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Impaired fibrinolysis in JAK2V617F-related myeloproliferative neoplasms JAK2V617F相关骨髓增殖性肿瘤中的纤维蛋白溶解功能受损。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-12 DOI: 10.1016/j.jtha.2024.07.031
Marie-Charlotte Bourrienne , Stéphane Loyau , Dorothée Faille , Juliette Gay , Séléna Akhenak , Carine Farkh , Véronique Ollivier , Mialitiana Solonomenjanahary , Sébastien Dupont , Christine Choqueux , Jean-Luc Villeval , Isabelle Plo , Valérie Edmond , Benoît Ho-Tin-Noé , Nadine Ajzenberg , Mikaël Mazighi

Background

Myeloproliferative neoplasms (MPNs) are characterized by a high rate of thrombotic complications that contribute to morbidity and mortality. MPN-related thrombogenesis is assumed to be multifactorial, involving both procoagulant and proinflammatory processes. Whether impaired fibrinolysis also participates in the prothrombotic phenotype of MPN has been poorly investigated.

Objectives

We determined whether MPN, particularly JAK2V617F-positive MPN, is associated with fibrinolytic changes.

Methods

Tissue-type plasminogen activator (tPA)–mediated fibrinolysis was evaluated both in whole blood and plasma from mice with a hematopoietic-restricted Jak2V617F expression compared with wild-type (WT) mice (Jak2WT) using (1) halo clot lysis, (2) front lysis, and (3) plasmin generation assays. tPA clot lysis assay was performed in the plasma from 65 MPN patients (JAK2V617F mutation, n = 50; CALR mutations, n = 9) compared with 28 healthy controls.

Results

In whole blood from Jak2V617F mice, we observed a decreased fibrinolysis characterized by a significantly lower halo clot lysis rate compared with Jak2WT (95 ± 22 vs 147 ± 39 AU/min; P < .05). Similar results were observed in plasma (halo clot lysis rate, 130 ± 27 vs 186 ± 29 AU/min; front lysis rate, 2.8 ± 1.6 vs 6.1 ± 1.2 μm.min−1; P < .05). Plasmin generation was significantly decreased both in plasma clots and standardized fibrin clots from Jak2V617F mice compared with Jak2WT mice. Among MPN patients, impaired tPA-related fibrinolysis with prolonged clot lysis time was observed in JAK2V617F and CALR patients. Plasminogen activator inhibitor-1 and α2-antiplasmin were significantly increased in plasma from JAK2V617F patients compared with controls.

Conclusion

Our results suggest that impaired tPA-mediated fibrinolysis represents an important prothrombotic mechanism in MPN patients that requires confirmation in larger studies.
背景骨髓增殖性肿瘤(MPN)的特点是血栓并发症发生率高,导致死亡率增加。与 MPN 相关的血栓形成被认为是多因素的,涉及促凝血和促炎症过程。纤溶功能受损是否也参与了 MPN 促血栓形成表型的形成,这一问题尚未得到深入研究。患者与野生型小鼠(Jak2WT)相比,我们使用(1)光环凝块裂解法、(2)前端裂解法和(3)血浆蛋白酶生成测定法,对造血受限的 Jak2V617F 表达小鼠的全血(WB)和血浆中组织纤溶酶原激活剂(tPA)介导的纤溶进行了评估。结果在Jak2V617F小鼠的WB中,我们观察到纤维蛋白溶解减少,其特征是与Jak2WT相比,晕凝块溶解率显著降低(95±22 vs 147±39 UA/min,p<0.05)。在血浆中也观察到类似的结果(晕凝块溶解率:130±27 vs 186±29 UA/min):130±27 vs 186±29 UA/min;正面裂解率:2.8±1.6 vs 6.1±1.2 μm.min-1,p<0.05)。与 Jak2WT 小鼠相比,Jak2V617F 小鼠血浆凝块和标准化纤维蛋白凝块中产生的凝血酶明显减少。在骨髓增生性疾病患者中,JAK2V617F 和 CALR 患者的 tPA 相关纤溶功能受损,血块溶解时间延长。与对照组相比,JAK2V617F 患者血浆中的纤溶酶原激活物抑制剂-1 和α-2-抗蛋白酶显著增加。
{"title":"Impaired fibrinolysis in JAK2V617F-related myeloproliferative neoplasms","authors":"Marie-Charlotte Bourrienne ,&nbsp;Stéphane Loyau ,&nbsp;Dorothée Faille ,&nbsp;Juliette Gay ,&nbsp;Séléna Akhenak ,&nbsp;Carine Farkh ,&nbsp;Véronique Ollivier ,&nbsp;Mialitiana Solonomenjanahary ,&nbsp;Sébastien Dupont ,&nbsp;Christine Choqueux ,&nbsp;Jean-Luc Villeval ,&nbsp;Isabelle Plo ,&nbsp;Valérie Edmond ,&nbsp;Benoît Ho-Tin-Noé ,&nbsp;Nadine Ajzenberg ,&nbsp;Mikaël Mazighi","doi":"10.1016/j.jtha.2024.07.031","DOIUrl":"10.1016/j.jtha.2024.07.031","url":null,"abstract":"<div><h3>Background</h3><div>Myeloproliferative neoplasms (MPNs) are characterized by a high rate of thrombotic complications that contribute to morbidity and mortality. MPN-related thrombogenesis is assumed to be multifactorial, involving both procoagulant and proinflammatory processes. Whether impaired fibrinolysis also participates in the prothrombotic phenotype of MPN has been poorly investigated.