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Lack of factor VIII detection in humans and dogs with an intron 22 inversion challenges hypothesis regarding inhibitor risk. 人类和狗体内未检测到 FVIII 内含子-22 倒位,这对有关抑制剂风险的假设提出了挑战。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-02 DOI: 10.1016/j.jtha.2024.08.007
Pooja Vir, Devi Gunasekera, Batsukh Dorjbal, Dennis McDaniel, Atul Agrawal, Elizabeth P Merricks, Margaret V Ragni, Cindy A Leissinger, Allen I Stering, Kenneth Lieuw, Timothy C Nichols, Kathleen P Pratt

Background: Almost half of severe hemophilia A (HA) cases are caused by an intron 22 inversion (Int22Inv) mutation, which truncates the 26-exon F8 messenger RNA (mRNA) after exon 22. Another F8 transcript, F8B, is initiated from within F8-intron-22. F8B mRNA consists of a short exon spliced to exons 23 to 26 and is expressed in multiple human cell types. It has been hypothesized that Int22Inv patients have self-tolerance to partial factor (F)VIII proteins expressed from these 2 transcripts. FVIII is expressed in endothelial cells, primarily in the liver and lungs. Several studies have reported FVIII expression in other cell types, although this has been controversial.

Objectives: To determine if partial FVIII proteins are expressed from intron 22-inverted and/or F8B mRNA and if FVIII is expressed in nonendothelial cells.

Methods: A panel of FVIII-specific antibodies was validated and employed to label FVIII in cells and tissues and for immunoprecipitation followed by western blots and mass spectrometry proteomics analysis.

Results: Immunofluorescent staining localized FVIII to endothelial cells in liver sections from non-HA but not HA-Int22Inv dogs. Neither FVIII nor FVIIIB was detected in human peripheral blood mononuclear cells, B cell or T cell lines, or cell lines expanded from peripheral blood mononuclear cells, whereas FVIII antigen and activity were readily detected in primary nonhemophilic liver sinusoidal endothelial cells.

Conclusion: If FVIII is expressed in nonendothelial cells or if partial FVIII proteins are expressed in HA-Int22Inv, the concentrations are below the detection limits of these sensitive assays. Our results argue against promotion of immune tolerance through expression of partial FVIII proteins in Int-22Inv patients.

