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Genetic variants, thrombocytopenia, and clinical phenotype of type 2B von Willebrand disease: a median 16-year follow-up study. 2B 型 von Willebrand 病的基因变异、血小板减少和临床表型:一项中位 16 年随访研究。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-28 DOI: 10.1016/j.jtha.2024.08.028
Calvin B van Kwawegen, Ferdows Atiq, Dara Endenburg, Karin Fijnvandraat, Karin P M van Galen, Marjon H Cnossen, Saskia E M Schols, Marieke J H A Kruip, Waander L van Heerde, Joke de Meris, Johanna G van der Bom, Jeroen Eikenboom, Karina Meijer, Frank W G Leebeek

Background: Type 2B von Willebrand disease (VWD) is a bleeding disorder caused by gain-of-function variants in the VWF gene. The laboratory and clinical phenotype of type 2B VWD is heterogeneous.

Objectives: We investigated associations between genotype and phenotype over a median of 16 years follow-up in a large cohort of well-characterized patients.

Methods: We included 64 genetically confirmed type 2B VWD patients from the national multicenter "Willebrand in the Netherlands" study and retrospectively collected clinical and laboratory data from electronic patient records. We analyzed associations between genotype and thrombocytopenia, bleeding phenotype, and events leading to endothelial activation and von Willebrand factor (VWF) secretion, including surgery, desmopressin administration, pregnancy, and delivery.

Results: Thrombocytopenia manifested in 67.2% of patients, with varying occurrences between genetic variants (p.Arg1306Trp: 75.0%, p.Arg1308Cys: 58.3%). The most important determinant of thrombocytopenia was the p.Arg1306Trp VWF variant (odds ratio, 25.1). Platelet counts strongly varied over time and were continuously <150 × 109/L in 37.5% of patients with p.Arg1306Trp vs 8.3% in p.Arg1308Cys. In our analysis, endothelial activation was not an independent determinant (odds ratio, 1.3) for thrombocytopenia occurrence. No association was found between thrombocytopenia and cumulative bleeding scores or annual bleeding rates. Four women showed declining platelet counts in all full-term pregnancies (n = 8) during the third trimester with a sharp decrease in the week before delivery. Postpartum hemorrhage, defined as >500 mL estimated blood loss at delivery, occurred in 5 of 8 deliveries, despite prophylactic treatment with VWF concentrates.

Conclusion: This study reveals a strong association between VWF variant p.Arg1306Trp and thrombocytopenia in type 2B VWD patients.

背景/目的:2B 型冯-威廉氏病(VWD)是由 VWF 基因的功能增益变异引起的出血性疾病。2B 型的实验室和临床表型各不相同。我们对一大批特征明确的患者进行了中位 16 年的随访,研究了基因型与表型之间的关联:我们纳入了 64 名经基因证实的 2B 型 VWD 患者,这些患者来自全国多中心 "荷兰的威廉"(WiN)研究,并从电子病历中回顾性地收集了临床和实验室数据。我们分析了基因型与血小板减少症、出血表型以及导致内皮激活和 VWF 分泌的事件(包括手术、去氨加压素用药、妊娠和分娩)之间的关系:67.2%的患者表现为血小板减少,不同基因变异的发生率不同(p.Arg1306Trp:75.0%;p.Arg1308Cys:58.3%)。决定血小板减少的最重要因素是 p.Arg1306Trp VWF 变异(OR 25.1)。血小板计数随时间变化很大,p.Arg1306Trp 患者中有 37.5%的血小板计数持续为 9,而 p.Arg1308Cys 患者中只有 8.3%的血小板计数持续为 9。在我们的分析中,内皮活化不是血小板减少症发生的独立决定因素(OR 1.3)。血小板减少与累积出血评分或年出血率之间没有关联。在所有足月妊娠(n=8)中,有四名妇女的血小板计数在妊娠三个月内下降,并在分娩前一周急剧下降。尽管使用 VWF 浓缩物进行了预防性治疗,但仍有 5/8 例分娩发生了产后出血(定义为分娩时估计失血量大于 500 毫升):本研究揭示了 VWF 变体 p.Arg1306Trp 与 2B 型患者血小板减少症之间的密切联系。
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引用次数: 0
Incidence, risk factors, and outcomes of patients with monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia who develop venous thromboembolism. 单克隆 B 细胞淋巴细胞增多症和慢性淋巴细胞白血病患者发生静脉血栓栓塞的发病率、风险因素和预后。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-27 DOI: 10.1016/j.jtha.2024.08.029
Amber B Koehler, Kari G Rabe, Daniel J Crusan, Timothy G Call, Sara J Achenbach, Paul J Hampel, Saad S Kenderian, Jose F Leis, Yucai Wang, Eli Muchtar, Mazie Tsang, Talal Hilal, Ricardo Parrondo, Kent R Bailey, Wei Ding, Rachel Bailen, Susan M Schwager, Min Shi, Curtis A Hanson, Susan L Slager, Neil E Kay, Aneel A Ashrani, Sameer A Parikh

Background: The incidence, risk factors, and outcomes of venous thromboembolism (VTE) in patients with chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL) are not well described.

Objectives: We aimed to determine the clinical characteristics, risk factors, and outcomes of incident VTE in patients with newly diagnosed MBL/CLL and compare the incidence to the age- and sex-matched general population.

Methods: Using the Mayo Clinic CLL Database, we identified 946 patients with newly diagnosed MBL/CLL between 1998 and 2021. Incidence of VTE was identified by querying the electronic health record for VTE-specific International Classification of Diseases-9 and -10 codes and reviewing results of radiographic studies.