</div></div><div><h3>Objectives</h3><div>We determined whether MPN, particularly <em>JAK2</em>V617F-positive MPN, is associated with fibrinolytic changes.</div></div><div><h3>Methods</h3><div>Tissue-type plasminogen activator (tPA)–mediated fibrinolysis was evaluated both in whole blood and plasma from mice with a hematopoietic-restricted Jak2<sup>V617F</sup> expression compared with wild-type (WT) mice (Jak2<sup>WT</sup>) using (1) halo clot lysis, (2) front lysis, and (3) plasmin generation assays. tPA clot lysis assay was performed in the plasma from 65 MPN patients (<em>JAK2</em>V617F mutation, <em>n</em> = 50; <em>CALR</em> mutations, <em>n</em> = 9) compared with 28 healthy controls.</div></div><div><h3>Results</h3><div>In whole blood from Jak2<sup>V617F</sup> mice, we observed a decreased fibrinolysis characterized by a significantly lower halo clot lysis rate compared with Jak2<sup>WT</sup> (95 ± 22 vs 147 ± 39 AU/min; <em>P</em> &lt; .05). Similar results were observed in plasma (halo clot lysis rate, 130 ± 27 vs 186 ± 29 AU/min; front lysis rate, 2.8 ± 1.6 vs 6.1 ± 1.2 μm.min<sup>−1</sup>; <em>P</em> &lt; .05). Plasmin generation was significantly decreased both in plasma clots and standardized fibrin clots from Jak2<sup>V617F</sup> mice compared with Jak2<sup>WT</sup> mice. Among MPN patients, impaired tPA-related fibrinolysis with prolonged clot lysis time was observed in <em>JAK2</em>V617F and <em>CALR</em> patients. Plasminogen activator inhibitor-1 and α2-antiplasmin were significantly increased in plasma from <em>JAK2</em>V617F patients compared with controls.</div></div><div><h3>Conclusion</h3><div>Our results suggest that impaired tPA-mediated fibrinolysis represents an important prothrombotic mechanism in MPN patients that requires confirmation in larger studies.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"22 11","pages":"Pages 3199-3208"},"PeriodicalIF":5.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142182687","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
Viral coagulation: pushing the envelope. 病毒感染:推陈出新。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-12 DOI: 10.1016/j.jtha.2024.08.014
Edward Louis George Pryzdial, John Ruggles Perrier, Mahamud-Ur Rashid, Henry Euan West, Michael Ross Sutherland

Many virus types affect the blood clotting system with correlations to pathology that range widely from thrombosis to hemorrhage linking to inflammation. Here we overview the intricate crosstalk induced by infection between proteins on the virus encoded by either the host or virus genomes, coagulation proteins, platelets, leukocytes, and endothelial cells. For blood-borne viruses with an outer covering acquired from the host cell, the envelope, a key player may be the cell-derived trigger of coagulation on the virus surface, tissue factor (TF). TF is a multifunctional transmembrane cofactor that accelerates factor (F)VIIa-dependent activation of FX to FXa, leading to clot formation. However, the nascent TF/FVIIa/FXa complex also facilitates G protein-coupled modulation of cells via protease-activated receptor 2. As a viral envelope constituent, TF can bypass the physiological modes of regulation, thereby initiating the activation of neighboring platelets, leukocytes, and endothelial cells. A thromboinflammatory environment is predicted due to feedback amplification in response to cellular release of cytokines, procoagulant proteins, neutrophil extracellular traps, and stimulus-induced accessibility of adhesive receptors, resulting in cellular aggregates. The pathobiological effects of thromboinflammation ultimately contribute to innate and adaptive immunity for viral clearance. In contrast, the preceding stages of viral infection may be enhanced via the TF-protease axis.

