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Disappearance of Antiphospholipid Antibodies after anti-CD19 CAR T-Cell Therapy of B-Cell Lymphoma in a Patient with Systemic Lupus Erythematosus and Antiphospholipid Syndrome. 一名患有系统性红斑狼疮和抗磷脂综合征的 B 细胞淋巴瘤患者在接受抗 CD19 CAR T 细胞治疗后抗磷脂抗体消失。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-09 DOI: 10.1016/j.jtha.2024.09.024
Eleonora Friedberg, Philipp Wohlfarth, Ana Iris Schiefer, Cathrin Skrabs, Winfried Franz Pickl, Nina Worel, Philipp Staber, Ulrich Jäger, Cihan Ay

Antiphospholipid syndrome is an autoimmune disorder characterized by the development of spontaneous venous, arterial, or microvascular thrombosis and/or pregnancy-related complications (e.g. miscarriages, fetal loss) in the presence of persistent antiphospholipid antibodies (aPL). Current state-of-the-art treatment consists of indefinite anticoagulation with vitamin K antagonists to prevent recurrence of thrombotic events. This, however, only represents a symptom-control oriented treatment approach. Until today, no curative option eradicating aPL permanently or addressing the underlying pathomechanism has been established. Here, we report the case of a woman with systemic lupus erythematosus and antiphospholipid syndrome with triple aPL-positivity who developed recurrent deep veinous thrombosis. After receiving CAR T-Cell therapy for aggressive B-Cell lymphoma, sustained eradication of all three aPL subtypes was observed, suggesting a promising role of immunotherapies targeting anti-CD19 for the treatment of pro-thrombotic autoimmune disorders.

抗磷脂综合征是一种自身免疫性疾病,其特点是在持续存在抗磷脂抗体(aPL)的情况下发生自发性静脉、动脉或微血管血栓和/或与妊娠有关的并发症(如流产、胎儿死亡)。目前最先进的治疗方法是使用维生素 K 拮抗剂进行无限期抗凝,以防止血栓事件再次发生。然而,这只是一种以症状控制为导向的治疗方法。到目前为止,还没有一种能永久根除 aPL 或解决其根本病理机制的治疗方案。在此,我们报告了一例患有系统性红斑狼疮和抗磷脂综合征并伴有三重 aPL 阳性的女性患者,她出现了复发性深静脉血栓。在接受 CAR T 细胞疗法治疗侵袭性 B 细胞淋巴瘤后,观察到所有三种 aPL 亚型均被持续清除,这表明靶向抗 CD19 的免疫疗法在治疗促血栓形成的自身免疫性疾病方面大有可为。
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引用次数: 0
Erythrophagocytosis-induced ferroptosis contributes to pulmonary microvascular thrombosis and thrombotic vascular remodeling in pulmonary arterial hypertension. 红细胞吞噬诱导的铁蛋白沉积有助于肺动脉高压中的肺微血管血栓形成和血栓性血管重塑。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-30 DOI: 10.1016/j.jtha.2024.09.011
Yao An, Minghui Xu, Meishan Yan, Hongyu Zhang, Caixia Li, Lifeng Wang, Caixu Liu, Haoran Dong, Li Chen, Lixin Zhang, Yingli Chen, Xu Han, Yun Li, Dongsheng Wang, Chunyan Gao

Background: Whether primary or just as a complication from the progression of pulmonary arterial hypertension (PAH), thrombosis seems to be an important player in this condition. The crosstalk between red blood cells (RBCs) and pulmonary microvascular endothelial cells (PMVECs) and their role in PAH remain undefined.

Objectives: The goals of this study were to assess the role of RBC-PMVEC interaction in microvascular thrombosis and thrombotic vascular remodeling under hypoxic conditions.

Methods: We established an in vitro hypoxic coincubation model of RBC and PMVEC as well as a hypoxic mouse model. We investigated erythrophagocytosis (EP), ferroptosis, thrombosis tendency, and pulmonary hemodynamics in experimental PAH.

Results: Increased EP in PMVEC triggered ferroptosis, enhanced procoagulant activity, and exacerbated vessel remodeling under hypoxic conditions. In the PAH mouse model induced by chronic hypoxia, EP-induced ferroptosis followed by upregulated TMEM16F led to a high tendency of thrombus formation and thrombotic vascular remodeling. Inhibition of ferroptosis or silencing of TMEM16F could alleviate hypercoagulable phenotype, reverse right ventricular systolic pressure, right ventricular hypertrophy index, and remodeling of pulmonary vessels.

Conclusion: These results illustrate the pathogenic RBC-PMVEC interactions in PAH. Inhibition EP, ferroptosis, or TMEM16F could be a novel therapeutic target to prevent PAH development and thrombotic complications.