Results: Eighty patients developed VTE. The incidence of VTE in patients with newly diagnosed MBL/CLL was ∼1% per year. In multivariable analyses, prior history of VTE (hazard ratio [HR]: 5.33; 95% CI: 1.93-14.68, P = .001) and high/very high-risk CLL-International Prognostic Index score (HR: 2.63; 95% CI: 1.31-5.26; P = .006) were associated with an increased risk of VTE; receipt of CLL treatment or occurrence of nonhematologic malignancy was not. Development of VTE was associated with shorter overall survival (HR: 1.82, 95% CI: 1.30-2.55) after adjusting for age, sex, prior history of VTE, and Rai stage. The age- and sex-adjusted VTE incidence rate for patients with MBL/CLL and no prior history of VTE (n = 904) was 1254 per 100 000 person-years compared with 204 per 100 000 person-years in the general population, reflecting a 5.9-fold increase.

Conclusion: Our study demonstrates a 6-fold increased risk of VTE in patients with MBL/CLL compared with the age- and sex-matched general population.

背景:慢性淋巴细胞白血病(CLL)和单克隆B细胞淋巴细胞增多症(MBL)患者静脉血栓栓塞症(VTE)的发病率、风险因素和预后尚未得到很好的描述:我们旨在确定新确诊的 MBL/CLL 患者发生 VTE 的临床特征、风险因素和结果,并将其发生率与年龄和性别匹配的普通人群进行比较:利用梅奥诊所 CLL 数据库,我们确定了 1998-2021 年间新确诊的 946 名 MBL/CLL 患者。通过查询电子病历中与 VTE 相关的 ICD-9 和 ICD-10 编码并查看放射学检查结果,确定了 VTE 的发生率:结果:80 名患者发生了 VTE。新确诊的 MBL/CLL 患者的 VTE 发生率为每年 1%。在多变量分析中,既往VTE病史(HR:5.33,95% CI:1.93-14.68,P=0.001)和高/极高风险CLL-国际预后指数评分(HR:2.63,95% CI:1.31-5.26,P=0.006)与VTE风险增加有关;接受CLL治疗或发生非血液恶性肿瘤则与之无关。在调整了年龄、性别、VTE既往史和莱氏分期后,VTE的发生与较短的总生存期相关(HR:1.82,95% CI:1.30-2.55)。经年龄和性别调整后,无VTE既往史的MBL/CLL患者(n=904)的VTE发病率为每10万人年1,254例,而普通人群为每10万人年204例,增加了5.9倍:我们的研究表明,与年龄和性别匹配的普通人群相比,MBL/CLL 患者发生 VTE 的风险增加了 6 倍。
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引用次数: 0
Genetic engineering of megakaryocytes from blood progenitor cells using messenger RNA lipid nanoparticles. 利用 mRNA 脂质纳米颗粒对血液祖细胞中的巨核细胞进行基因工程改造。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-26 DOI: 10.1016/j.jtha.2024.09.008
Jerry Leung, Asel Primbetova, Colton Strong, Brenna N Hay, Han Hsuan Hsu, Andrew Hagner, Leonard J Foster, Dana Devine, Pieter R Cullis, Peter W Zandstra, Christian J Kastrup

Background: Platelets are an essential component of hemorrhage control and management, and engineering platelets to express therapeutic proteins could expand their use as a cell therapy. Genetically engineered platelets can be achieved by modifying the platelet precursor cells, megakaryocytes (MKs). Current strategies include transfecting MK progenitors ex vivo with viral vectors harboring lineage-driven transgenes and inducing the production of in vitro modified platelets. The use of viruses, however, poses challenges in clinical implementation, and no methods currently exist to genetically modify MKs with nonviral techniques. Lipid nanoparticles (LNPs) are a nonviral delivery system that could enable a facile strategy to modify MKs with a variety of nucleic acid payloads.

Objectives: To investigate whether LNPs can transfect cultured hematopoietic stem/progenitor cell-derived MKs to express exogenous proteins and induce functional changes.

Methods: MK and MK progenitors differentiated from cord blood-derived hematopoietic stem/progenitor cells were treated with LNP formulations containing messenger RNA and resembling the clinically approved LNP formulations. Transfection efficiency was assessed through flow cytometry by expression of enhanced green fluorescent protein. Functional changes to the MKs were assessed through rotational thromboelastometry by expression of exogenous coagulation factor (F)VII, a representative physiologically relevant protein.

Results: LNPs enabled transfection efficiencies of 99% in MKs and did not impair MK maturation, viability, and morphology. MKs engineered to express exogenous FVII decreased clotting time in FVII-deficient plasma following clot initiation.

Conclusion: This approach provides an easy-to-use modular platform to genetically modify MK and MK progenitors, which can be potentially extended to producing genetically modified cultured platelets.

背景:血小板是控制和处理出血的重要组成部分,通过工程改造血小板来表达治疗蛋白可扩大血小板作为细胞疗法的用途。基因工程血小板可通过改造血小板前体细胞巨核细胞(MK)来实现。目前的策略包括在体外用携带品系驱动转基因的病毒载体转染巨核细胞祖细胞,诱导产生 "体外 "改造血小板。然而,病毒的使用给临床应用带来了挑战,目前还没有利用非病毒技术对 MK 进行基因改造的方法。脂质纳米颗粒(LNP)是一种非病毒递送系统,能以简便的策略用各种核酸载荷修饰 MKs:目的:研究LNP是否能转染培养的造血干细胞/祖细胞(HSPC)衍生的MK,使其表达外源蛋白并诱导功能变化:方法:用含有mRNA的脂质纳米颗粒制剂(类似于临床批准的LNP制剂)处理从脐血衍生的HSPC分化而来的MK和MK祖细胞。转染效率通过增强型绿色荧光蛋白表达的流式细胞术进行评估。通过表达外源性凝血因子 VII(FVII)(一种具有代表性的生理相关蛋白),采用旋转血栓弹力仪评估 MK 的功能变化:结果:LNP 可使 MK 的转染效率达到 99%,并且不会影响 MK 的成熟、活力和形态。表达外源 FVII 的 MK 在 FVII 缺乏的血浆中可缩短凝血开始后的凝血时间:这种方法提供了一个易于使用的模块化平台,用于对 MK 和 MK 祖细胞进行基因修饰,并有可能扩展到生产基因修饰的培养血小板。
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引用次数: 0
Circulating tumor DNA predicts venous thromboembolism in patients with cancers. 循环肿瘤 DNA 可预测癌症患者的静脉血栓栓塞。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-26 DOI: 10.1016/j.jtha.2024.09.009
Shengling Ma, Jun Y Jiang, Rock Bum Kim, Elizabeth Chiang, Joyce Wan Theng Tiong, Justine Ryu, Danielle Guffey, Raka Bandyo, Heidi Dowst, Kaitlin N Swinnerton, Nathanael R Fillmore, Jennifer La, Ang Li

Introduction: Despite rapid advances in liquid biopsy for circulating tumor DNA (ctDNA), its prognostic value for venous thromboembolism (VTE) in patients with cancer is underexplored, particularly in underserved and minoritized populations.