许多病毒类型都会影响凝血系统,并与从血栓形成到大出血再到炎症等各种病理现象相关联。在此,我们将概述由宿主或病毒基因组编码的病毒蛋白质、凝血蛋白、血小板、白细胞和内皮细胞之间因感染而产生的错综复杂的相互影响。对于从宿主细胞获得外壳(包膜)的血源性病毒来说,病毒表面源自细胞的凝血触发因子--组织因子(TF)可能是一个关键角色。TF 是一种多功能跨膜辅助因子,可加速因子(F)VIIa 依赖性活化 FX 为 FXa,从而形成血凝块。不过,新生的 TF/FVIIa/FXa 复合物还能通过蛋白酶激活受体-2 促进 G 蛋白耦合调节细胞。作为一种病毒包膜成分,TF 可以绕过生理调节模式,从而激活邻近的血小板、白细胞和内皮细胞。细胞因子、促凝血蛋白和中性粒细胞胞外捕获物的细胞释放,以及刺激引起的粘附受体的可及性导致细胞聚集,由此产生的反馈放大作用预示着血栓性炎症环境的形成。血栓栓塞性炎症的病理生物学效应最终会促进先天性和适应性免疫,从而清除病毒。相反,病毒感染的前几个阶段可能会通过 TF 蛋白酶轴得到加强。
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引用次数: 0
Estimation of Gestational Age-Specific Reference Intervals for Coagulation Assays in a Neonatal Intensive Care Unit Using Real-World Data. 利用实际数据估算新生儿重症监护室凝血检测的妊娠年龄特异性参考区间。
IF 10.4 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-11 DOI: 10.1016/j.jtha.2024.08.017
Natasha Lalos,Zachary Vesoulis,Carly Maucione,Charles Eby,Dennis J Dietzen,Stephen Roper,Nicholas C Spies
BACKGROUNDInterpretation of coagulation testing in neonates currently relies on reference intervals (RIs) defined from older patient cohorts. Direct RI studies are difficult, but indirect estimation may allow us to infer normative neonatal distributions from routinely collected clinical data.METHODSWe analyzed first-in-life coagulation testing results from all patients admitted to a level IV neonatal intensive care unit between 1/1/2018-1/1/2024. Results obtained after transfusion of any blood product were excluded. Indirect RIs were estimated across gestational age groups using refineR and compared to currently reported intervals for patients less than one year of age.RESULTSProthrombin times (PT) and international normalized ratios (INR) were available for 1,128 neonates, while activated partial thromboplastin times (aPTT) were available for 790 neonates. The indirect RI was 10-25s in preterm, 10-22s in term, and 10-24s in all neonates for PT, 0.7-2.1 in preterm, 0.8-1.8 in term, and 0.8-1.9 in all neonates for INR, and 25-68s in preterm, 25-58s in term, and 25-62s in all neonates for aPTT. Compared to our current intervals, the indirect RIs would flag 58% fewer PT, 43% fewer INR, and 17% fewer aPTT results as abnormal.CONCLUSIONSIndirectly estimated RIs in neonates admitted to intensive care show substantial divergence from current, first-year-of-life RIs, leading to an abundance of abnormal flags. The associations between these flags and provider behavior, transfusion practice, or clinical outcomes is an area of future exploration.