背景:无论是原发性还是肺动脉高压(PAH)进展的并发症,血栓形成似乎都是这种疾病的一个重要因素。红细胞(RBC)和肺微血管内皮细胞(PMVECs)之间的交叉对话及其在 PAH 中的作用仍未确定:本研究旨在评估缺氧条件下红细胞与肺微血管内皮细胞相互作用在微血管血栓形成和血栓性血管重塑中的作用:我们建立了 RBC 和 PMVEC 的体外缺氧共孵育模型以及缺氧小鼠模型。我们研究了实验性 PAH 的红细胞吞噬功能(EP)、铁蛋白沉积、血栓形成倾向和肺血流动力学:结果:我们发现,在缺氧条件下,PMVEC 中 EP 的增加引发了铁跃迁,增强了促凝活性,并加剧了血管重塑。在慢性缺氧诱导的 PAH 小鼠模型中,EP 诱导的嗜铁细胞增多和 TMEM16F 的上调导致血栓形成和血栓性血管重塑的高度倾向。抑制铁蛋白沉积或沉默 TMEM16F 可缓解高凝表型,逆转右心室收缩压、右心室肥厚指数和肺血管重塑:这些结果说明了 PAH 中 RBC-PMVEC 相互作用的致病性。这些结果说明了 PAH 中 RBC-PMVEC 相互作用的致病性。抑制 EP、铁肽化或 TMEM16F 可能是预防 PAH 发展和血栓并发症的新型治疗靶点。
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引用次数: 0
Antiproliferative agent attenuates postthrombotic vein wall remodeling in murine and human subjects. 抗增殖剂可减轻小鼠和人类血栓后静脉壁的重塑。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-30 DOI: 10.1016/j.jtha.2024.09.012
Hongji Pu, Jiahao Lei, Guodong Du, Qun Huang, Peng Qiu, Junchao Liu, Chenshu Li, Xiaoliang Ying, Kailang Liu, Zhijue Xu, Xinwu Lu, Ruihua Wang

Background: Despite appropriate treatment, up to 50% of patients with proximal deep vein thrombosis will develop postthrombotic syndrome (PTS). Once PTS occurs, there is no specific treatment, and some patients constantly experience intolerable symptoms. Hence, prevention of PTS is important.

Objectives: To characterize vein wall remodeling after thrombus and investigate the effects of antiproliferative agent on postthrombotic vein wall remodeling in murine and human subjects.

Methods: Features of postthrombotic vein wall remodeling in murine and human subjects were characterized using imaging and histologic examinations. Paclitaxel-loaded hydrogels were used to assess the effects of antiproliferative agent on the remodeling in murine model. Based on the abovementioned results, a pilot study was conducted to assess the effects of paclitaxel-coated balloon dilation in patients with severe PTS experiencing intolerable symptoms. The control cohort was obtained by 1:1 propensity score matching from a prospective database.

Results: Structural and functional alterations in postthrombotic vein wall were verified by imaging and histologic examinations, and predominant active α-smooth muscle actin-positive cells and fibroblast-specific protein 1-positive cells proliferation was observed. In the murine model, the application of paclitaxel-loaded hydrogels inhibited the remodeling. In the pilot clinical study, patients receiving drug-coated balloon demonstrated benefits in Villalta scores and venous clinical severity scores compared with those not receiving drug-coated balloon, and no severe adverse events were reported except for thrombosis recurrence.

Conclusion: Cell proliferation plays an important role in postthrombotic vein wall remodeling. Inhibition of cell proliferation inhibits the remodeling in murine model and may reduce signs and symptoms in patients with severe PTS.

背景:尽管接受了适当的治疗,但仍有多达 50% 的近端深静脉血栓(DVT)患者会出现血栓后综合征(PTS)。一旦发生血栓后综合征,目前尚无特效治疗方法,部分患者会持续出现难以忍受的症状。如何预防 PTS 非常重要:目的:描述血栓后静脉壁重塑的特征,研究抗增殖剂对小鼠和人类血栓后静脉壁重塑的影响:方法:通过成像和组织学检查,确定小鼠和人类血栓后静脉壁重塑的特征。使用紫杉醇水凝胶评估抗增殖剂对小鼠模型重塑的影响。基于上述结果,我们进行了一项试验性研究,以评估紫杉醇涂层球囊扩张对症状难以忍受的严重 PTS 患者的影响。对照组是通过前瞻性数据库的 1:1 倾向性评分匹配获得的:结果:影像学和组织学检查证实了血栓后静脉壁的结构和功能改变,并观察到活跃的α-SMA+细胞和FSP-1+细胞增殖。在小鼠模型中,应用紫杉醇水凝胶抑制了重塑。在试验性临床研究中,与未接受 DCB 治疗的患者相比,接受 DCB 治疗的患者在 Villalta 评分和 VCSS 评分方面均有获益,且除血栓复发外未报告严重不良事件:结论:细胞增殖在血栓后静脉壁重塑中起着重要作用。结论:细胞增殖在血栓后静脉壁重塑中起着重要作用,抑制细胞增殖可抑制小鼠模型中的重塑,并可减轻严重 PTS 患者的体征和症状。
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引用次数: 0
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。
{"title":"Incidence, risk factors, and outcomes of patients with monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia who develop venous thromboembolism.","authors":"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","doi":"10.1016/j.jtha.2024.08.029","DOIUrl":"10.1016/j.jtha.2024.08.029","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objectives: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>Our study demonstrates a 6-fold increased risk of VTE in patients with MBL/CLL compared with the age- and sex-matched general population.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142349117","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
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。
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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。
{"title":"Invasive procedures and surgery following etranacogene dezaparvovec gene therapy in people with hemophilia B.","authors":"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","doi":"10.1016/j.jtha.2024.08.027","DOIUrl":"10.1016/j.jtha.2024.08.027","url":null,"abstract":"<p><strong>Background: </strong>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).</p><p><strong>Objectives: </strong>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.</p><p><strong>Methods: </strong>This retrospective analysis included invasive procedures performed within 3 and 2 years following a single infusion of 2 × 10<sup>13</sup> 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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142349118","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
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":null,"pages":null},"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
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Journal of Thrombosis and Haemostasis
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