lower mortality than non-VKA in observational studies (odds ratio [OR], 0.84; 95% CI, 0.78-0.91; I2 = 81%; n = 6 studies) but not in randomized controlled trials (OR, 0.99; 95% CI, 0.86-1.13; I2 = 0%; n = 8 studies). In subgroup analysis, follow-up period of >6 months (OR, 0.85; 95% CI, 0.79-0.92; I2 = 75%), solid malignancies (OR, 0.81; 95% CI, 0.75-0.88; I2 = 78%), and indication of VTE only (OR, 0.89; 95% CI, 0.83-0.96; I2 = 42%) demonstrated improved survival with VKA.

Conclusion

The use of VKA was associated with lower mortality than non-VKA anticoagulation in patients with cancer in observational studies but not in randomized trials. The analysis was limited by high heterogeneity, which must be considered when interpreting results.
背景:静脉血栓栓塞(VTE)是恶性肿瘤的常见并发症。低分子肝素和直接口服抗凝剂已取代维生素K拮抗剂(VKAs)成为癌症相关性静脉血栓栓塞的标准治疗方法。然而,与VKA相比,临床试验尚未确定这些药物的生存获益。目的:我们进行了一项系统回顾和荟萃分析,比较接受VKA和其他抗凝药物治疗的癌症患者的生存率。方法我们检索Embase、Web of Science、PubMed、ClinicalTrials.gov和Cochrane,检索时间从成立到2025年4月10日,重点关注VKA和非VKA在癌症患者中的应用。主要结局是死亡率,次要结局包括血栓栓塞和出血。结果在筛选的11,198项研究中,纳入了14项研究(70,025例患者)。在观察性研究中,VKA与非VKA的死亡率相关(比值比[OR], 0.84; 95% CI, 0.78-0.91; I2 = 81%; n = 6项研究),但在随机对照试验中无相关(OR, 0.99; 95% CI, 0.86-1.13; I2 = 0%; n = 8项研究)。在亚组分析中,随访6个月(OR, 0.85; 95% CI, 0.79-0.92; I2 = 75%)、实体恶性肿瘤(OR, 0.81; 95% CI, 0.75-0.88; I2 = 78%)和仅VTE指征(OR, 0.89; 95% CI, 0.83-0.96; I2 = 42%)表明VKA改善了生存率。结论:在观察性研究中,使用VKA抗凝治疗的癌症患者死亡率低于不使用VKA抗凝治疗的癌症患者死亡率,而在随机试验中则没有。分析受到高度异质性的限制,在解释结果时必须考虑到这一点。
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引用次数: 0
Monitoring ADAMTS-13 conformation in immune-mediated thrombotic thrombocytopenic purpura: toward personalized management 监测免疫介导的血栓性血小板减少性紫癜的ADAMTS-13构象:面向个性化管理
IF 3.4 3区 医学 Q2 HEMATOLOGY Pub Date : 2026-01-01 DOI: 10.1016/j.rpth.2025.103288
Bérangère S. Joly , Elien Roose , Charlotte Dekimpe , Karen Vanhoorelbeke , Agnès Veyradier , Paul Coppo

Background

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy caused by an autoimmune-driven deficiency of ADAMTS-13. Despite remission, relapses remain a major concern for patients and are currently predicted by monitoring ADAMTS-13 activity.

Objectives

This study evaluated the association between ADAMTS-13 conformation and relapse risk in patients with iTTP during follow-up.

Methods

We conducted a retrospective monocentric study involving patients with iTTP with ADAMTS-13 monitoring from 2008 to 2020. ADAMTS-13 antigen and conformation were assessed in plasma samples using our 3H9-ELISA and 1C4-ELISA, respectively.

Results

Fifteen patients with iTTP were monitored for a median of 7 years (IQR, 6-11) with a total of 479 plasma samples. Based on annual relapse rate (RR; median, 0.5), they were categorized as low (group 1; RR, <0.50, n = 8) or high relapsers (group 2; RR, ≥0.50, n = 7). ADAMTS-13 activity normalized between iTTP relapses in all patients. However, the time from normalization with an open conformation to relapse was shorter in group 2 (5 vs 21 months; P < .001). Median annual ADAMTS-13 activity differ significantly between groups (54.1% vs 50.0%; P = .1893). A trend suggested greater time spent in an open conformation in group 2 (0.6 vs 0.2; P = .1427). Rituximab was effective in group 1, while group 2 patients often required alternative therapies.