背景目前,对新生儿凝血检测结果的解释主要依赖于根据年龄较大的患者队列确定的参考区间(RI)。我们分析了 2018 年 1 月 1 日至 2024 年 1 月 1 日期间入住 IV 级新生儿重症监护病房的所有患者的首次生命凝血检测结果。不包括输注任何血液制品后获得的结果。结果1128名新生儿的凝血酶原时间(PT)和国际正常化比率(INR)可用,790名新生儿的活化部分凝血活酶时间(aPTT)可用。早产儿的 PT 间接 RI 为 10-25,足月儿为 10-22,所有新生儿为 10-24;早产儿的 INR 为 0.7-2.1,足月儿为 0.8-1.8,所有新生儿为 0.8-1.9;早产儿的 aPTT 为 25-68,足月儿为 25-58,所有新生儿为 25-62。结论重症监护室收治的新生儿中,间接估计的 RI 与当前的新生儿第一年 RI 有很大差异,导致了大量异常标记。这些标记与医疗服务提供者的行为、输血实践或临床结果之间的关联是未来需要探索的领域。
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引用次数: 0
Professor Victor S. Blanchette, MA, MB, Bchir (Cantab), FRCP(C), FRCP (1945-2024). 维克托-S-布兰切特教授,硕士、医学博士、英国皇家医学会会员(坎塔布)、英国皇家医学会会员(C)、英国皇家医学会会员(1945-2024)。
IF 10.4 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-11 DOI: 10.1016/j.jtha.2024.09.002
Margaret L Rand,Nicholas Blanchette,Manuel D Carcao
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引用次数: 0
The management of liver disease in people with congenital bleeding disorders: guidance from EAHAD, EHC, ISTH, WFH. 先天性出血性疾病患者的肝病管理:来自 EAHAD、EHC、ISTH 和 WFH 的指南。
IF 10.4 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-11 DOI: 10.1016/j.jtha.2024.08.018
Vincenzo LA Mura,Massimo Colombo,Graham R Foster,Paolo Angeli,Wolfgang Miesbach,Robert Klamroth,Glenn F Pierce,Brian O'Mahony,Ming Y Lim,Virginia Hernandez-Gea,Michael Makris,Flora Peyvandi
People with bleeding disorders (PWBD) have been exposed to the risk of developing chronic viral hepatitis and cirrhosis after replacement therapy. At today, the advent of new pharmacological strategies for the control of hemostasis and the efficacious antiviral therapies against HCV and HBV have significantly reduced this risk. However, the real success for liver health in this clinical setting is based on other risk factors, among them, the severity of liver disease at time of HBV/HCV antiviral therapy and the exposure to highly prevalent factors of chronic liver damage (e.g.; metabolic dysfunction and/or alcohol) that can cause a residual risk of complications such as hepatocellular carcinoma, portal hypertension, liver insufficiency. With this background, a group of experts selected among hepatologists, PWBD treaters and patient representatives, produced this practical multisociety guidance for the protection of liver health and the prevention and management of liver complications in PWBD based on the most updated protocols of care.
出血性疾病患者(PWBD)在接受替代治疗后,面临着罹患慢性病毒性肝炎和肝硬化的风险。如今,控制止血的新药策略以及针对丙型肝炎病毒(HCV)和乙型肝炎病毒(HBV)的高效抗病毒疗法的出现大大降低了这一风险。然而,在这种临床环境下,肝脏健康的真正成功取决于其他风险因素,其中包括 HBV/HCV 抗病毒治疗时肝脏疾病的严重程度,以及是否暴露于慢性肝损伤的高发因素(如代谢功能障碍和/或酒精),这些因素会导致肝细胞癌、门静脉高压症、肝功能不全等并发症的残余风险。在此背景下,一组从肝病专家、肺结核患者治疗者和患者代表中挑选出来的专家,根据最新的护理方案,为保护肝脏健康、预防和管理肺结核患者的肝脏并发症制定了这份实用的多协会指南。
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引用次数: 0
Low VWF - unravelling an enigma wrapped in a conundrum. 低 VWF--揭开谜团中的谜底。
IF 10.4 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-10 DOI: 10.1016/j.jtha.2024.08.015
James S O'Donnell,Ross I Baker,Ferdows Atiq
The 2021 ASH ISTH NHF WFH guidelines recommendation that patients with VWF levels of 30-50 IU/dL and an increased bleeding phenotype be categorized as type 1 VWD rather than Low VWF has proved controversial. However, in support of that decision, recent data have demonstrated that individuals with partial quantitative VWF deficiency exhibit an age-dependent evolving phenotype and confirmed that Low VWF represents a sub-group within heterogeneous type 1 VWD. Nonetheless, type 1 VWD heterogeneity continues to pose significant diagnostic challenges. In this Forum Article, we address outstanding issues critical to preventing the inappropriate overdiagnosis of type 1 VWD, while maximizing access to healthcare and minimizing diagnostic delays. In addition, we propose an algorithm for type 1 VWD diagnosis. This algorithm pays special attention to individuals with plasma VWF levels in the 30-50 IU/dL range who have no or minimal bleeding history and have not yet been exposed to significant hemostatic challenges.