背景:近一半的严重 A 型血友病(HA)病例是由内含子-22 倒位突变(Int22Inv)引起的,这种突变会在外显子 22 之后截断 26 外显子 F8 mRNA。另一个 F8 转录本 F8B 从 F8 内含子-22 开始。F8B mRNA 由一个短外显子剪接成 23-26 号外显子,在多种人类细胞类型中表达。据推测,Int22Inv 患者对这两种转录本表达的部分 FVIII 蛋白具有自身耐受性。FVIII 主要在肝脏和肺部的内皮细胞中表达。一些研究报告称 FVIII 在其他细胞类型中也有表达,但这一点一直存在争议:目的:确定部分 FVIII 蛋白是否由内含子 22 倒置和/或 F8B mRNA 表达,以及 FVIII 是否在非内皮细胞中表达:方法: 验证并使用一组FVIII特异性抗体标记细胞和组织中的FVIII,并进行免疫沉淀,然后进行Western印迹和质谱-蛋白质组学分析:结果:免疫荧光(IF)染色将 FVIII 定位于非 HA 而非 HA-Int22Inv 狗肝脏切片的内皮细胞。在人类 PBMCs、B 细胞系或 T 细胞系或由 PBMCs 扩增的细胞系中均未检测到 FVIII 或 FVIIIB,而在原代非血友病肝窦内皮细胞中很容易检测到 FVIII 抗原和活性:结论:如果 FVIII 在非内皮细胞中表达,或部分 FVIII 蛋白在 HA-Int22Inv 中表达,则其浓度低于这些灵敏检测方法的检测限。我们的结果表明,Int-22Inv 患者体内部分 FVIII 蛋白的表达不会促进免疫耐受。
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引用次数: 0
The use of direct oral anticoagulants in the secondary prevention of venous thromboembolism in patients with severe thrombophilia: communication from the ISTH SSC Subcommittee on Physiological Anticoagulants and Thrombophilia 在严重血栓性疾病患者静脉血栓栓塞症二级预防中使用 DOACs:ISTH SSC 生理抗凝剂和血栓性疾病小组委员会的来文。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-02 DOI: 10.1016/j.jtha.2024.08.006
Mirjana Kovac , Vera Ignjatovic , Christelle Orlando , Zsuzsanna Bereczky , Beverley J. Hunt
Direct oral anticoagulants (DOACs) are the first-line anticoagulants for the secondary prevention of venous thromboembolism (VTE). However, patients with severe inherited thrombophilias represent a group in whom the efficiency and safety of DOACs is poorly studied. In this communication, we focus on the utility of DOACs in the secondary prevention of VTE in patients with severe thrombophilia. Current evidence is based only on cohort or single-center studies, and poor data are available on compliance of the patients in the studies. Analysis of the studies suggested that full-dose DOACs and vitamin K antagonists have a similar efficacy and bleeding risk in the secondary prevention of VTE in patients with thrombophilia, with a low hazard ratio for recurrent VTE calculated from cohort studies for DOAC vs warfarin, ranging from 0.3 to 0.75. We wish to highlight that treatment failure is greater in those with severe forms of protein S deficiency (below 20%) and possibly in antithrombin deficiency type II heparin-binding site homozygous Budapest 3. In summary, the current approach to using DOACs in patients with severe thrombophilia is dependent on clinical judgment and experience. Limited evidence suggests that for those with severe thrombophilias, full-dose DOACs have similar utility as vitamin K antagonists. We recommend caution in using low-dose DOACs due to lack of evidence. Ideally, large randomized multicenter studies are required to develop a reliable treatment algorithm.
直接口服抗凝剂(DOAC)是静脉血栓栓塞症(VTE)二级预防的一线抗凝剂。然而,对于患有严重遗传性血栓性疾病的患者,DOACs 的有效性和安全性研究尚不充分。在这篇通讯中,我们重点讨论了 DOACs 在严重血栓性疾病患者 VTE 二级预防中的作用。目前的证据仅基于队列研究或单中心研究,关于研究中患者依从性的数据较少。研究分析表明,全剂量 DOAC 和维生素 K 拮抗剂 (VKAs) 对血栓性 VTE 患者的二级预防具有相似的疗效和出血风险;根据队列研究计算,DOAC 与华法林的复发性 VTE 危险比值较低,从 0.3 到 0.75 不等。我们希望强调的是,对于严重的蛋白 S 缺乏症患者(低于 20%),以及可能患有 AT 缺乏症的 II 型 HBS 布达佩斯 3 基因型患者,治疗失败的可能性更大。 总之,目前对严重血栓性疾病患者使用 DOACs 的方法取决于临床判断和经验。有限的证据表明,对于严重血栓性血友病患者,全剂量 DOACs 具有与 VKAs 相似的效用。由于缺乏证据,我们建议谨慎使用低剂量 DOAC。理想情况下,需要进行大型随机多中心研究,以制定可靠的治疗算法。
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引用次数: 0
Biomarker-enhanced cardiovascular risk prediction in patients with cancer: a prospective cohort study 癌症患者生物标志物增强心血管风险预测:一项前瞻性队列研究。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-01 DOI: 10.1016/j.jtha.2024.07.019
Simon Kraler , Luca Liberale , Stephan Nopp , Cornelia Englisch , Ella Grilz , Tetiana Lapikova-Bryhinska , Alexander Akhmedov , Federico Carbone , Davide Ramoni , Amedeo Tirandi , Alessandro Scuricini , Simone Isoppo , Curzia Tortorella , Federica La Rosa , Cristina Michelauz , Federica Frè , Aurora Gavoci , Anna Lisa , Thomas M. Suter , Arnold von Eckardstein , Florian Moik

Background

Continuously improving cancer-specific survival puts a growing proportion of cancer patients at risk of major adverse cardiovascular events (MACE), but tailored tools for cardiovascular risk prediction remain unavailable.

Objectives

To assess a broad panel of cardiovascular biomarkers and risk factors for the prediction of MACE and cardiovascular death in cancer patients.

Methods

In total, 2192 patients with newly diagnosed or recurrent cancer were followed prospectively for the occurrence of 2-year MACE and 5-year cardiovascular death. Univariable and multivariable risk models were fit to assess independent associations of cardiovascular risk factors and biomarkers with adverse outcomes, and a risk score was developed.

Results

Traditional cardiovascular risk factors and selected cancer types were linked to higher MACE risk. While levels of Lp(a), CRP, and GDF-15 did not associate with MACE, levels of ICAM-1, P-/E-/L-selectins, and NT-proBNP were independently linked to 2-year MACE risk. A clinical risk score was derived, assigning +1 point for male sex, smoking, and age of ≥60 years and +2 points for atherosclerotic disease, yielding a bootstrapped C-statistic of 0.76 (95% CI: 0.71-0.81) for the prediction of 2-year MACE. Implementation of biomarker data conferred improved performance (0.83, 95% CI: 0.78-0.88), with a simplified model showing similar performance (0.80, 95% CI: 0.74-0.86). The biomarker-enhanced and simplified prediction models achieved a C-statistic of 0.82 (95% CI: 0.71-0.93) and 0.74 (95% CI: 0.64-0.83) for the prediction of 5-year cardiovascular death.