Conclusion

Persistent open ADAMTS-13 conformation in remission samples was observed more frequently in patients with higher relapse risk and could potentially serve as a biomarker for detecting low levels of circulating autoantibodies. This potential biomarker requires prospective validation before it can be used to guide individualized iTTP management.
免疫介导的血栓性血小板减少性紫癜(iTTP)是一种危及生命的血栓性微血管疾病,由自身免疫驱动的ADAMTS-13缺乏引起。尽管缓解,复发仍然是患者主要关注的问题,目前通过监测ADAMTS-13活性来预测。目的评估iTTP患者随访期间ADAMTS-13符合性与复发风险之间的关系。方法:我们对2008年至2020年期间接受ADAMTS-13监测的iTTP患者进行了回顾性单中心研究。采用我们的3H9-ELISA和1C4-ELISA分别评估血浆样品中的ADAMTS-13抗原和构象。结果15例iTTP患者共获得479份血浆样本,监测时间中位数为7年(IQR, 6-11)。根据年复发率(RR;中位数,0.5),将患者分为低复发率(1组;RR, <0.50, n = 8)和高复发率(2组;RR,≥0.50,n = 7)。所有患者在iTTP复发期间ADAMTS-13活性恢复正常。然而,第二组从开放构象正常化到复发的时间较短(5个月vs 21个月;P < 0.001)。各组间每年ADAMTS-13活动的中位数差异显著(54.1% vs 50.0%; P = .1893)。趋势表明第二组在开放构象中花费的时间更长(0.6 vs 0.2; P = .1427)。利妥昔单抗在1组患者中有效,而2组患者通常需要替代治疗。结论缓解样本中持续开放的ADAMTS-13构象在复发风险较高的患者中更常见,可能作为检测低水平循环自身抗体的生物标志物。这种潜在的生物标志物在用于指导个体化iTTP管理之前需要进行前瞻性验证。
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引用次数: 0
Urine-based point-of-care detection of direct oral anticoagulant activity in acute stroke—accuracy at anti-Xa thresholds relevant for intravenous thrombolysis 急性卒中患者直接口服抗凝血活性的尿液即时检测——与静脉溶栓相关的抗xa阈值的准确性
IF 3.4 3区 医学 Q2 HEMATOLOGY Pub Date : 2026-01-01 DOI: 10.1016/j.rpth.2025.103331
Stefan T. Gerner , Alina Braemer , Martin B. Juenemann , Anne Mrochen , Tobias Braun , Linus Olbricht , Norma J. Diel , Ulrich J. Sachs , Hagen B. Huttner , Omar Alhaj Omar

Background

Rapid assessment of direct oral anticoagulant (DOAC) activity is essential in acute ischemic stroke (AIS), particularly because intravenous thrombolysis (IVT) may be considered at anti-Xa levels ≤ 100 ng/mL. Laboratory drug-specific assays; however, are often limited by availability and turnaround time. A urine-based point-of-care (POC) test may provide a rapid alternative.

Objectives

To determine the diagnostic accuracy of a urine-based POC dipstick for detecting clinically relevant DOAC activity at (1) the established screening threshold (≥30 ng/mL) and (2) the IVT-relevant threshold (≥100 ng/mL), using calibrated plasma DOAC levels as a reference standard.

Methods

In this prospective diagnostic accuracy study (UPTURN trial), consecutive AIS patients underwent urine-based POC testing. Dipstick results, recorded as visual and automatic readouts, were analyzed against plasma DOAC activity. Relevant anticoagulant activity was defined as anti-Xa ≥30 ng/mL; the IVT eligibility threshold was defined as anti-Xa <100 ng/mL. Factor Xa inhibitors were quantified using drug-specific chromogenic anti-Xa assays; dabigatran activity was measured using Biophen DTI. Diagnostic accuracy metrics were calculated with exact 95% CIs. Time-to-result was compared between POC testing and plasma assays.

Results

Among 101 AIS patients (55 with DOAC intake), the urine-based dipstick test reliably identified relevant anticoagulatory activity (anti-Xa ≥30 ng/mL) with a sensitivity of 100% and specificity of 96.3% (automated readout). Visual interpretation yielded similar accuracy. For higher anti-Xa levels (≥100 ng/mL), sensitivity remained 100%, though specificity decreased (74.4%). A double-positive visual result increased specificity to 92.8% at 84.4% sensitivity. Median time to result was 19 minutes for urine testing versus 144 minutes for blood-based assays. Test performance was consistent across DOAC agents, dosages, and intake timing. Visual grading enabled semiquantitative discrimination of DOAC levels.