2021 年 ASH ISTH NHF WFH 指南建议将 VWF 水平为 30-50 IU/dL 且出血表型增加的患者归类为 1 型 VWD,而不是低 VWF,这一建议引起了争议。然而,为了支持这一决定,最近的数据表明,部分定量 VWF 缺乏的患者表现出与年龄相关的演变表型,并证实低 VWF 代表了异质性 1 型 VWD 中的一个亚组。尽管如此,1 型 VWD 的异质性仍给诊断带来巨大挑战。在这篇论坛文章中,我们探讨了一些悬而未决的问题,这些问题对于防止不适当地过度诊断 1 型 VWD 至关重要,同时还能最大限度地提高医疗服务的可及性和减少诊断延误。此外,我们还提出了一种 1 型 VWD 诊断算法。该算法特别关注血浆 VWF 水平在 30-50 IU/dL 范围内、无出血史或出血史极少、尚未面临重大止血挑战的个体。
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引用次数: 0
The changing face of cerebral venous sinus thrombosis - emerging new causes and treatments. 不断变化的脑静脉窦血栓--新出现的病因和治疗方法。
IF 10.4 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-09 DOI: 10.1016/j.jtha.2024.08.012
Caroline Dix,Beverley J Hunt
Cerebral venous sinus thrombosis (CVST) is an uncommon site of venous thromboembolism. CVST more commonly affects younger people and women, in stark contrast to other forms of venous thrombosis where incidence increases with age and overall affects men. Traditional risk factors for the development of CVST include endogenous and exogenous estrogen (combined oral contraceptives and pregnancy and the puerperium), thrombophilias and rare haematologic disorders. New and emerging risk factors include obesity, polycystic ovary syndrome, COVID-19 infection, and vaccine-induced thrombocytopenia and thrombosis (VITT) and VITT-like disorders. Management centres around anticoagulation, managing the underlying cause, and consideration of invasive measures including endovascular thrombolysis and/or thrombectomy and craniectomy for severe cases. This review discusses the emerging risk factors and their identification, evidence for treatment including the use of direct oral anticoagulants, and the role of invasive management options.
脑静脉窦血栓形成(CVST)是一种不常见的静脉血栓栓塞症。脑静脉窦血栓更常见于年轻人和女性,这与其他形式的静脉血栓形成形成鲜明对比,后者的发病率随着年龄的增长而增加,而且总体上影响男性。发生 CVST 的传统风险因素包括内源性和外源性雌激素(联合口服避孕药、妊娠和产褥期)、血栓性疾病和罕见的血液病。新出现的风险因素包括肥胖、多囊卵巢综合征、COVID-19 感染、疫苗诱发的血小板减少症和血栓形成(VITT)以及 VITT 类疾病。治疗主要围绕抗凝、控制潜在病因以及考虑采取侵入性措施,包括血管内溶栓和/或血栓切除术,严重病例还需进行颅骨切除术。本综述讨论了新出现的风险因素及其识别、治疗证据(包括使用直接口服抗凝剂)以及侵入性治疗方案的作用。
{"title":"The changing face of cerebral venous sinus thrombosis - emerging new causes and treatments.","authors":"Caroline Dix,Beverley J Hunt","doi":"10.1016/j.jtha.2024.08.012","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.08.012","url":null,"abstract":"Cerebral venous sinus thrombosis (CVST) is an uncommon site of venous thromboembolism. CVST more commonly affects younger people and women, in stark contrast to other forms of venous thrombosis where incidence increases with age and overall affects men. Traditional risk factors for the development of CVST include endogenous and exogenous estrogen (combined oral contraceptives and pregnancy and the puerperium), thrombophilias and rare haematologic disorders. New and emerging risk factors include obesity, polycystic ovary syndrome, COVID-19 infection, and vaccine-induced thrombocytopenia and thrombosis (VITT) and VITT-like disorders. Management centres around anticoagulation, managing the underlying cause, and consideration of invasive measures including endovascular thrombolysis and/or thrombectomy and craniectomy for severe cases. This review discusses the emerging risk factors and their identification, evidence for treatment including the use of direct oral anticoagulants, and the role of invasive management options.","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142182690","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
Clinical validation and application of targeted long-range PCR and long-read sequencing-based analysis for haemophilia: experience from a haemophilia treatment centre in China. 基于长程定量 PCR 和长序列测序的血友病靶向分析的临床验证和应用:来自中国一家血友病治疗中心的经验。