Methods: We analyzed data from 1,038 cancer patients who underwent ctDNA measurement for oncologic care at a large safety-net hospital system in the US. We investigated the association between ctDNA and VTE after adjusting for cancer type, stage, treatment, and time from initial diagnosis using Fine-Gray models. We further assessed the discrimination of the genetic, clinical-only, and combined models using the area under the time-dependent receiver operating characteristic curve (AUC).

Results: The presence of pathogenic ctDNA was independently associated with VTE after adjusting for clinical variables. Independent of tumor type, the number of pathogenic ctDNA mutations was predictive of future VTE risk (adjusted subdistribution hazard ratio 2.75, 1.94, and 1.38 for ≥3, 2, and 1 pathogenic mutation, respectively, compared to none; p<0.0001). The association was primarily driven by mutations in KRAS, PTEN, CDKN2A, NF1, and EGFR genes. Compared to the clinical-only model (AUC 0.71, 95% CI 0.64-0.76), the combined clinical and ctDNA model had a numerically higher time-dependent AUC (AUC 0.74, 95% CI 0.67-0.80).

Conclusions: CtDNA testing may serve as an adjunctive tool to clinical risk assessment models in cancer patients to improve personalized VTE risk assessment and management.

导言:尽管循环肿瘤 DNA(ctDNA)的液体活检技术发展迅速,但其对癌症患者静脉血栓栓塞症(VTE)的预后价值尚未得到充分探索,尤其是在服务不足和少数群体中:我们分析了在美国一家大型安全网医院系统接受ctDNA检测的1038名肿瘤患者的数据。在使用 Fine-Gray 模型对癌症类型、分期、治疗和初始诊断时间进行调整后,我们研究了 ctDNA 与 VTE 之间的关联。我们使用时间依赖性接收器操作特征曲线下面积(AUC)进一步评估了基因模型、纯临床模型和组合模型的区分度:结果:在对临床变量进行调整后,致病性ctDNA的存在与VTE独立相关。与肿瘤类型无关,致病性ctDNA突变的数量可预测未来的VTE风险(与无致病性突变相比,≥3、2和1个致病性突变的调整亚分布危险比分别为2.75、1.94和1.38;p结论:CtDNA检测可作为癌症患者临床风险评估模型的辅助工具,以改善个性化的VTE风险评估和管理。
{"title":"Circulating tumor DNA predicts venous thromboembolism in patients with cancers.","authors":"Shengling Ma, Jun Y Jiang, Rock Bum Kim, Elizabeth Chiang, Joyce Wan Theng Tiong, Justine Ryu, Danielle Guffey, Raka Bandyo, Heidi Dowst, Kaitlin N Swinnerton, Nathanael R Fillmore, Jennifer La, Ang Li","doi":"10.1016/j.jtha.2024.09.009","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.09.009","url":null,"abstract":"<p><strong>Introduction: </strong>Despite rapid advances in liquid biopsy for circulating tumor DNA (ctDNA), its prognostic value for venous thromboembolism (VTE) in patients with cancer is underexplored, particularly in underserved and minoritized populations.</p><p><strong>Methods: </strong>We analyzed data from 1,038 cancer patients who underwent ctDNA measurement for oncologic care at a large safety-net hospital system in the US. We investigated the association between ctDNA and VTE after adjusting for cancer type, stage, treatment, and time from initial diagnosis using Fine-Gray models. We further assessed the discrimination of the genetic, clinical-only, and combined models using the area under the time-dependent receiver operating characteristic curve (AUC).</p><p><strong>Results: </strong>The presence of pathogenic ctDNA was independently associated with VTE after adjusting for clinical variables. Independent of tumor type, the number of pathogenic ctDNA mutations was predictive of future VTE risk (adjusted subdistribution hazard ratio 2.75, 1.94, and 1.38 for ≥3, 2, and 1 pathogenic mutation, respectively, compared to none; p<0.0001). The association was primarily driven by mutations in KRAS, PTEN, CDKN2A, NF1, and EGFR genes. Compared to the clinical-only model (AUC 0.71, 95% CI 0.64-0.76), the combined clinical and ctDNA model had a numerically higher time-dependent AUC (AUC 0.74, 95% CI 0.67-0.80).</p><p><strong>Conclusions: </strong>CtDNA testing may serve as an adjunctive tool to clinical risk assessment models in cancer patients to improve personalized VTE risk assessment and management.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142349114","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 intricate allostery in factor VIIa: triggering the trigger. 因子 VIIa 中错综复杂的异构体:触发器。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-26 DOI: 10.1016/j.jtha.2024.08.026
Jesper J Madsen, Egon Persson, Ole H Olsen

In the last couple of decades, numerous investigations have shed considerable light on how precisely factor (F)VIIa mediates the initiation of blood coagulation upon association with its cofactor, tissue factor (TF). The role of the cofactor in this process is indispensable under physiological conditions, serving as a membrane-tethering allosteric activator of FVIIa also interacting with substrates (eg, FX). Available evidence reveals the induction and manifestation of complex allostery within FVIIa when stimulated by TF, involving at least 2 connected pathways spanning the interactive interface of the FVIIa-TF complex and the functional segments of FVIIa. Carefully designed FVIIa variants demonstrate corresponding modulations of their properties and response to TF-triggered allostery and activation. In addition, antibodies can stimulate FVIIa activity in both similar and distinctly different ways compared to that employed by TF. The mechanistic insights obtained through basic biochemical investigations have been validated through select engineered FVIIa constructs which, even in vivo, demonstrate beneficial, proof-of-concept effects. Altogether, we have recently gained unprecedented knowledge about and control over FVIIa allostery, enabling us to influence FVIIa activity in advanced manners and in a desired direction. Here, we summarize our current understanding of the allosteric activation of FVIIa ending up with some prospects of future investigations.