Conclusion

Urine-based DOAC dipstick testing is a rapid, accurate, and reliable method for detecting anticoagulatory activity in AIS patients, providing a valuable tool to guide acute therapeutic decisions. Future studies are warranted to validate its clinical impact and broader applicability, especially in the emergency setting.
背景:在急性缺血性卒中(AIS)中,快速评估直接口服抗凝剂(DOAC)活性是必不可少的,特别是当抗xa水平≤100 ng/mL时,静脉溶栓(IVT)可能会被考虑。实验室药物特异性分析;然而,它们通常受到可用性和周转时间的限制。基于尿液的即时检测(POC)可以提供一种快速的替代方法。目的以校正后的血浆DOAC水平作为参考标准,确定基于尿液的POC试纸在(1)既定筛选阈值(≥30 ng/mL)和(2)ivt相关阈值(≥100 ng/mL)下检测临床相关DOAC活性的诊断准确性。方法在这项前瞻性诊断准确性研究(UPTURN试验)中,连续的AIS患者接受了基于尿液的POC检测。量尺结果,记录为视觉和自动读数,与血浆DOAC活性进行分析。相关抗凝活性定义为anti-Xa≥30 ng/mL;IVT合格阈值定义为抗- xa 100 ng/mL。Xa因子抑制剂采用药物特异性显色抗Xa测定法定量;采用Biophen DTI法测定达比加群活性。诊断准确度指标以95% ci计算。比较POC检测与血浆测定的结果时间。结果101例AIS患者(55例服用DOAC)中,基于尿液的试纸试验可靠地识别出相关的抗凝活性(抗xa≥30 ng/mL),灵敏度为100%,特异性为96.3%(自动读数)。视觉解释也产生了类似的准确性。对于较高的抗xa水平(≥100 ng/mL),敏感性保持100%,但特异性降低(74.4%)。双阳性的视觉结果将特异性提高到92.8%,敏感性为84.4%。尿液检测到结果的中位时间为19分钟,而血液检测为144分钟。DOAC药物、剂量和摄入时间的测试表现是一致的。视觉分级可以半定量地区分DOAC水平。结论基于尿液的DOAC试纸检测是一种快速、准确、可靠的检测AIS患者抗凝血活性的方法,为指导急性治疗决策提供了有价值的工具。未来的研究有必要验证其临床影响和更广泛的适用性,特别是在急诊环境中。
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引用次数: 0
Platelet lipidome alterations in septic shock: a matched case-control study 感染性休克的血小板脂质组改变:一项匹配的病例对照研究
IF 3.4 3区 医学 Q2 HEMATOLOGY Pub Date : 2026-01-01 DOI: 10.1016/j.rpth.2025.103332
Emma de Cartier d’Yves , Melanie Dechamps , Jérôme Ambroise , Anik Forest , Caroline Daneault , Alessandro Campion , Valentine Robaux , Julien De Poortere , Marie Octave , Audrey Ginion , Laurence Pirotton , Gabriele Muscia , Claudia Tersteeg , Damien Gruson , Marie-Astrid Van Dievoet , Jonathan Douxfils , Hélène Haguet , Laure Morimont , Marc Derive , Virginie Montiel , Christophe Beauloye

Background

Platelets play a central role in hemostatic and inflammatory responses during septic shock, with lipids being essential for their function. However, the specific lipidomic alterations occurring in platelets during septic shock remain poorly understood.

Objectives

This study aimed to characterize platelet lipidomic changes in septic shock and investigate their associations with disease severity.

Methods

In this matched case-control study, platelets were isolated from 49 septic shock patients and 47 nonseptic controls (matched for age, gender, and comorbidities). Lipidomic profiling was performed using untargeted lipidomics to identify significant alterations in the platelet lipidome. Associations among lipid changes, clinical data, and plasma biomarkers of coagulopathy and inflammation were explored.

Results

More than 60% of the annotated platelet lipids were significantly altered in septic shock. Cholesteryl esters, sphingomyelins, lysophosphatidylcholines, and ether-lipids were significantly reduced, while ceramide levels increased. Fatty acyl chain remodeling displayed distinct patterns, with polyunsaturated fatty acids increasing in triacylglycerols and decreasing in phospholipids. Lipid alterations were strongly associated with thrombocytopenia, and lysophosphatidylcholine levels inversely correlated with disease severity, as indicated by the Sequential Organ Failure Assessment score.