Conclusion

Biomarker-enhanced risk prediction strategies allow the identification of cancer patients at high risk of MACE and cardiovascular death. While external validation studies are ongoing, this first-of-its-kind risk score may provide the basis for personalized cardiovascular risk assessment across cancer entities.
背景:癌症特异性生存率的不断提高使越来越多的癌症患者面临重大不良心血管事件(MACE)的风险,但目前仍缺乏量身定制的心血管风险预测工具:评估一系列心血管生物标志物和风险因素,以预测癌症患者的 MACE 和心血管死亡:方法:共对2192名新确诊或复发癌症患者进行了前瞻性随访,以观察2年MACE和5年心血管死亡的发生情况。拟合了单变量和多变量风险模型,以评估心血管风险因素和生物标志物与不良结局的独立关联,并制定了风险评分:结果:传统的心血管风险因素和某些癌症类型与较高的MACE风险有关。虽然脂蛋白(a)、CRP和GDF-15的水平与MACE无关,但ICAM-1、P-/E-/L-选择素和NT-proBNP的水平与2年MACE风险独立相关。得出的临床风险评分为:男性、吸烟和年龄≥60 岁+1 分,动脉粥样硬化性疾病+2 分,预测 2 年 MACE 的自引导 C 统计量为 0.76(95% CI:0.71-0.81)。生物标志物数据的应用提高了预测效果(0.83,95% CI:0.78-0.88),简化模型的预测效果与之相似(0.80,95% CI:0.74-0.86)。在预测5年心血管死亡方面,生物标志物增强预测模型和简化预测模型的C统计量分别为0.82(95% CI:0.71-0.93)和0.74(95% CI:0.64-0.83):结论:生物标志物增强风险预测策略可识别出MACE和心血管死亡风险较高的癌症患者。虽然外部验证研究仍在进行中,但这一首创的风险评分可为跨癌症实体的个性化心血管风险评估奠定基础。
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引用次数: 0
Epidemiology, natural history, diagnosis, and management of ovarian vein thrombosis: a scoping review 卵巢静脉血栓的流行病学、自然史、诊断和管理:范围综述。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-08-30 DOI: 10.1016/j.jtha.2024.07.033
Margaux Monnet , Virginie Dufrost , Denis Wahl , Olivier Morel , Mikaël Agopiantz , Stéphane Zuily
Ovarian vein thrombosis (OVT) is a rare but potentially serious condition. We conducted a scoping review of published data to provide a better understanding of OVT management. MEDLINE and Cochrane databases were searched. The eligibility criterion was original articles including women with OVT until May 2024. Quantitative data were pooled via Comprehensive Meta-Analysis software (Biostat, Inc). Quality of the primary studies was assessed via the Newcastle‒Ottawa Scale. Out of 1007 identified records, 19 primary studies including 1128 patients were selected. Mean age at OVT diagnosis was 37 years old. Frequency of OVT depended on the clinical situation: cancer (37%) and postpartum (0.06%), including cesarean (0.19%), or persistent fever despite antibiotics (23%). Magnetic resonance imaging was associated with the best diagnostic performance, followed by computed tomography. Pulmonary embolism and extension to the iliac vein, inferior vena cava, or left renal vein occurred in 6.5%, 5.9%, 10.3%, and 9.6% of patients, respectively. Among anticoagulants, low-molecular-height heparin with/without oral anticoagulant was preferred for 3 to 6 months. Among the women tested, thrombophilia was present in 18% of the patients. Recanalization, recurrent thrombosis, or major bleeding occurred in 70%, 8%, and 2% of patients, respectively. The majority of studies had poor evidence. This scoping review provides a comprehensive evaluation of available data. Frequency of OVT depends on the clinical setting. Physicians should be aware of OVT in postpartum women with persistent fever despite the use of antibiotics. OVT belongs to the spectrum of venous thromboembolism and should be considered both in puerperal settings and in cancer patients.
卵巢静脉血栓(OVT)是一种罕见但潜在的严重疾病。为了更好地了解卵巢静脉血栓的治疗,我们对已发表的数据进行了范围界定。我们检索了 MEDLINE 和 Cochrane 数据库。资格标准是在 2024 年 5 月之前发表的包含 OVT 女性患者的原创文章。通过 CMA 软件汇总定量数据。主要研究的质量通过纽卡斯尔-渥太华量表进行评估。在已确定的 1,007 份记录中,选出了 19 项主要研究,其中包括 1,128 名患者。确诊 OVT 的平均年龄为 37 岁。OVT的发生率取决于临床情况:癌症(37%)、产后(0.06%),包括剖腹产(0.19%)或使用抗生素后仍持续发热(23%)。磁共振成像的诊断效果最好,其次是计算机断层扫描。分别有6.5%、5.9%、10.3%和9.6%的患者发生肺栓塞并扩展至髂静脉、下腔静脉或左肾静脉。在抗凝剂中,首选低分子量肝素加/不加口服抗凝剂,疗程为 3 至 6 个月。在接受检测的女性患者中,18%患有血栓性疾病。分别有 70%、8% 和 2% 的患者出现再狭窄、血栓复发或大出血。大多数研究证据不足。本范围综述对现有数据进行了全面评估。OVT 的发生频率取决于临床环境。对于使用抗生素后仍持续发热的产后妇女,医生应警惕卵巢静脉血栓。卵巢静脉血栓属于静脉血栓栓塞症的一种,在产褥期和癌症患者中均应考虑。
{"title":"Epidemiology, natural history, diagnosis, and management of ovarian vein thrombosis: a scoping review","authors":"Margaux Monnet ,&nbsp;Virginie Dufrost ,&nbsp;Denis Wahl ,&nbsp;Olivier Morel ,&nbsp;Mikaël Agopiantz ,&nbsp;Stéphane Zuily","doi":"10.1016/j.jtha.2024.07.033","DOIUrl":"10.1016/j.jtha.2024.07.033","url":null,"abstract":"<div><div>Ovarian vein thrombosis (OVT) is a rare but potentially serious condition. We conducted a scoping review of published data to provide a better understanding of OVT management. MEDLINE and Cochrane databases were searched. The eligibility criterion was original articles including women with OVT until May 2024. Quantitative data were pooled via Comprehensive Meta-Analysis software (Biostat, Inc). Quality of the primary studies was assessed via the Newcastle‒Ottawa Scale. Out of 1007 identified records, 19 primary studies including 1128 patients were selected. Mean age at OVT diagnosis was 37 years old. Frequency of OVT depended on the clinical situation: cancer (37%) and postpartum (0.06%), including cesarean (0.19%), or persistent fever despite antibiotics (23%). Magnetic resonance imaging was associated with the best diagnostic performance, followed by computed tomography. Pulmonary embolism and extension to the iliac vein, inferior vena cava, or left renal vein occurred in 6.5%, 5.9%, 10.3%, and 9.6% of patients, respectively. Among anticoagulants, low-molecular-height heparin with/without oral anticoagulant was preferred for 3 to 6 months. Among the women tested, thrombophilia was present in 18% of the patients. Recanalization, recurrent thrombosis, or major bleeding occurred in 70%, 8%, and 2% of patients, respectively. The majority of studies had poor evidence. This scoping review provides a comprehensive evaluation of available data. Frequency of OVT depends on the clinical setting. Physicians should be aware of OVT in postpartum women with persistent fever despite the use of antibiotics. OVT belongs to the spectrum of venous thromboembolism and should be considered both in puerperal settings and in cancer patients.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"22 11","pages":"Pages 2991-3003"},"PeriodicalIF":5.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108691","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
Fibrinolysis is impaired in patients with primary immune thrombocytopenia 原发性免疫血小板减少症患者的纤溶功能受损。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-08-28 DOI: 10.1016/j.jtha.2024.07.034
Theresa Schramm , Jasmin Rast , Dino Mehic , Stéphanie E. Reitsma , Claire de Moreuil , Michael Fillitz , Peter Quehenberger , Bas de Laat , Alisa S. Wolberg , Cihan Ay , Ingrid Pabinger , Johanna Gebhart