IF 10.4 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-09 DOI: 10.1016/j.jtha.2024.08.013
Meizhen Shi,Yunting Ma,Xianwei Peng,Xu Zhou,Zifeng Cheng,Bobo Xie,Xianda Wei,Chunrong Gui,Aiping Mao,Wenting Lin,Jiefeng Luo,Yinghui Lai,Baoheng Gui
BACKGROUNDTargeted long-read sequencing (LRS) is expected to comprehensively analyse diverse complex variants in haemophilia A (HA) and B (HB), caused by the F8 and F9 genes, respectively. However, its clinical applicability still requires extensive validation.OBJECTIVESTo evaluate the clinical applicability of targeted LRS-based analysis, compared with routine PCR-based methods.METHODSGene variants of retrieved subjects were retrospectively and prospectively analysed. Whole-genome sequencing (WGS) was performed to further analyse undiagnosed cases. Breakpoints of novel genomic rearrangements were mapped and validated using long-distance-PCR and long-range-PCR combined with sequencing.RESULTSTotally, 122 subjects were retrieved. In retrospective analysis of the 90 HA cases, HA-LRS assay showed consistent results in 84 cases compared with routine methods, and characterized six large deletions with their exact breakpoints confirmed by further validation in six cases (routine methods only presented failure in amplifying the involved exons). In prospective analysis of the 21 HA subjects, 20 variants of F8 were identified in 20 cases. For the remaining HA patient, no duplication/deletion or SNV/InDel was found, but a potential recombination involving exons 14 and 21 of F8 was observed by LRS. WGS analysis and further verification defined a 30,478bp tandem repeat involving exons 14-21 of F8. Among the 11 HB patients, HB-LRS analysis detected 11 SNVs/InDels in F9, consistent with routine methods.CONCLUSIONSTargeted LRS-based analysis is efficient and comprehensive to identify SNVs/InDels and genomic rearrangements of haemophilia genes, especially we first expanding the panel including F9. However, further investigation for complex gross rearrangement is still essential.
背景靶向长读测序(LRS)有望全面分析分别由 F8 和 F9 基因引起的血友病 A(HA)和血友病 B(HB)的各种复杂变异。方法对检索对象的基因变异进行回顾性和前瞻性分析。为进一步分析未确诊病例,还进行了全基因组测序(WGS)。利用长程 PCR 和长程 PCR 结合测序技术绘制并验证了新型基因组重排的断点。在对 90 例 HA 病例的回顾性分析中,与常规方法相比,HA-LRS 检测法在 84 例病例中显示出一致的结果,并在 6 例病例中通过进一步验证确认了 6 个大缺失的特征及其确切断点(常规方法仅在扩增涉及的外显子时出现失败)。在对 21 名 HA 受试者的前瞻性分析中,在 20 个病例中发现了 20 个 F8 变异。其余一名 HA 患者没有发现重复/缺失或 SNV/InDel,但通过 LRS 观察到了涉及 F8 第 14 和 21 号外显子的潜在重组。WGS 分析和进一步验证确定了涉及 F8 第 14-21 号外显子的 30,478bp 串联重复。结论基于 LRS 的靶向分析能高效、全面地鉴定血友病基因的 SNVs/InDels 和基因组重排,尤其是我们首次扩大了包括 F9 基因在内的面板。然而,进一步研究复杂的总重排仍是必要的。
{"title":"Clinical validation and application of targeted long-range PCR and long-read sequencing-based analysis for haemophilia: experience from a haemophilia treatment centre in China.","authors":"Meizhen Shi,Yunting Ma,Xianwei Peng,Xu Zhou,Zifeng Cheng,Bobo Xie,Xianda Wei,Chunrong Gui,Aiping Mao,Wenting Lin,Jiefeng Luo,Yinghui Lai,Baoheng Gui","doi":"10.1016/j.jtha.2024.08.013","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.08.013","url":null,"abstract":"BACKGROUNDTargeted long-read sequencing (LRS) is expected to comprehensively analyse diverse complex variants in haemophilia A (HA) and B (HB), caused by the F8 and F9 genes, respectively. However, its clinical applicability still requires extensive validation.OBJECTIVESTo evaluate the clinical applicability of targeted LRS-based analysis, compared with routine PCR-based methods.METHODSGene variants of retrieved subjects were retrospectively and prospectively analysed. Whole-genome sequencing (WGS) was performed to further analyse undiagnosed cases. Breakpoints of novel genomic rearrangements were mapped and validated using long-distance-PCR and long-range-PCR combined with