Conclusions

Septic shock induces significant disruptions in the platelet lipidome, with the extent of these alterations correlating with sepsis-associated thrombocytopenia severity. The observed changes affect multiple lipid classes, surpassing those reported under physiological conditions or in other diseases. These findings highlight the impact of sepsis-driven dysregulated inflammation and coagulopathy on platelet lipid composition, providing new insights into sepsis pathophysiology.
背景:血小板在脓毒性休克期间的止血和炎症反应中起核心作用,脂质对其功能至关重要。然而,感染性休克期间血小板发生的特异性脂质组学改变仍然知之甚少。目的探讨感染性休克患者血小板脂质组学的变化及其与疾病严重程度的关系。方法在这项匹配的病例对照研究中,从49例感染性休克患者和47例非感染性休克对照组(年龄、性别和合并症匹配)中分离血小板。脂质组学分析使用非靶向脂质组学来确定血小板脂质组的显著改变。探讨了血脂变化、临床数据、凝血功能障碍和炎症的血浆生物标志物之间的关系。结果60%以上的血小板脂质在脓毒性休克中发生显著改变。胆固醇酯、鞘磷脂、溶血磷脂酰胆碱和醚脂明显降低,而神经酰胺水平升高。脂肪酸酰基链重构表现出不同的模式,多不饱和脂肪酸在三酰基甘油中增加,在磷脂中减少。脂质改变与血小板减少密切相关,溶血磷脂酰胆碱水平与疾病严重程度呈负相关,如序贯器官衰竭评估评分所示。结论:脓毒症休克可引起血小板脂质组的显著破坏,这种破坏的程度与脓毒症相关的血小板减少的严重程度有关。观察到的变化影响多种脂质类别,超过在生理条件下或其他疾病中报道的变化。这些发现强调了脓毒症驱动的炎症失调和凝血功能障碍对血小板脂质组成的影响,为脓毒症的病理生理学提供了新的见解。
{"title":"Platelet lipidome alterations in septic shock: a matched case-control study","authors":"Emma de Cartier d’Yves ,&nbsp;Melanie Dechamps ,&nbsp;Jérôme Ambroise ,&nbsp;Anik Forest ,&nbsp;Caroline Daneault ,&nbsp;Alessandro Campion ,&nbsp;Valentine Robaux ,&nbsp;Julien De Poortere ,&nbsp;Marie Octave ,&nbsp;Audrey Ginion ,&nbsp;Laurence Pirotton ,&nbsp;Gabriele Muscia ,&nbsp;Claudia Tersteeg ,&nbsp;Damien Gruson ,&nbsp;Marie-Astrid Van Dievoet ,&nbsp;Jonathan Douxfils ,&nbsp;Hélène Haguet ,&nbsp;Laure Morimont ,&nbsp;Marc Derive ,&nbsp;Virginie Montiel ,&nbsp;Christophe Beauloye","doi":"10.1016/j.rpth.2025.103332","DOIUrl":"10.1016/j.rpth.2025.103332","url":null,"abstract":"<div><h3>Background</h3><div>Platelets play a central role in hemostatic and inflammatory responses during septic shock, with lipids being essential for their function. However, the specific lipidomic alterations occurring in platelets during septic shock remain poorly understood.</div></div><div><h3>Objectives</h3><div>This study aimed to characterize platelet lipidomic changes in septic shock and investigate their associations with disease severity.</div></div><div><h3>Methods</h3><div>In this matched case-control study, platelets were isolated from 49 septic shock patients and 47 nonseptic controls (matched for age, gender, and comorbidities). Lipidomic profiling was performed using untargeted lipidomics to identify significant alterations in the platelet lipidome. Associations among lipid changes, clinical data, and plasma biomarkers of coagulopathy and inflammation were explored.</div></div><div><h3>Results</h3><div>More than 60% of the annotated platelet lipids were significantly altered in septic shock. Cholesteryl esters, sphingomyelins, lysophosphatidylcholines, and ether-lipids were significantly reduced, while ceramide levels increased. Fatty acyl chain remodeling displayed distinct patterns, with polyunsaturated fatty acids increasing in triacylglycerols and decreasing in phospholipids. Lipid alterations were strongly associated with thrombocytopenia, and lysophosphatidylcholine levels inversely correlated with disease severity, as indicated by the Sequential Organ Failure Assessment score.</div></div><div><h3>Conclusions</h3><div>Septic shock induces significant disruptions in the platelet lipidome, with the extent of these alterations correlating with sepsis-associated thrombocytopenia severity. The observed changes affect multiple lipid classes, surpassing those reported under physiological conditions or in other diseases. These findings highlight the impact of sepsis-driven dysregulated inflammation and coagulopathy on platelet lipid composition, providing new insights into sepsis pathophysiology.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103332"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146022855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Etranacogene dezaparvovec in people with hemophilia B and without adeno-associated virus serotype 5 neutralizing antibodies: a 4-year subgroup analysis of the Health Outcomes with Padua Gene; Evaluation in Hemophilia B (HOPE-B) trial 无腺相关病毒血清5型中和抗体的B型血友病患者的地扎帕洛夫韦外透基因:Padua基因健康结局的4年亚组分析血友病B (HOPE-B)试验的评价
IF 3.4 3区 医学 Q2 HEMATOLOGY Pub Date : 2026-01-01 DOI: 10.1016/j.rpth.2025.103321
Priyanka Raheja , Niamh O’Connell , Peter Verhamme , Peter Kampmann , Richard S. Lemons , Fei Wang , Sean Gill , Paul E. Monahan , Sandra Le Quellec , Frank W.G. Leebeek

Background

In the phase 3 Health Outcomes with Padua Gene; Evaluation in Hemophilia B (HOPE-B) trial, a single dose of etranacogene dezaparvovec was administered to people with severe or moderately severe hemophilia B following a lead-in period (≥6 months) during which they received factor (F)IX prophylaxis. Participants were enrolled regardless of adeno-associated virus serotype 5 (AAV5)-neutralizing antibody (NAb) status at screening.