在过去几十年中,大量研究揭示了因子 VIIa(FVIIa)与其辅助因子组织因子(TF)结合后如何精确介导血液凝固的启动过程。在生理条件下,辅助因子在这一过程中的作用是不可或缺的,它是 FVIIa 的膜系异位激活剂,还能与底物(如因子 X)相互作用。现有证据显示,在 TF 的刺激下,FVIIa 内的复杂异构体会被诱导并表现出来,这至少涉及两条相互连接的途径,横跨 FVIIa-TF 复合物的交互界面和 FVIIa 的功能片段。精心设计的 FVIIa 变体对其特性和对 TF 触发的异位和活化的反应有相应的调节作用。此外,与 TF 所采用的方式相比,抗体既能以相似的方式刺激 FVIIa 的活性,也能以截然不同的方式刺激 FVIIa 的活性。通过基础生化研究获得的机理认识已通过精选的工程 FVIIa 构建物得到验证,这些构建物甚至在体内也能显示出有益的概念验证效果。总之,我们最近对 FVIIa 异构体获得了前所未有的了解和控制,使我们能够以先进的方式和所需的方向影响 FVIIa 的活性。在此,我们总结了目前我们对 FVIIa 异构激活的理解,并展望了未来研究的一些前景。
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引用次数: 0
Invasive procedures and surgery following etranacogene dezaparvovec gene therapy in people with hemophilia B. 血友病 B 患者接受 etranacogene dezaparvovec 基因治疗后的侵入性程序和手术。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-26 DOI: 10.1016/j.jtha.2024.08.027
Niamh O'Connell, Paul van der Valk, Sandra Le Quellec, Esteban Gomez, Paul E Monahan, Shelley E Crary, Michiel Coppens, Richard Lemons, Giancarlo Castaman, Robert Klamroth, Emily Symington, Doris V Quon, Peter Kampmann

Background: Little information regarding the management of invasive procedures in people with hemophilia B (HB) after undergoing gene therapy is available. Here, we report the management of invasive procedures in people with severe or moderately severe HB who had previously been treated with etranacogene dezaparvovec in the phase 2b and phase 3 Health Outcomes with Padua Gene; Evaluation in Hemophilia B clinical trials (NCT03489291 and NCT03569891).

Objectives: The objective of this study was to describe the use of exogenous FIX, endogenous FIX activity prior to invasive procedures, and peri- and postoperative bleeds in participants who underwent invasive procedures after receiving etranacogene dezaparvovec gene therapy.

Methods: This retrospective analysis included invasive procedures performed within 3 and 2 years following a single infusion of 2 × 1013 gc/kg of etranacogene dezaparvovec in participants in the phase 2b and Health Outcomes with Padua Gene; Evaluation in Hemophilia B trials, respectively. Data for factor (F)IX dosing, duration of postoperative FIX use, FIX activity prior to invasive procedures, and postoperative bleeds were collected and analyzed.

Results: The analysis included 64 procedures in 29 participants: 9 major surgeries, 24 minor surgeries, 11 endoscopies, 3 endoscopies with biopsy/polypectomy, and 17 dental procedures. Uncontaminated endogenous FIX activity corresponded to mild hemophilia or normal levels prior to 98% of all procedures, with a median endogenous FIX activity of 43.8 IU/dL (range, 3.1-113 IU/dL). All major surgeries were managed with exogenous FIX, 67% with ≤4 days of FIX infusion. Most minor surgeries (88%), endoscopies (82%), and dental procedures (94%) were managed with no or a single FIX infusion. Postoperative bleeds occurred after 1 minor surgery and 4 dental procedures. There were no symptomatic thrombotic events or FIX inhibitor developments.

Conclusion: Etranacogene dezaparvovec has the potential to facilitate perioperative management in people with HB by reducing the need for perioperative exogenous FIX and its associated risks.

背景:有关血友病 B(HB)患者接受基因治疗后侵入性程序管理的信息很少。在此,我们报告了曾在 2b 期和 3 期 HOPE-B 临床试验(NCT03489291、NCT03569891)中接受 etranacogene dezaparvovec 治疗的重度或中度 HB 患者的侵入性手术管理情况:这项回顾性分析包括分别在 2b 期和 HOPE-B 期临床试验参与者单次输注 2x1013 gc/kg etranacogene dezaparvovec 后 3 年和 2 年内进行的侵入性手术。收集并分析了FIX剂量、术后使用FIX的持续时间、侵入性手术前的FIX活性以及术后出血等数据:分析包括 29 名参与者的 64 项手术:9 项大手术、24 项小手术、11 项内窥镜手术、3 项带活检/息肉切除术的内窥镜手术和 17 项牙科手术。在 98% 的手术前,未受污染的内源性 FIX 活性相当于轻度血友病或正常水平,内源性 FIX 活性中位数为 43.8 IU/dL(范围为 3.1-113 IU/dL)。所有大手术都使用外源性 FIX,67% 的手术输注 FIX 的时间少于 4 天。大多数小手术(88%)、内窥镜手术(82%)和牙科手术(94%)无需输注或只需输注一次 FIX。在一次小手术和四次牙科手术后发生了术后出血。没有出现无症状血栓事件或FIX抑制剂不良反应:结论:Etranacogene dezaparvovec 有可能减少围手术期外源性 FIX 的需求及其相关风险,从而促进 HB 患者的围手术期管理。
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引用次数: 0
A novel role for thioredoxin-related transmembrane protein TMX4 in platelet activation and thrombus formation. 硫氧还蛋白相关跨膜蛋白 TMX4 在血小板活化和血栓形成中的新作用
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-20 DOI: 10.1016/j.jtha.2024.09.007
Zhenzhen Zhao, Yucan Wang, Aizhen Yang, Yi Lu, Xiaofeng Yan, Meinan Peng, Yue Han, Chao Fang, Depei Wu, Yi Wu