sequencing.RESULTSTotally, 122 subjects were retrieved. In retrospective analysis of the 90 HA cases, HA-LRS assay showed consistent results in 84 cases compared with routine methods, and characterized six large deletions with their exact breakpoints confirmed by further validation in six cases (routine methods only presented failure in amplifying the involved exons). In prospective analysis of the 21 HA subjects, 20 variants of F8 were identified in 20 cases. For the remaining HA patient, no duplication/deletion or SNV/InDel was found, but a potential recombination involving exons 14 and 21 of F8 was observed by LRS. WGS analysis and further verification defined a 30,478bp tandem repeat involving exons 14-21 of F8. Among the 11 HB patients, HB-LRS analysis detected 11 SNVs/InDels in F9, consistent with routine methods.CONCLUSIONSTargeted LRS-based analysis is efficient and comprehensive to identify SNVs/InDels and genomic rearrangements of haemophilia genes, especially we first expanding the panel including F9. However, further investigation for complex gross rearrangement is still essential.","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"33 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142182689","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
Factors Associated with Venous Thromboembolism Pharmacoprophylaxis Initiation in Hospitalized Medical Patients: The Medical Inpatients Thrombosis and Hemostasis (MITH) Study. 住院病人静脉血栓栓塞药物预防的相关因素:住院医患血栓与止血(MITH)研究》。
IF 10.4 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-09 DOI: 10.1016/j.jtha.2024.08.016
Allen B Repp,Andrew D Sparks,Katherine Wilkinson,Nicholas S Roetker,Jordan K Schaefer,Ang Li,Leslie A McClure,Deirdra R Terrell,Augusto Ferraris,Alys Adamski,Nicholas L Smith,Neil A Zakai
BACKGROUNDAlthough guidelines recommend risk assessment for hospital-acquired venous thromboembolism (HA-VTE) to inform prophylaxis decisions, studies demonstrate inappropriate utilization of pharmacoprophylaxis in hospitalized medical patients. Predictors of pharmacoprophylaxis initiation in medical inpatients remain largely unknown.OBJECTIVETo determine factors associated with HA-VTE pharmacoprophylaxis initiation in adults hospitalized on medical services.DESIGNCohort study using electronic health record data from adult patients hospitalized on medical services at four academic medical centers between 2016 and 2019.PARTICIPANTSAmong 111,550 admissions not on intermediate or full-dose anticoagulation, 48,520 (43.5%) received HA-VTE pharmacoprophylaxis on the day of or the day after admission.MAIN MEASURESCandidate predictors of HA-VTE pharmacoprophylaxis initiation, including known HA-VTE risk factors, predicted HA-VTE risk, and bleeding diagnoses present on admission.KEY RESULTSAfter adjustment for age, sex, race/ethnicity, and study site, the strongest clinical predictors of HA-VTE pharmacoprophylaxis initiation were malnutrition and chronic obstructive pulmonary disease. Thrombocytopenia and history of gastrointestinal bleeding were associated with decreased odds of HA-VTE pharmacoprophylaxis initiation. Patients in the highest two tertiles of predicted HA-VTE risk were less likely to receive HA-VTE pharmacoprophylaxis than patients in the lowest (1st) tertile (OR 0.84, 95% CI [0.81, 0.86] for 2nd tertile, OR 0.95, 95% CI [0.92, 0.98] for 3rd tertile).CONCLUSIONSAmong patients not already receiving anticoagulants, HA-VTE pharmacoprophylaxis initiation during the first two hospital days was lower in patients with higher predicted HA-VTE risk and those with risk factors for bleeding. Reasons for not initiating pharmacoprophylaxis in those with higher predicted risk could not be assessed.