Objectives

To determine efficacy, pharmacokinetic, and safety outcomes over 4 years postgene therapy in HOPE-B participants who were NAb-negative (NAb−).

Methods

Participants provided serum samples for AAV5 NAb determination using an in vitro AAV5 transduction inhibition assay prior to etranacogene dezaparvovec infusion. Participants who were AAV5 NAb− at this time point were examined in the post hoc subgroup analysis.

Results

In NAb− participants (N = 33), the mean adjusted annualized bleeding rate was significantly reduced between months 7 and 48 postetranacogene dezaparvovec vs lead-in (0.57 vs 3.80; P < .0001). In years 1 to 4, the annualized bleeding rates were 0.99, 0.72, 0.41, and 0.41, respectively (P < .0001 vs lead-in; N = 33 throughout). The mean (SD) endogenous FIX activity was 40.6 IU/dL (18.6) at month 6 postinfusion (N = 33), remained stable, and was 39.0 IU/dL (16.8) at year 4 (N = 33). Exogenous FIX consumption decreased by 99% during months 7 to 48 vs the lead-in period, and no NAb− participant returned to continuous FIX prophylaxis for 4 years postinfusion. No treatment-related oncogenic events or persistent late hepatotoxicity were observed.

Conclusion

Etranacogene dezaparvovec proved to be highly effective, superior to FIX prophylaxis for bleeding protection, and safe for 4 years postinfusion in NAb− persons with severe or moderately severe hemophilia B.
Padua基因的3期健康结局研究在血友病B (HOPE-B)试验评估中,在接受因子(F)IX预防治疗的引入期(≥6个月)后,对重度或中重度血友病B患者给予单剂量地扎帕洛夫韦。无论筛查时腺相关病毒血清5型(AAV5)中和抗体(NAb)状态如何,均纳入受试者。目的确定NAb阴性(NAb -) HOPE-B参与者基因治疗后4年的疗效、药代动力学和安全性结果。方法参与者在输注地扎帕韦前提供血清样本,采用体外AAV5转导抑制法测定AAV5 NAb。在此时间点为AAV5 NAb -的参与者在事后亚组分析中进行检查。结果在NAb−参与者(N = 33)中,经调整后的平均年化出血率在注射dezaparvovec后7至48个月显著降低(0.57 vs 3.80; P < 0.0001)。在第1 ~ 4年,年化出血率分别为0.99、0.72、0.41和0.41 (P <; 0.0001 vs引入组;N = 33)。注射后第6个月(N = 33),内源性FIX的平均(SD)活性为40.6 IU/dL(18.6),保持稳定,第4年(N = 33)为39.0 IU/dL(16.8)。与引入期相比,在第7至48个月期间,外源性FIX消耗减少了99%,并且没有NAb -参与者在输注后4年内恢复持续的FIX预防。没有观察到与治疗相关的致癌事件或持续的晚期肝毒性。结论etranacogene dezaparvovec对重度或中重度乙型血友病NAb患者输注后4年是安全的,在出血保护方面优于FIX预防。
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引用次数: 0
Mutations of six amino acid residues in a B domain-deleted blood coagulation factor VIII have a cumulative effect on increasing its secretion 血凝因子VIII B结构域缺失的6个氨基酸残基突变对其分泌增加具有累积效应
IF 3.4 3区 医学 Q2 HEMATOLOGY Pub Date : 2026-01-01 DOI: 10.1016/j.rpth.2025.103325
Bo Shi , Philip Olivares , Leonid A. Parunov , Yideng Liang , Haarin Chun , Wells W. Wu , Vijaya L. Simhadri , Pratima Bajgain , Wojciech Jankowski , Margarita Krivega , Julia Poniatowski , Elizabeth Del Greco , Ivan Krivega , Svetlana A. Shestopal , Abu Hasanat Md Zulfiker , Zuben E. Sauna , Andrey G. Sarafanov

Background

High levels of factor VIII (FVIII) expression are needed for various applications to treat Hemophilia A. Besides deletion of the B-domain (BDD) and codon-optimization, F309S mutation, and other 5 mutations (X5) in FVIII were previously described to increase its expression.

Objectives

To investigate whether combining the 6 aforementioned mutations (X6) results in a further increase of FVIII expression.

Methods

The 5 (X5) and 6 (X6) mutations were introduced into a BDD-FVIII (wild-type [WT]), and proteins were expressed in cell cultures with different transgene copy numbers, purified, and tested for specific activity, binding to von Willebrand factor and a low-density lipoprotein receptor-related protein fragment, tyrosine sulfation levels and immunogenicity in silico and in human T-cell culture. The 6 mutations were also reproduced in full-length FVIII (FL-FVIII) and tested for secretion levels.