Background

Patients with primary immune thrombocytopenia (ITP) have an increased risk of thrombosis, which may be due to altered fibrinolysis.

Objectives

To elucidate the clinical impact of delayed fibrinolysis in ITP patients.

Methods

A turbidimetric clot formation and lysis assay and a fluorometric plasmin generation (PG) assay were performed, and levels of plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), tPA-PAI-1 complexes, α2-antiplasmin, thrombin activatable fibrinolysis inhibitor, and D-dimer were assessed in 86 adult primary ITP patients and 78 healthy controls (HCs).

Results

ITP patients showed significantly delayed clot formation, increased clot density, and prolonged clot lysis time (CLT) compared with HCs, with a median (IQR) CLT of 28.0 (13.7-34.7) minutes in patients and 17.3 (12.0-28.0) minutes in HCs, while in the PG assay, only the lag time was prolonged. In ITP patients compared with controls, PAI-1 was higher (1.2 [0.8-2.6] vs 1.1 [0.6-2.1] U/mL) and tPA antigen and activity were lower (tPA antigen: 2.6 [1.1-4.4] vs 3.7 [3.2-4.7] ng/mL; tPA activity ≤ 0 U/mL: 26% vs 7%). TPA-PAI-1 complex levels were positively associated with CLT in multiple linear regression analysis (β = 0.241; P = .019), whereas PG parameters were not associated with CLT. Six patients who developed thrombosis during follow-up had higher levels of tPA-PAI-1 complexes.