Background: The functions of critical platelet proteins are controlled by thiol-disulfide exchanges, which are mediated by the protein disulfide isomerase (PDI) family. It has been shown that some PDI family members are important in platelet activation and thrombosis with distinct functions. TMX4, a membrane-type PDI family member, is expressed in platelets, but whether it has a role in platelet activation remains unknown.

Objectives: To determine the role of TMX4 in platelet activation and thrombosis.

Methods: The phenotypes of TMX4-deficient mice were evaluated in tail bleeding time assay and laser-induced and FeCl3-induced arterial injury models. The functions of TMX4 in platelets were assessed in vitro using TMX4-null platelets, recombinant TMX4 protein, and anti-TMX4 antibody.

Results: Compared with the control mice, Tie2-Cre/TMX4fl/fl mice deficient of hematopoietic and endothelial TMX4 exhibited prolonged tail bleeding times and reduced platelet thrombus formation. Pf4-Cre/TMX4fl/fl mice deficient of platelet TMX4 also had prolonged tail bleeding times and decreased thrombus formation, which was rescued by injection of recombinant TMX4 protein. Consistently, TMX4 deficiency inhibited platelet aggregation, integrin αIIbβ3 activation, P-selectin expression, phosphatidylserine exposure, and thrombin generation, without affecting tyrosine phosphorylation of intracellular signaling molecules Syk, LAT, PLCγ2 and calcium mobilization. Recombinant TMX4 protein enhanced platelet aggregation and reduced integrin αIIbβ3 disulfide bonds, and TMX4 deficiency decreased free thiols of integrin αIIbβ3, consistent with a potent reductase activity of TMX4. In contrast, an inactive TMX4 protein and a specific anti-TMX4 antibody inhibited platelet aggregation.

Conclusion: TMX4 is a novel PDI family member that enhances platelet activation and thrombosis.

背景:关键血小板蛋白的功能由硫醇-二硫化物交换控制,而硫醇-二硫化物交换是由蛋白二硫化物异构酶(PDI)家族介导的。研究表明,一些 PDI 家族成员在血小板活化和血栓形成过程中起着重要作用,并具有不同的功能。TMX4是一种膜型PDI家族成员,在血小板中表达,但它在血小板活化中是否发挥作用仍不清楚:确定 TMX4 在血小板活化和血栓形成中的作用:方法:在尾部出血时间测定、激光诱导和氯化铁诱导的动脉损伤模型中评估 TMX4 基因缺陷小鼠的表型。使用TMX4无效血小板、重组TMX4蛋白和抗TMX4抗体在体外评估了TMX4在血小板中的功能:结果:与对照组小鼠相比,缺乏造血和内皮 TMX4 的 Tie2-Cre/TMX4fl/fl 小鼠表现出尾部出血时间延长和血小板血栓形成减少。缺乏血小板 TMX4 的 Pf4-Cre/TMX4fl/fl 小鼠也会出现尾部出血时间延长和血栓形成减少的情况,注射重组 TMX4 蛋白后血栓形成可被挽救。同样,TMX4 缺乏可抑制血小板聚集、整合素 αⅡbβ3 活化、P-选择素表达、磷脂酰丝氨酸暴露和凝血酶生成,但不影响细胞内信号分子 Syk、LAT 和 PLCγ2 的酪氨酸磷酸化以及钙动员。重组 TMX4 蛋白增强了血小板聚集,减少了整合素 αIIbβ3 的二硫键,缺乏 TMX4 会减少整合素 αIIbβ3 的游离硫醇,这与 TMX4 强大的还原酶活性一致。相反,非活性 TMX4 蛋白和特异性抗 TMX4 抗体可抑制血小板聚集:结论:TMX4 是一种新型 PDI 家族成员,可增强血小板活化和血栓形成。
{"title":"A novel role for thioredoxin-related transmembrane protein TMX4 in platelet activation and thrombus formation.","authors":"Zhenzhen Zhao, Yucan Wang, Aizhen Yang, Yi Lu, Xiaofeng Yan, Meinan Peng, Yue Han, Chao Fang, Depei Wu, Yi Wu","doi":"10.1016/j.jtha.2024.09.007","DOIUrl":"10.1016/j.jtha.2024.09.007","url":null,"abstract":"<p><strong>Background: </strong>The functions of critical platelet proteins are controlled by thiol-disulfide exchanges, which are mediated by the protein disulfide isomerase (PDI) family. It has been shown that some PDI family members are important in platelet activation and thrombosis with distinct functions. TMX4, a membrane-type PDI family member, is expressed in platelets, but whether it has a role in platelet activation remains unknown.</p><p><strong>Objectives: </strong>To determine the role of TMX4 in platelet activation and thrombosis.</p><p><strong>Methods: </strong>The phenotypes of TMX4-deficient mice were evaluated in tail bleeding time assay and laser-induced and FeCl<sub>3</sub>-induced arterial injury models. The functions of TMX4 in platelets were assessed in vitro using TMX4-null platelets, recombinant TMX4 protein, and anti-TMX4 antibody.</p><p><strong>Results: </strong>Compared with the control mice, Tie2-Cre/TMX4<sup>fl/fl</sup> mice deficient of hematopoietic and endothelial TMX4 exhibited prolonged tail bleeding times and reduced platelet thrombus formation. Pf4-Cre/TMX4<sup>fl/fl</sup> mice deficient of platelet TMX4 also had prolonged tail bleeding times and decreased thrombus formation, which was rescued by injection of recombinant TMX4 protein. Consistently, TMX4 deficiency inhibited platelet aggregation, integrin αIIbβ3 activation, P-selectin expression, phosphatidylserine exposure, and thrombin generation, without affecting tyrosine phosphorylation of intracellular signaling molecules Syk, LAT, PLCγ2 and calcium mobilization. Recombinant TMX4 protein enhanced platelet aggregation and reduced integrin αIIbβ3 disulfide bonds, and TMX4 deficiency decreased free thiols of integrin αIIbβ3, consistent with a potent reductase activity of TMX4. In contrast, an inactive TMX4 protein and a specific anti-TMX4 antibody inhibited platelet aggregation.</p><p><strong>Conclusion: </strong>TMX4 is a novel PDI family member that enhances platelet activation and thrombosis.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289957","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
Paclitaxel improves thrombopoiesis in the absence of thrombopoietin receptor (Mpl). 紫杉醇能在缺乏血小板生成素受体(Mpl)的情况下改善血栓形成。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-20 DOI: 10.1016/j.jtha.2024.08.025
Panpan Meng, Wenyu Liu, Jiawen Lao, Xunwei Liu, Yangping Zhang, Ying Sun, Riyang Zhou, Changhong Du, Junping Wang, Dejian Zhao, Qing Lin, Yiyue Zhang