Results

From the single-copy transgene cell lines, secretion levels of X5 and X6 increased 1.6-fold and 2.3-fold, respectively, compared with WT. These levels increased proportionally with increasing transgene copy number, approaching saturation. The specific activity, binding to von Willebrand factor and lipoprotein receptor-related protein fragment, and assessments of immunogenicity of X6 in model systems were similar to WT, while tyrosine sulfation levels, were moderately lower at the highest gene dose. However, the 6 mutations reproduced in FL-FVIII did not result in increased secretion.

Conclusion

Combining the 6 mutations in BDD-FVIII improved its expression and did not affect general protein properties, making it promising for future product development. The data also indicate that BDD-FVIII and FL-FVIII have different expression mechanisms.
在治疗a型血友病的各种应用中,需要高水平表达因子VIII (FVIII)。除了b结构域(BDD)的缺失和密码子优化,FVIII中的F309S突变和其他5个突变(X5)先前被描述为增加其表达。目的探讨联合上述6种突变(X6)是否会导致FVIII表达进一步升高。方法将5 (X5)和6 (X6)突变基因导入野生型BDD-FVIII(野生型[WT]),在不同转基因拷贝数的细胞培养中表达蛋白,纯化蛋白,并在硅细胞和人t细胞培养中检测特异性活性、与血管性血通病因子和低密度脂蛋白受体相关蛋白片段的结合、酪氨酸硫酸化水平和免疫原性。6个突变也在全长FVIII (FL-FVIII)中复制,并检测其分泌水平。结果在单拷贝转基因细胞系中,X5和X6的分泌水平分别比WT增加1.6倍和2.3倍,随着转基因拷贝数的增加,X5和X6的分泌水平成比例增加,接近饱和。X6在模型系统中的特异性活性、与血管性血血病因子和脂蛋白受体相关蛋白片段的结合以及免疫原性评估与WT相似,而酪氨酸硫化水平在最高基因剂量下略低。然而,在FL-FVIII中复制的6个突变并未导致分泌增加。结论BDD-FVIII的6个突变组合提高了BDD-FVIII的表达,且不影响其一般蛋白特性,具有良好的产品开发前景。数据还表明BDD-FVIII和FL-FVIII具有不同的表达机制。
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引用次数: 0
Health-related quality of life and mental health in autoimmune thrombotic thrombocytopenic purpura patients in the caplacizumab era 卡普拉珠单抗时代自身免疫性血栓性血小板减少性紫癜患者的健康相关生活质量和心理健康
IF 3.4 3区 医学 Q2 HEMATOLOGY Pub Date : 2026-01-01 DOI: 10.1016/j.rpth.2025.103297
Julia Weisinger , Christina Tites , Laurent Gilardin , Aki Baba , Ygal Benhamou , Elie Azoulay , Jean-Francois Augusto , Thomas Papo , Claire Cartery , Olivier Moranne , Gabriel Choukroun , Loïc Lièvre , Jehane Fadlallah , Pascale Poullin , Arnaud Jaccard , Claire Presne , Bérangère Joly , Agnès Veyradier , Raida Bouzid , Paul Coppo

Background

Despite improvement in acute care of immune-mediated thrombotic thrombocytopenic purpura (iTTP), numerous studies showed that patients with iTTP have inferior mental health and health-related quality of life (HRQoL). Caplacizumab led to shorter hospitalization, less plasma exchange, and improved survival in iTTP and might influence long-term HRQoL.

Objectives

We aimed to address the impact of iTTP on HRQoL, posttraumatic stress disease, depression, and anxiety, as well as the possible role of caplacizumab on improving these features.

Methods

We conducted a survey among patients with iTTP enrolled in the French thrombotic microangiopathy registry: patients completed the Short Form (SF)-36 HRQoL, the Hospital Anxiety and Depression Scale screening for anxiety and depression, and the Posttraumatic Stress Disorder Checklist for DSM-IV posttraumatic stress disease questionnaires. Results were compared to those of a sample of the French general population.

Results

A total of 101 patients with iTTP in remission (45 patients previously treated with caplacizumab and 56 patients without caplacizumab) and 76 healthy controls were included. Patients with iTTP had significantly lower scores in all domains in the SF-36 survey and higher anxiety and depression scores than healthy controls. Advanced age was associated with improved SF-36 scores, lower anxiety scores and less severe anxiety cases. Furthermore, the use of caplacizumab led to a lower risk of severe anxiety.