Conclusion

Prolonged CLT and delayed onset of PG may indicate a hypofibrinolytic tendency in ITP patients, as also indicated by high PAI-1 and low tPA levels. No association was found between fibrinolytic potential and the bleeding phenotype, whereas higher tPA-PAI-1 complex levels were associated with prolonged CLT and increased in patients with future thrombosis.
背景:原发性免疫性血小板减少症(ITP)患者血栓形成的风险增加:原发性免疫性血小板减少症(ITP)患者血栓形成的风险增加,这可能是由于纤溶改变所致:阐明延迟纤溶对ITP患者的临床影响:方法:对86名成人原发性ITP患者和78名健康对照组(HC)进行了血凝块形成和溶解浊度测定以及血浆生成素(PG)荧光测定,并评估了血浆蛋白酶原激活物抑制剂-1(PAI-1)、组织血浆蛋白酶原激活物(tPA)、tPA-PAI-1复合物、α2-抗蛋白酶、TAFI和D-二聚体的水平:结果:与健康对照组相比,ITP 患者的血凝块形成明显延迟,血凝块密度增加,血凝块溶解时间(CLT)延长,患者的 CLT 中位数(IQR)为 28.0(13.7-34.7)分钟,健康对照组为 17.3(12.0-28.0)分钟,而 PG 仅滞后时间延长。与对照组相比,ITP 患者的 PAI-1 较高(1.2 (0.8-2.6) vs 1.1 (0.6-2.1) U/mL),而 tPA 抗原和活性较低(tPA 抗原:2.6 (1.1-4.4) vs 3.7 (3.2-4.7) ng/mL;tPA 活性≤0 U/mL:26% vs 7%)。在多元线性回归分析中,TPA-PAI-1 复合物水平与 CLT 呈正相关(β=0.241,P=0.019),而 PG 参数与 CLT 无关。随访期间出现血栓形成的六名患者的tPA-PAI-1复合物水平较高:结论:CLT延长和PG起始延迟可能表明ITP患者存在低纤维蛋白溶解倾向,高PAI-1和低tPA水平也表明了这一点。纤溶潜能与出血表型之间没有关联,而较高的tPA-PAI-1复合物水平与CLT延长有关,并在未来出现血栓的患者中有所增加。
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引用次数: 0
RUNX1 isoforms regulate RUNX1 and target genes differentially in platelets-megakaryocytes: association with clinical cardiovascular events. RUNX1 异构体对血小板-巨核细胞中的 RUNX1 和靶基因有不同的调控作用:与临床心血管事件的关系
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-08-23 DOI: 10.1016/j.jtha.2024.07.032
Liying Guan, Deepak Voora, Rachel Myers, Fabiola Del Carpio-Cano, A Koneti Rao

Background: Hematopoietic transcription factor RUNX1 is expressed from proximal P2 and distal P1 promoters to yield isoforms RUNX1 B and C, respectively. The roles of these isoforms in RUNX1 autoregulation and downstream gene regulation in megakaryocytes and platelets are unknown.

Objectives: To understand the regulation of RUNX1 and its target genes by RUNX1 isoforms.

Methods: We performed studies on RUNX1 isoforms in megakaryocytic human erythroleukemia (HEL) cells and HeLa cells (lack endogenous RUNX1), in platelets from 85 healthy volunteers administered aspirin or ticagrelor, and on the association of RUNX1 target genes with acute events in 587 patients with cardiovascular disease (CVD).

Results: In chromatin immunoprecipitation and luciferase promoter assays, RUNX1 isoforms B and C bound and regulated P1 and P2 promoters. In HeLa cells, RUNX1B decreased and RUNX1C increased P1 and P2 activities, respectively. In HEL cells, RUNX1B overexpression decreased RUNX1C and RUNX1A expression; RUNX1C increased RUNX1B and RUNX1A. RUNX1B and RUNX1C regulated target genes (MYL9, F13A1, PCTP, PDE5A, and others) differentially in HEL cells. In platelets, RUNX1B transcripts (by RNA sequencing) correlated negatively with RUNX1C and RUNX1A; RUNX1C correlated positively with RUNX1A. RUNX1B correlated positively with F13A1, PCTP, PDE5A, RAB1B, and others, and negatively with MYL9. In our previous studies, RUNX1C transcripts in whole blood were protective against acute events in CVD patients. We found that higher expression of RUNX1 targets F13A1 and RAB31 associated with acute events.

Conclusion: RUNX1 isoforms B and C autoregulate RUNX1 and regulate downstream genes in a differential manner, and this is associated with acute events in CVD.

背景:造血转录因子 RUNX1 由近端 P2 和远端 P1 启动子表达,分别产生异构体 RUNX1 B 和 C。这些异构体在巨核细胞和血小板中的 RUNX1 自调节和下游基因调节中的作用尚不清楚:目的:了解 RUNX1 及其靶基因受 RUNX1 同工酶调控的情况:我们对巨核细胞HEL细胞和HeLa细胞(缺乏内源性RUNX1)中的RUNX1同工酶、85名服用阿司匹林或替卡格雷的健康志愿者的血小板中的RUNX1同工酶以及587名心血管疾病(CVD)患者的RUNX1靶基因与急性事件的相关性进行了研究:结果:在染色质免疫沉淀和荧光素酶启动子试验中,RUNX1同工酶B和C与P1和P2启动子结合并对其进行调控。在 HeLa 细胞中,RUNX1B 分别降低了 P1 和 P2 的活性,而 RUNX1C 则提高了 P1 和 P2 的活性。在 HEL 细胞中,RUNX1B 过表达会降低 RUNX1C 和 RUNX1A 的表达;RUNX1C 会增加 RUNX1B 和 RUNX1A 的表达。在 HEL 细胞中,RUNX1B 和 RUNX1C 对靶基因(MYL9、F13A1、PCTP、PDE5A 等)的调控存在差异。在血小板中,RUNX1B 转录物(通过 RNAseq)与 RUNX1C 和 RUNX1A 呈负相关;RUNX1C 与 RUNX1A 呈正相关。RUNX1B 与 F13A1、PCTP、PDE5A、RAB1B 等呈正相关,与 MYL9 呈负相关。在我们之前的研究中,全血中的 RUNX1C 转录物对心血管疾病患者的急性事件具有保护作用。我们发现,RUNX1靶标F13A1和RAB31的高表达与急性事件有关:结论:RUNX1同工酶B和C以不同的方式自动调节RUNX1并调控下游基因,这与心血管疾病的急性事件有关。
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引用次数: 0
Gene therapy for people with hemophilia B: a proposed care delivery model in Italy 血友病 B 患者的基因治疗:意大利的一种拟议护理模式。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-08-22 DOI: 10.1016/j.jtha.2024.07.029
Giancarlo Castaman , Giovanni Di Minno , Paolo Simioni , Angelo Claudio Molinari , Sergio Siragusa , Erminia Baldacci , Vincenzo La Mura , Angelo Lupi , Enrico Ferri Grazzi , Flora Peyvandi