Background: Platelets are critical for thrombosis and hemostasis. The THPO-MPL pathway is the primary pathway for generating thrombocytes. Dysregulation of thrombopoiesis results in platelet formation and/or function-related disorders, such as thrombocytopenia. Paclitaxel is an extensively utilized chemotherapeutic agent and its activity may be related to platelets, but the effect of paclitaxel on thrombocytopoiesis warrants comprehensive exploration.

Objectives: We focused on identifying factors that regulate thrombocyte production and elucidating paclitaxel's regulatory mechanisms on thrombocytopoiesis, with a particular emphasis on discovering mechanisms that bypass THPO-MPL pathways.

Methods: We performed drug screenings using the Tg(mpl:eGFP) zebrafish model in vivo to identify Food and Drug Administration-approved compounds capable of boosting thrombocyte production. An injury experiment was used to evaluate thrombocyte function. Bromodeoxyuridine assays, terminal deoxynucleotidyl transferase dUTP nick-end labeling, and RNA sequencing analyses were performed to explore cytological and molecular mechanisms. Routine blood testing and flow cytometry were used to analyze mouse phenotypes.

Results: We found that paclitaxel expands thrombocytes by accelerating the proliferation of thrombocytic lineage cells in zebrafish and elevates platelet levels in mice. This effect occurs by bypassing the thrombopoietin receptor (Mpl). We found that paclitaxel promotes thrombopoiesis, potentially involving the JAK2-ERK1/2 MAPK signaling cascade, a pathway integral to MPL and other regulators. Our results further demonstrate that ERK1/2 is at least partially downstream of JAK2 in paclitaxel-induced thrombopoiesis.

Conclusion: Paclitaxel could promote thrombopoiesis by bypassing Mpl but presumably via the JAK2-ERK1/2 MAPK pathways. It will aid in understanding the relationship between paclitaxel and platelets clinically, and paclitaxel may have potential value for safeguarding platelets and improving thrombocytosis in related diseases.

背景:血小板对血栓形成和止血至关重要:血小板对血栓形成和止血至关重要。TPO-MPL 途径是生成血小板的主要途径。血小板生成失调会导致血小板形成和/或功能相关性疾病,如血小板减少症。紫杉醇是一种广泛使用的化疗药物,可能与血小板有关,但紫杉醇对血小板生成的影响值得全面探讨:我们的研究重点是确定调节血小板生成的因素,阐明紫杉醇对血小板生成的调节机制,尤其是发现绕过 TPO-MPL 的途径:我们使用 Tg(mpl:eGFP) 斑马鱼体内模型进行了药物筛选,以确定 FDA 批准的能够促进血小板生成的化合物。损伤实验用于评估血小板功能。进行了 BrdU、TUNEL 和 RNA-Seq 分析,以探索细胞学和分子机制。常规血液检测和流式细胞术用于分析小鼠表型:结果:我们发现紫杉醇能够通过加速斑马鱼血小板系细胞的增殖来扩增血小板,并提高小鼠的血小板水平。这种效应是绕过血小板生成素受体(Mpl)产生的。我们发现,紫杉醇促进血小板生成可能涉及 JAK2-ERK1/2 MAPK 信号级联,这是 MPL 和其他调节因子不可或缺的途径。我们的研究结果进一步证明,在紫杉醇诱导的血栓形成过程中,ERK1/2至少部分处于JAK2的下游:结论:紫杉醇可绕过 Mpl 但可能通过 Jak2-Erk1/2 MAPK 通路促进血栓形成。结论:紫杉醇可通过绕过Mpl,但推测是通过Jak2-Erk1/2 MAPK通路促进血小板生成,这将有助于临床上理解紫杉醇与血小板之间的关系,紫杉醇在相关疾病中可能具有保护血小板和改善血小板增多的潜在价值。
{"title":"Paclitaxel improves thrombopoiesis in the absence of thrombopoietin receptor (Mpl).","authors":"Panpan Meng, Wenyu Liu, Jiawen Lao, Xunwei Liu, Yangping Zhang, Ying Sun, Riyang Zhou, Changhong Du, Junping Wang, Dejian Zhao, Qing Lin, Yiyue Zhang","doi":"10.1016/j.jtha.2024.08.025","DOIUrl":"10.1016/j.jtha.2024.08.025","url":null,"abstract":"<p><strong>Background: </strong>Platelets are critical for thrombosis and hemostasis. The THPO-MPL pathway is the primary pathway for generating thrombocytes. Dysregulation of thrombopoiesis results in platelet formation and/or function-related disorders, such as thrombocytopenia. Paclitaxel is an extensively utilized chemotherapeutic agent and its activity may be related to platelets, but the effect of paclitaxel on thrombocytopoiesis warrants comprehensive exploration.</p><p><strong>Objectives: </strong>We focused on identifying factors that regulate thrombocyte production and elucidating paclitaxel's regulatory mechanisms on thrombocytopoiesis, with a particular emphasis on discovering mechanisms that bypass THPO-MPL pathways.</p><p><strong>Methods: </strong>We performed drug screenings using the Tg(mpl:eGFP) zebrafish model in vivo to identify Food and Drug Administration-approved compounds capable of boosting thrombocyte production. An injury experiment was used to evaluate thrombocyte function. Bromodeoxyuridine assays, terminal deoxynucleotidyl transferase dUTP nick-end labeling, and RNA sequencing analyses were performed to explore cytological and molecular mechanisms. Routine blood testing and flow cytometry were used to analyze mouse phenotypes.</p><p><strong>Results: </strong>We found that paclitaxel expands thrombocytes by accelerating the proliferation of thrombocytic lineage cells in zebrafish and elevates platelet levels in mice. This effect occurs by bypassing the thrombopoietin receptor (Mpl). We found that paclitaxel promotes thrombopoiesis, potentially involving the JAK2-ERK1/2 MAPK signaling cascade, a pathway integral to MPL and other regulators. Our results further demonstrate that ERK1/2 is at least partially downstream of JAK2 in paclitaxel-induced thrombopoiesis.</p><p><strong>Conclusion: </strong>Paclitaxel could promote thrombopoiesis by bypassing Mpl but presumably via the JAK2-ERK1/2 MAPK pathways. It will aid in understanding the relationship between paclitaxel and platelets clinically, and paclitaxel may have potential value for safeguarding platelets and improving thrombocytosis in related diseases.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289963","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
Enhanced venous thrombosis and hypercoagulability in murine and human metabolic dysfunction-associated steatohepatitis. 小鼠和人类代谢功能障碍相关性脂肪性肝炎的静脉血栓形成和高凝状态增强
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.jtha.2024.08.023
Nilesh Pandey, Sumit Kumar Anand, Harpreet Kaur, Koral S E Richard, Lakshmi Chandaluri, Megan E Butler, Xiaolu Zhang, Brenna Pearson-Gallion, Sumati Rohilla, Sandeep Das, Tarek Magdy, Palaniappan Sethu, Kelley G Núñez, A Wayne Orr, Karen Y Stokes, Paul T Thevenot, Ari J Cohen, Oren Rom, Nirav Dhanesha