Conclusion

Based on our results, HRQoL is decreased in patients with iTTP, and depression and anxiety are more prevalent. Caplacizumab treatment might influence long-term mental and psychological outcomes in iTTP by shortening the duration of treatment with plasma exchange.
尽管免疫介导的血栓性血小板减少性紫癜(iTTP)的急性护理有所改善,但大量研究表明,iTTP患者的心理健康和健康相关生活质量(HRQoL)较差。卡普拉珠单抗缩短了iTTP患者的住院时间,减少了血浆置换,提高了患者的生存率,并可能影响长期HRQoL。目的:研究iTTP对HRQoL、创伤后应激疾病、抑郁和焦虑的影响,以及卡普拉珠单抗在改善这些特征方面的可能作用。方法对法国血栓性微血管病登记的iTTP患者进行调查:患者完成短表(SF)-36 HRQoL,医院焦虑和抑郁量表筛查焦虑和抑郁,以及DSM-IV创伤后应激障碍检查表问卷。结果与法国普通人群的样本进行了比较。结果共纳入101例缓解期iTTP患者(45例既往卡普拉珠单抗治疗,56例未卡普拉珠单抗治疗)和76例健康对照。与健康对照组相比,iTTP患者在SF-36调查中所有领域的得分都明显较低,焦虑和抑郁得分较高。年龄越大,SF-36评分越高,焦虑评分越低,焦虑病例越少。此外,卡普拉珠单抗的使用降低了严重焦虑的风险。结论iTTP患者HRQoL下降,抑郁和焦虑更为普遍。卡普拉珠单抗治疗可能通过缩短血浆置换治疗的持续时间来影响iTTP患者的长期精神和心理结局。
{"title":"Health-related quality of life and mental health in autoimmune thrombotic thrombocytopenic purpura patients in the caplacizumab era","authors":"Julia Weisinger ,&nbsp;Christina Tites ,&nbsp;Laurent Gilardin ,&nbsp;Aki Baba ,&nbsp;Ygal Benhamou ,&nbsp;Elie Azoulay ,&nbsp;Jean-Francois Augusto ,&nbsp;Thomas Papo ,&nbsp;Claire Cartery ,&nbsp;Olivier Moranne ,&nbsp;Gabriel Choukroun ,&nbsp;Loïc Lièvre ,&nbsp;Jehane Fadlallah ,&nbsp;Pascale Poullin ,&nbsp;Arnaud Jaccard ,&nbsp;Claire Presne ,&nbsp;Bérangère Joly ,&nbsp;Agnès Veyradier ,&nbsp;Raida Bouzid ,&nbsp;Paul Coppo","doi":"10.1016/j.rpth.2025.103297","DOIUrl":"10.1016/j.rpth.2025.103297","url":null,"abstract":"<div><h3>Background</h3><div>Despite improvement in acute care of immune-mediated thrombotic thrombocytopenic purpura (iTTP), numerous studies showed that patients with iTTP have inferior mental health and health-related quality of life (HRQoL). Caplacizumab led to shorter hospitalization, less plasma exchange, and improved survival in iTTP and might influence long-term HRQoL.</div></div><div><h3>Objectives</h3><div>We aimed to address the impact of iTTP on HRQoL, posttraumatic stress disease, depression, and anxiety, as well as the possible role of caplacizumab on improving these features.</div></div><div><h3>Methods</h3><div>We conducted a survey among patients with iTTP enrolled in the French thrombotic microangiopathy registry: patients completed the Short Form (SF)-36 HRQoL, the Hospital Anxiety and Depression Scale screening for anxiety and depression, and the Posttraumatic Stress Disorder Checklist for DSM-IV posttraumatic stress disease questionnaires. Results were compared to those of a sample of the French general population.</div></div><div><h3>Results</h3><div>A total of 101 patients with iTTP in remission (45 patients previously treated with caplacizumab and 56 patients without caplacizumab) and 76 healthy controls were included. Patients with iTTP had significantly lower scores in all domains in the SF-36 survey and higher anxiety and depression scores than healthy controls. Advanced age was associated with improved SF-36 scores, lower anxiety scores and less severe anxiety cases. Furthermore, the use of caplacizumab led to a lower risk of severe anxiety.</div></div><div><h3>Conclusion</h3><div>Based on our results, HRQoL is decreased in patients with iTTP, and depression and anxiety are more prevalent. Caplacizumab treatment might influence long-term mental and psychological outcomes in iTTP by shortening the duration of treatment with plasma exchange.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103297"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145885112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Mortality and complications in low-dose vs standard-dose unfractionated heparin anticoagulation for extracorporeal membrane oxygenation: a systematic review and meta-analysis 低剂量与标准剂量肝素抗凝用于体外膜氧合的死亡率和并发症:一项系统回顾和荟萃分析
IF 3.4 3区 医学 Q2 HEMATOLOGY Pub Date : 2026-01-01 DOI: 10.1016/j.rpth.2025.102732
Wincy Wing-Sze Ng , Rex Wan-Hin Hui , Ka-Chun Leung , Pauline Yeung Ng , Chun-Wai Ngai , Simon Wai-Ching Sin , Chun-Fung Sin

Background

Controversies exist in anticoagulation practices in extracorporeal membrane oxygenation (ECMO). It is uncertain whether the intensity of anticoagulation affects ECMO outcomes.