Background

Gene therapy is designed to provide people with hemophilia B with a steady and elevated factor (F)IX activity, thereby strengthening protection and relieving the burden of frequent replacement therapy infusions. The European Medicines Agency has approved gene therapy for the severe and moderately severe forms of hemophilia B that uses the FIX-Padua variant (etranacogene dezaparvovec).

Objectives

The aim was to provide a document dedicated to hemophilia B gene therapy and give a comprehensive overview of the topic.

Methods

An Italian group of experts in hemophilia carried out a narrative review of the literature and discussed during a virtual meeting several key aspects of the delivery of this treatment in Italy. The discussion covered the organizational model, the role of the multidisciplinary team, the laboratory surveillance, and the patient’s journey, from the follow-up to the identification of safety issues and outcome measures.

Results

This article highlights the need to follow the Hub and Spoke organizational model and sheds light on the role of each professional figure within the multidisciplinary teams to favor patient engagement, management, and retention. Moreover, this article stresses the need to perform laboratory tests for patient screening and follow-up and proposes a checklist to help patient identification. Finally, the needs of Italian hemophilia centers have been considered to ensure an efficient implementation of the care delivery model.

Conclusion

It is crucial to ensure that centers are appropriately organized, equipped, and trained to adequately select patients, deliver the gene therapy, and perform follow-up.
背景:基因疗法旨在为乙型血友病患者提供稳定、高活性的 IX 因子,从而加强保护并减轻频繁输注替代疗法的负担。欧洲药品管理局已经批准了一种针对重度和中度血友病 B 型的基因疗法,该疗法使用因子 IX 帕多瓦变体(etranacogene dezaparvovec)。本文旨在提供一份有关 B 型血友病基因疗法的专门文件,并对该主题进行全面概述:一个由血友病专家组成的意大利小组对文献进行了叙述性回顾,并在一次虚拟会议上讨论了在意大利提供这种治疗的几个关键方面。讨论内容包括组织模式、多学科团队的作用、实验室监测以及从随访到确定安全问题和结果衡量标准的患者治疗过程:结果:本文强调了遵循 "枢纽和辐条 "组织模式的必要性,并阐明了多学科团队中各专业人员的作用,以促进患者参与、管理和留住患者。此外,本文还强调了为患者筛查和随访进行实验室检测的必要性,并提出了一份有助于识别患者的核对表。最后,还考虑了意大利血友病中心的需求,以确保有效实施护理服务模式:至关重要的是,要确保各中心有适当的组织、设备和培训,以充分甄选患者、提供基因治疗和进行随访。
{"title":"Gene therapy for people with hemophilia B: a proposed care delivery model in Italy","authors":"Giancarlo Castaman ,&nbsp;Giovanni Di Minno ,&nbsp;Paolo Simioni ,&nbsp;Angelo Claudio Molinari ,&nbsp;Sergio Siragusa ,&nbsp;Erminia Baldacci ,&nbsp;Vincenzo La Mura ,&nbsp;Angelo Lupi ,&nbsp;Enrico Ferri Grazzi ,&nbsp;Flora Peyvandi","doi":"10.1016/j.jtha.2024.07.029","DOIUrl":"10.1016/j.jtha.2024.07.029","url":null,"abstract":"<div><h3>Background</h3><div>Gene therapy is designed to provide people with hemophilia B with a steady and elevated factor (F)IX activity, thereby strengthening protection and relieving the burden of frequent replacement therapy infusions. The European Medicines Agency has approved gene therapy for the severe and moderately severe forms of hemophilia B that uses the FIX-Padua variant (etranacogene dezaparvovec).</div></div><div><h3>Objectives</h3><div>The aim was to provide a document dedicated to hemophilia B gene therapy and give a comprehensive overview of the topic.</div></div><div><h3>Methods</h3><div>An Italian group of experts in hemophilia carried out a narrative review of the literature and discussed during a virtual meeting several key aspects of the delivery of this treatment in Italy. The discussion covered the organizational model, the role of the multidisciplinary team, the laboratory surveillance, and the patient’s journey, from the follow-up to the identification of safety issues and outcome measures.</div></div><div><h3>Results</h3><div>This article highlights the need to follow the Hub and Spoke organizational model and sheds light on the role of each professional figure within the multidisciplinary teams to favor patient engagement, management, and retention. Moreover, this article stresses the need to perform laboratory tests for patient screening and follow-up and proposes a checklist to help patient identification. Finally, the needs of Italian hemophilia centers have been considered to ensure an efficient implementation of the care delivery model.</div></div><div><h3>Conclusion</h3><div>It is crucial to ensure that centers are appropriately organized, equipped, and trained to adequately select patients, deliver the gene therapy, and perform follow-up.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"22 11","pages":"Pages 3084-3096"},"PeriodicalIF":5.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142036171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Platelet HMGB1 steers intravascular immunity and thrombosis. 血小板 HMGB1 引导血管内免疫和血栓形成
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-08-22 DOI: 10.1016/j.jtha.2024.07.030
Norma Maugeri, Angelo A Manfredi