Background: Patients with metabolic dysfunction-associated steatohepatitis (MASH) are at an increased risk of developing venous thromboembolic events, including deep vein thrombosis (DVT). To date, the study of DVT in MASH has been hampered by the lack of reliable models that mimic the pathologic aspects of human disease.

Objectives: To evaluate DVT severity and hypercoagulability in murine and human MASH.

Methods: Transcriptional changes in the liver, plasma markers of coagulation, and DVT severity were evaluated in mice fed a standard chow diet or a high-fructose, high-fat, and high-cholesterol MASH diet for 24 weeks. Plasma analyses of coagulation markers and thrombin generation assays were performed in a well-characterized cohort of patients with or without MASH.

Results: Mice fed the MASH diet developed steatohepatitis and fibrosis, mimicking human MASH. Liver RNA sequencing revealed a significant upregulation of pathways related to inflammation and coagulation concomitant with increased levels of plasma coagulation markers including increased prothrombin fragment 1+2, thrombin-antithrombin complex, plasminogen activator inhibitor-1 levels, and endothelin 1. MASH exacerbated DVT severity in mice, as evidenced by increased thrombus weight and higher thrombosis incidence (15/15 vs 11/15 in controls, P = .0317). Higher endothelin 1 release and increased apoptosis were found in endothelial cells stimulated with supernatants of palmitate-stimulated HepG2 cells. Patients with MASH exhibited increased levels of plasma coagulation markers and delayed thrombin generation.

Conclusion: We report enhanced DVT severity and hypercoagulability, both in murine and human MASH. Our model of MASH-DVT can facilitate a better understanding of the fundamental mechanisms leading to increased venous thromboembolic events in patients with MASH.

背景:代谢功能障碍相关性脂肪性肝炎(MASH)患者发生静脉血栓栓塞事件(VTE),包括深静脉血栓形成(DVT)的风险增加。迄今为止,对 MASH 患者深静脉血栓形成的研究一直受阻于缺乏模拟人类疾病病理方面的可靠模型:评估小鼠和人类 MASH 的深静脉血栓严重程度和高凝状态:方法:对以饲料或高果糖、高脂肪和高胆固醇 MASH 食物喂养 24 周的小鼠的肝脏转录变化、血浆凝血标志物和深静脉血栓严重程度进行评估。在一组特征明确的 MASH 患者或非 MASH 患者中进行了血浆凝血标志物分析和凝血酶生成测定:结果:喂食 MASH 食物的小鼠出现了脂肪性肝炎和纤维化,与人类 MASH 相似。肝脏 RNA 测序显示,与炎症和凝血相关的通路显著上调,同时血浆凝血标志物增加,包括凝血酶原片段 1+2、凝血酶-抗凝血酶复合物、纤溶酶原激活物抑制剂-1 水平和内皮素 1 增加。用棕榈酸酯刺激的 HepG2 细胞的上清液刺激内皮细胞时,发现内皮素 1 释放更多,细胞凋亡增加。MASH患者的血浆凝血标志物增加,凝血酶生成延迟:我们报告了小鼠和人类 MASH 的深静脉血栓严重程度和高凝状态。我们的 MASH-DVT 模型有助于更好地了解导致 MASH 患者 VTE 增加的基本机制。
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引用次数: 0
Incidence and clinical course of chronic thromboembolic pulmonary hypertension with or without a history of venous thromboembolism in Denmark. 丹麦有静脉血栓栓塞史或无静脉血栓栓塞史的慢性血栓栓塞性肺动脉高压的发病率和临床过程。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.jtha.2024.09.006
Frederikus A Klok, Emese Vágó, Erzsébet Horváth-Puhó, Stefano Barco, Asger Andersen, Kasper Bonnesen, Anton Vonk-Noordegraaf, Marion Delcroix, Stavros V Konstantinides, Dieuwke Luijten, Suzanne C Cannegieter, Henrik Toft Sørensen

Background: A considerable number of patients with chronic thromboembolic pulmonary hypertension (CTEPH) lack a history of venous thromboembolism (VTE).