背景尽管指南建议对医院获得性静脉血栓栓塞症(HA-VTE)进行风险评估,以便为预防决策提供依据,但研究表明,住院内科病人药物预防使用不当。目标确定在医疗服务机构住院的成人中启动 HA-VTE 药物预防的相关因素.设计使用 2016 年至 2019 年期间在四个学术医疗中心医疗服务机构住院的成人患者的电子健康记录数据进行队列研究.参与者在 111,550 例未接受中剂量或全剂量抗凝治疗的入院患者中,有 48,520 例(43.主要测量HA-VTE药物预防启动的候选预测因素,包括已知的HA-VTE风险因素、预测的HA-VTE风险和入院时存在的出血诊断。主要结果经年龄、性别、种族/民族和研究地点调整后,HA-VTE药物预防启动的最强临床预测因素是营养不良和慢性阻塞性肺病。血小板减少症和胃肠道出血史与启动 HA-VTE 药物预防的几率降低有关。预测 HA-VTE 风险最高的两个三分位数的患者接受 HA-VTE 药物预防的几率低于最低(第一)三分位数的患者(第二三分位数的 OR 为 0.84,95% CI [0.81,0.86];第三三分位数的 OR 为 0.95,95% CI [0.92,0.98])。结论在尚未接受抗凝药物治疗的患者中,预测HA-VTE风险较高和有出血风险因素的患者在住院头两天开始接受HA-VTE药物预防治疗的比例较低。无法评估预测风险较高的患者未开始药物预防的原因。
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引用次数: 0
Endothelial colony-forming cells in the spotlight: insights into the pathophysiology of von Willebrand disease and rare bleeding disorders. 聚焦内皮集落形成细胞,深入了解冯-威廉氏病和罕见出血性疾病的病理生理学。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-05 DOI: 10.1016/j.jtha.2024.08.011
Sebastiaan N J Laan, Britte G Lenderink, Jeroen C J Eikenboom, Ruben Bierings

Endothelial cells deliver a vital contribution to the maintenance of hemostasis by constituting an anatomical as well as functional barrier between the blood and the rest of the body. Apart from the physical barrier function, endothelial cells maintain the hemostatic equilibrium by their pro- and anticoagulant functions. An important part of their procoagulant contribution is the production of von Willebrand factor (VWF), which is a carrier protein for coagulation factor VIII and facilitates the formation of a platelet plug. Thus, VWF is indispensable for both primary and secondary hemostasis, which is exemplified by the bleeding disorder von Willebrand disease that results from qualitative or quantitative deficiencies in VWF. A cellular model that was found to accurately reflect the endothelium and its secretory organelles are endothelial colony-forming cells, which can be readily isolated from peripheral blood and constitute a robust ex vivo model to investigate the donor's endothelial cell function. This review summarizes some of the valuable insights on biology of VWF and pathogenic mechanisms of von Willebrand disease that have been made possible using studies with endothelial colony-forming cells derived from patients with bleeding disorders.

内皮细胞是血液和身体其他部分之间的解剖学和功能性屏障,对维持止血做出了重要贡献。除了物理屏障功能外,内皮细胞还通过其促凝和抗凝功能维持止血平衡。内皮细胞促凝功能的一个重要部分是产生冯-威廉因子(VWF),它是凝血因子 VIII(FVIII)的载体蛋白,可促进血小板栓的形成。因此,VWF 对于原发性和继发性止血都是不可或缺的,出血性疾病 Von Willebrand Disease(VWD)就是一个很好的例子,它是由 VWF 的定性或定量缺陷引起的。内皮集落成形细胞(ECFCs)是一种能准确反映内皮及其分泌细胞器的细胞模型,它能很容易地从外周血中分离出来,是研究供体内皮细胞功能的一种强大的体外模型。本综述总结了利用从出血性疾病患者体内提取的 ECFCs 进行的研究对 VWF 生物学和 VWD 致病机制的一些有价值的见解。
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引用次数: 0
期刊
Journal of Thrombosis and Haemostasis
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