Platelets navigate the fine balance between homeostasis and injury. They regulate vascular homeostasis and drive repair after injury amidst leukocyte extravasation. Crucially, platelets initiate extracellular traps generation and promote immunothrombosis. In chronic human diseases, platelet action often extends beyond its normative role, sparking sustained reciprocal activation of leukocytes and mural cells, culminating in adverse vascular remodeling. Studies in the last decade have spotlighted a novel key player in platelet activation, the high mobility group box 1 (HMGB1) protein. Despite its initial characterization as a chromatin molecule, anucleated platelets express abundant HMGB1, which has emerged as a linchpin in thromboinflammatory risks and microvascular remodeling. We propose that a comprehensive assessment of platelet HMGB1, spanning quantification of content, membrane localization, and accumulation of HMGB1-expressing vesicles in biological fluids should be integral to dissecting and quantifying platelet activation. This review provides evidence supporting this claim and underscores the significance of platelet HMGB1 as a biomarker in conditions associated with heightened thrombotic risks and systemic microvascular involvement, spanning cardiovascular, autoimmune, and infectious diseases.

血小板在稳态和损伤之间保持着微妙的平衡。它们调节血管稳态,并在白细胞外渗的情况下推动损伤后的修复。最重要的是,血小板能启动细胞外陷阱的生成并促进免疫血栓形成。在人类慢性疾病中,血小板的作用往往超出其正常作用,引发白细胞和壁细胞的持续相互激活,最终导致不良的血管重塑。过去十年的研究发现了血小板活化过程中的一个新的关键角色--高迁移率基团框 1(HMGB1)蛋白。尽管高迁移率基团框 1 蛋白最初被定性为染色质分子,但无核血小板表达大量的 HMGB1,它已成为血栓炎症风险和微血管重塑的关键因素。我们建议对血小板 HMGB1 进行全面评估,包括对其含量、膜定位和生物液体中表达 HMGB1 的囊泡的积累进行量化,这对于剖析和量化血小板活化不可或缺。本综述提供了支持这一观点的证据,并强调了血小板 HMGB1 作为生物标记物在与血栓风险增加和全身微血管受累相关的疾病(包括心血管疾病、自身免疫性疾病和传染性疾病)中的重要性。
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引用次数: 0
Production of physiological amounts of hemostatic proteins by human donor livers during ex situ long-term normothermic machine perfusion for up to 7 days 在长达七天的原位长期常温机器灌注过程中,人体捐献肝脏产生生理数量的止血蛋白。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-08-22 DOI: 10.1016/j.jtha.2024.08.004
Bianca Lascaris , Silke B. Bodewes , Jelle Adelmeijer , Maarten W.N. Nijsten , Robert J. Porte , Vincent E. de Meijer , Ton Lisman

Background

Normothermic machine perfusion (NMP) is used for preservation and assessment of human donor livers prior to transplantation. During NMP, the liver is metabolically active, which allows detailed studies on the physiology of human livers.

Objectives

To study the production of hemostatic proteins in human donor livers during NMP for up to 7 days.

Methods

In this observational study, 9 livers underwent NMP for up to 7 days with a heparinized perfusate based on red blood cells and colloids using a modified Liver Assist device (XVIVO). Perfusate samples were collected before NMP and daily thereafter for measurement of antigen and activity levels of a comprehensive panel of hemostatic proteins after heparin neutralization.

Results

Within 1 day, perfusate samples displayed the potential for coagulation activation as evidenced by international normalized ratio and activated partial thromboplastin assays. This was accompanied by detection of substantial quantities of functionally active coagulation proteins and inhibitors, although the specific activity of many proteins was decreased, compared with that in normal plasma. Perfusate levels of hemostatic proteins increased in the first days, reaching a stable level after 3 to 4 days of perfusion.