Objectives: We aimed to examine the annual incidence and prevalence of CTEPH in Denmark and to compare the rates of VTE, bleeding, and mortality between CTEPH patients with and without a history of VTE.

Methods: The Danish National Patient Registry covering all Danish hospitals was used to identify all CTEPH cases between 2009 and 2018, based on combinations of discharge diagnoses using International Classification of Diseases, 10th Revision codes for CTEPH and relevant diagnostic and/or therapeutic interventions. Incidence rates of CTEPH per 100 000 person-years, rates of VTE and bleeding, and 5-year survival estimates were calculated.

Results: In total, 509 CTEPH patients were identified, of whom 82% had a history of VTE. The yearly incidence rate of CTEPH was 0.5 to 0.8 per 100 000 person-years during the study period. Patients with a history of VTE experienced a 2.5-fold rate of VTE compared with those without prior VTE (2571 vs 980 per 100 000 person-years), while the rate of bleeding events was lower (5008 vs 7139 per 100 000 person-years). The 5-year survival of CTEPH patients with a VTE history was 65% (95% CI, 58%-71%) compared with 45% (95% CI, 31%-58%) in patients without a history of VTE.

Conclusion: The Danish incidence rate of CTEPH was comparable with that of other European countries. We identified notable differences in the prognosis of patients with CTEPH with or without a history of VTE. These findings may support generation of hypotheses regarding the pathophysiology of CTEPH and inform current patient care.

导言:相当多的慢性血栓栓塞性肺动脉高压(CTEPH)患者没有静脉血栓栓塞症(VTE)病史。我们研究了丹麦 CTEPH 的年发病率和患病率,并比较了有 VTE 病史和无 VTE 病史的 CTEPH 患者的 VTE 发生率、出血率和死亡率:利用覆盖丹麦所有医院的丹麦国家患者登记处,根据使用ICD-10代码的CTEPH出院诊断和相关诊断和/或治疗干预的组合,确定2009年至2018年期间的所有CTEPH病例。计算了每10万人年的CTEPH发病率、VTE和出血率以及5年生存率:结果:共发现 509 名 CTEPH 患者,其中 82% 有 VTE 病史。在研究期间,CTEPH的年发病率为0.5-0.8/100,000人年。与无 VTE 病史的患者相比,有 VTE 病史的患者的 VTE 发生率是无 VTE 患者的 2.5 倍(2571 对 980/100,000/人-年),而出血事件的发生率较低(分别为 5008 对 7139/100,000/人-年)。有 VTE 病史的 CTEPH 患者的 5 年生存率为 65%(95% 置信区间 (CI) 58-71),而无 VTE 病史的患者的 5 年生存率为 45%(95% 置信区间 (CI) 31-58):结论:丹麦的 CTEPH 发病率与其他欧洲国家相当。我们发现,有无 VTE 病史的 CTEPH 患者的预后存在明显差异。这些发现有助于提出 CTEPH 的病理生理学假设,并为当前的患者护理提供参考。
{"title":"Incidence and clinical course of chronic thromboembolic pulmonary hypertension with or without a history of venous thromboembolism in Denmark.","authors":"Frederikus A Klok, Emese Vágó, Erzsébet Horváth-Puhó, Stefano Barco, Asger Andersen, Kasper Bonnesen, Anton Vonk-Noordegraaf, Marion Delcroix, Stavros V Konstantinides, Dieuwke Luijten, Suzanne C Cannegieter, Henrik Toft Sørensen","doi":"10.1016/j.jtha.2024.09.006","DOIUrl":"10.1016/j.jtha.2024.09.006","url":null,"abstract":"<p><strong>Background: </strong>A considerable number of patients with chronic thromboembolic pulmonary hypertension (CTEPH) lack a history of venous thromboembolism (VTE).</p><p><strong>Objectives: </strong>We aimed to examine the annual incidence and prevalence of CTEPH in Denmark and to compare the rates of VTE, bleeding, and mortality between CTEPH patients with and without a history of VTE.</p><p><strong>Methods: </strong>The Danish National Patient Registry covering all Danish hospitals was used to identify all CTEPH cases between 2009 and 2018, based on combinations of discharge diagnoses using International Classification of Diseases, 10th Revision codes for CTEPH and relevant diagnostic and/or therapeutic interventions. Incidence rates of CTEPH per 100 000 person-years, rates of VTE and bleeding, and 5-year survival estimates were calculated.</p><p><strong>Results: </strong>In total, 509 CTEPH patients were identified, of whom 82% had a history of VTE. The yearly incidence rate of CTEPH was 0.5 to 0.8 per 100 000 person-years during the study period. Patients with a history of VTE experienced a 2.5-fold rate of VTE compared with those without prior VTE (2571 vs 980 per 100 000 person-years), while the rate of bleeding events was lower (5008 vs 7139 per 100 000 person-years). The 5-year survival of CTEPH patients with a VTE history was 65% (95% CI, 58%-71%) compared with 45% (95% CI, 31%-58%) in patients without a history of VTE.</p><p><strong>Conclusion: </strong>The Danish incidence rate of CTEPH was comparable with that of other European countries. We identified notable differences in the prognosis of patients with CTEPH with or without a history of VTE. These findings may support generation of hypotheses regarding the pathophysiology of CTEPH and inform current patient care.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289962","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
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Journal of Thrombosis and Haemostasis
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