Objectives

To conduct a meta-analysis to determine whether anticoagulation intensity affects ECMO outcomes.

Methods

The Medical Literature Analysis and Retrieval System Online, Embase, and Central Register of Controlled Trials’ databases were searched from inception to October 2024 for trials comparing the use of low-dose (LD) and standard-dose unfractionated heparin anticoagulation in patients on ECMO. The primary outcome was short-term mortality. Secondary outcomes included major bleeding events, intracranial hemorrhage (ICH), oxygenator changes, systemic thrombotic events, and ECMO duration. Data were pooled using a random-effects meta-analysis. The risk-of-bias was assessed using the Cochrane Risk-of-Bias 2 tool for randomized controlled trials and the Risk-of-Bias in Non-Randomized Studies of Interventions for nonrandomized controlled trials.

Results

Seven studies with 619 patients were included. LD anticoagulation was associated with significant reduction in the relative risk (RR) of mortality compared to standard-dose anticoagulation (RR, 0.69; 95% CI, 0.52-0.91; I2 = 38%). Patients receiving LD anticoagulation had significantly lower risk of ICH (RR, 0.29; 95% CI, 0.13-0.63, I2 = 0%), while the risk of major bleeding events was not significantly different between groups (RR, 0.78; 95% CI, 0.51-1.21; I2 = 55%). LD anticoagulation did not significantly increase the risk of oxygenator changes (RR, 1.54; 95% CI, 0.94-2.53; I2 = 42%) or systemic thrombotic events (RR, 1.27; 95% CI, 0.88-1.84; I2 = 0%).

Conclusion

This meta-analysis suggests that LD unfractionated heparin anticoagulation is associated with significantly better survival and a lower risk of ICH without an increase in the risk of thrombotic events. LD anticoagulation should be considered a reasonable strategy in ECMO.
背景体外膜氧合(ECMO)抗凝实践存在争议。抗凝强度是否影响ECMO结果尚不确定。目的通过荟萃分析确定抗凝强度是否影响ECMO结果。方法检索医学文献分析与检索系统(Medical Literature Analysis and Retrieval System Online)、Embase和Central Register of Controlled Trials数据库,检索从成立到2024年10月ECMO患者使用低剂量(LD)和标准剂量未分级肝素抗凝治疗的比较试验。主要结局是短期死亡率。次要结局包括大出血事件、颅内出血(ICH)、氧合器改变、全身血栓形成事件和ECMO持续时间。采用随机效应荟萃分析汇总数据。对随机对照试验使用Cochrane risk-of-bias 2工具评估偏倚风险,对非随机对照试验使用干预措施的非随机研究评估偏倚风险。结果纳入7项研究,619例患者。与标准剂量抗凝相比,LD抗凝与死亡率相对风险(RR)显著降低相关(RR, 0.69; 95% CI, 0.52-0.91; I2 = 38%)。接受LD抗凝治疗的患者发生ICH的风险显著降低(RR, 0.29; 95% CI, 0.13-0.63, I2 = 0%),而组间大出血事件的风险无显著差异(RR, 0.78; 95% CI, 0.51-1.21; I2 = 55%)。LD抗凝没有显著增加氧合器改变的风险(RR, 1.54; 95% CI, 0.94-2.53; I2 = 42%)或系统性血栓形成事件(RR, 1.27; 95% CI, 0.88-1.84; I2 = 0%)。结论:该荟萃分析表明,LD非分级肝素抗凝与更好的生存率和更低的脑出血风险相关,而不会增加血栓事件的风险。在ECMO中,LD抗凝应被视为一种合理的策略。
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引用次数: 0
“DOACs for Left Ventricular Thrombus: Persistent Equipoise Despite New Observational and Randomized Data”: comment “左心室血栓DOACs:尽管有新的观察和随机数据,但仍保持平衡”:评论
IF 3.4 3区 医学 Q2 HEMATOLOGY Pub Date : 2026-01-01 DOI: 10.1016/j.rpth.2025.103339
Artur Dziewierz , Piotr Jarosz , Tomasz Rakowski
{"title":"“DOACs for Left Ventricular Thrombus: Persistent Equipoise Despite New Observational and Randomized Data”: comment","authors":"Artur Dziewierz ,&nbsp;Piotr Jarosz ,&nbsp;Tomasz Rakowski","doi":"10.1016/j.rpth.2025.103339","DOIUrl":"10.1016/j.rpth.2025.103339","url":null,"abstract":"","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103339"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145978190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
期刊
Research and Practice in Thrombosis and Haemostasis
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