Conclusion

During long-term NMP of human livers, functionally active hemostatic proteins are released into the perfusate in substantial quantities, but some proteins appear to have decreased functional properties compared with proteins in normal human plasma. We propose that NMP may be used as a platform to test efficacy of drugs that stimulate or inhibit the production of coagulation factors or to test liver-mediated clearance of prohemostatic protein therapeutics.
背景:常温机器灌注(NMP)用于保存和评估移植前的人体捐献肝脏。在 NMP 期间,肝脏新陈代谢活跃,可以对人体肝脏的生理机能进行详细研究:研究人体供体肝脏在长达 7 天的 NMP 期间止血蛋白的生成情况:在这项观察性研究中,九个肝脏接受了长达 7 天的 NMP,并使用改良的肝脏辅助装置获得了以红细胞和胶体为基础的肝素化灌注液。在进行 NMP 之前收集灌注液样本,之后每天收集样本,以便在肝素中和后测量止血蛋白综合面板的抗原和活性水平:结果:在一天内,灌注液样本显示出凝血活化的可能性,国际归一化比率和活化部分凝血活酶检测证明了这一点。与正常血浆相比,虽然许多蛋白的特异性活性降低了,但同时还检测到了大量具有功能活性的凝血蛋白和抑制剂。灌流液中的止血蛋白水平在最初几天有所增加,在灌流 3-4 天后达到稳定水平:结论:在对人类肝脏进行长期 NMP 灌注期间,大量具有功能活性的止血蛋白被释放到灌流液中,但与正常人血浆中的蛋白相比,某些蛋白的功能特性似乎有所下降。我们建议将 NMP 作为一个平台,用于测试刺激或抑制凝血因子产生的药物的疗效,或测试肝脏介导的止血蛋白治疗药物的清除率。
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引用次数: 0
Early thrombus formation is required for eccentric and heterogeneous neointimal hyperplasia under disturbed flow. 在血流紊乱的情况下,偏心和异源性新内膜增生需要早期血栓形成。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-08-21 DOI: 10.1016/j.jtha.2024.07.028
Hualong Bai, Zhuo Li, Weichang Zhang, Carly Thaxton, Yuichi Ohashi, Luis Gonzalez, Masaki Kano, Bogdan Yatsula, John Hwa, Alan Dardik

Background: Anticoagulation and antiplatelet therapy effectively inhibit neointimal hyperplasia (NIH) in both arterial and venous systems but not in arteriovenous fistulae (AVF). The main site of AVF failure is the juxta-anastomotic area that is characterized by disturbed flow compared with laminar flow in the arterial inflow and the venous outflow.

Objectives: We hypothesized that early thrombus formation is required for eccentric and heterogeneous NIH in the presence of disturbed flow.

Methods: Needle puncture and sutured AVF were created in C57BL/6 mice, in PF4-Cre × mT/mG reporter mice, and in Wistar rats. Human AVF samples were second-stage basilic vein transpositions. The tissues were examined by histology, immunofluorescence, immunohistochemistry, and en face staining.

Results: In the presence of disturbed flow, both mouse and human AVF showed eccentric and heterogeneous NIH. Maladapted vein wall was characterized by eccentric and heterogeneous neointima that was composed of a different abundance of thrombus and smooth muscle cells. PF4-cre × mT/mG reporter mice AVF showed that green fluorescent protein-labeled platelets deposit on the wall directly facing the fistula exit with endothelial cell loss and continue to accumulate in the presence of disturbed flow. Neither disturbed flow with limited endothelial cell loss nor nondisturbed flow induced heterogeneous neointima in different animal models.

Conclusion: Early thrombus contributes to late heterogeneous NIH in the presence of disturbed flow. Disturbed flow, large area of endothelial cell loss, and thrombus formation are critical to form eccentric and heterogeneous NIH. Categorization of adapted or maladapted walls may be helpful for therapy targeting heterogeneous NIH.

背景:抗凝和抗血小板疗法能有效抑制动脉和静脉系统的新内膜增生(NIH),但不能抑制动静脉瘘(AVF)。动静脉瘘失败的主要部位是吻合口附近区域,与动脉流入和静脉流出的层流相比,该区域的特点是血流紊乱。我们假设,在血流紊乱的情况下,偏心和异源性 NIH 需要早期血栓形成:方法:在 C57BL/6 小鼠、PF4-cre × mT/mG 报告小鼠和 Wistar 大鼠身上建立针刺和缝合的动静脉瘘。转位收获人类动静脉瘘样本。通过组织学、免疫荧光、免疫组织化学和表面染色对组织进行检查:结果:在血流紊乱的情况下,小鼠和人类的动静脉瘘都表现出偏心和异质的 NIH。适应不良的静脉壁表现为偏心和异质的新内膜,由不同数量的血栓和平滑肌细胞(SMC)组成。PF4-cre × mT/mG 报告小鼠 AVF 显示,GFP 标记的血小板沉积在直接面向瘘管出口的静脉壁上,内皮细胞脱落,并在血流紊乱的情况下继续聚集。在不同的动物模型中,内皮细胞损失有限的干扰血流和非干扰血流都不会诱发异源性新生内膜:结论:在血流紊乱的情况下,早期血栓会导致晚期异源性新生内膜。干扰血流、大面积内皮细胞缺失和血栓形成是形成偏心和异源性 NIH 的关键。对适应或不适应的血管壁进行分类可能有助于针对异源性 NIH 的治疗。
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引用次数: 0
期刊
Journal of Thrombosis and Haemostasis
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