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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。
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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
Treatment of atrial fibrillation and venous thromboembolism with factor Xa inhibitors in severely obese patients. 用 Xa 因子抑制剂治疗严重肥胖患者的心房颤动和静脉血栓栓塞。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-05 DOI: 10.1016/j.jtha.2024.08.009
Paul Dobry, Stephanie B Edwin, Brian Haymart, Geoffrey D Barnes, Scott Kaatz, Mona A Ali, Christopher Giuliano

Background: A paucity of data exists to support the use of factor (F)Xa inhibitors in severely obese patients with a weight of ≥150 kg or body mass index (BMI) of ≥50 kg/m2.

Objectives: The purpose of this study was to evaluate whether FXa inhibitors are as safe and effective as warfarin for the treatment of atrial fibrillation (AF) and/or venous thromboembolism (VTE) in individuals with a BMI of ≥50 kg/m2 and/or weight of ≥150 kg.

Methods: This was a multicenter retrospective cohort study of severely obese adult patients with AF and/or VTE treated with a FXa inhibitor or warfarin. The primary effectiveness outcome was composite odds of stroke, systemic embolism, or VTE; the primary safety outcome was odds of major bleeding. Secondary outcomes included incidence of stroke or systemic embolism, VTE, major bleeding, clinically relevant nonmajor bleeding, all-cause mortality, change in anticoagulation, and total number of hospital encounters. Outcomes were assessed for 12 months following initiation of study drug.

Results: A total of 1736 patients were included. The mean weight and BMI of the overall cohort were 164.4 kg and 54.6 kg/m2, respectively. There was no difference in odds of stroke, systemic embolism or VTE (odds ratio, 1.005; 95% CI, 0.6-1.68), or major bleeding (odds ratio, 0.9; 95% CI, 0.47-1.7) between groups.

Conclusion: These data suggest that apixaban and rivaroxaban are safe and effective alternatives to warfarin for the treatment of AF and/or VTE in individuals with a BMI of ≥50 kg/m2 and/or weight of ≥150 kg.

背景:在体重≥150公斤或体重指数≥50公斤/平方米的重度肥胖患者中,支持使用Xa因子抑制剂的数据很少:本研究旨在评估Xa因子抑制剂在治疗体重≥50 kg/m2和/或体重≥150 kg的心房颤动(AF)和/或静脉血栓栓塞(VTE)时是否与华法林一样安全有效:这是一项多中心回顾性队列研究,研究对象是接受 Xa 因子抑制剂或华法林治疗的房颤和/或 VTE 重度肥胖成年患者。主要有效性结局是中风、全身性栓塞或 VTE 的复合几率;主要安全性结局是大出血的几率。次要结局包括中风或全身性栓塞、VTE、大出血、临床相关的非大出血、全因死亡率、抗凝剂量变化和住院总次数。在开始服用研究药物后的 12 个月内对结果进行评估:共纳入了 1,736 名患者。总体组群的平均体重和体重指数分别为 164.4 千克和 54.6 千克/平方米。各组间发生中风、全身性栓塞或 VTE(OR 1.005,95% CI 0.6 - 1.68)或大出血(OR 0.9,95% CI 0.47 - 1.7)的几率没有差异:这些数据表明,对于体重指数≥50 kg/m2和/或体重≥150 kg的患者,阿哌沙班和利伐沙班是华法林治疗房颤和/或VTE的安全有效的替代药物。
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引用次数: 0
Development of an assay using a modified coagulation factor V to measure protein S activity. 开发一种使用改良凝血因子 V 测量蛋白 S 活性的检测方法。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-05 DOI: 10.1016/j.jtha.2024.08.010
Keiko Maruyama, Koichi Kokame

Background: Protein S (PS) is an anticoagulant that functions as a cofactor for activated protein C and the tissue factor pathway inhibitor. PS deficiency is a risk factor for venous thromboembolism. PS activity is commonly measured using clot-based assays involving fibrin and thrombin production, but improvements are needed.

Objectives: To develop a new assay for measuring plasma PS activity by quantifying the amount of activated coagulation factor (F)V cleaved by activated protein C.

Methods: We designed a recombinant, modified FV (FVm) that mimicked FVa. We analyzed 160 purposively selected plasma samples from the Biobank of the National Cerebral and Cardiovascular Center.

Results: The assay using mixed normal and PS-deficient plasma detected FVm cleavage in a PS concentration-dependent manner. The correlation between PS activity, measured using the FVm cleavage assay, and free PS antigen levels was relatively weak. We then sequenced all exons of PROS1 from 47 subjects with <60% activity in either the FVm cleavage assay or the clot-based assay. Nonsynonymous variants were identified in 12 of 24 subjects with <60% activity in both assays and in 2 of 7 subjects with <60% activity in the FVm cleavage assay alone. No variants were identified in 16 subjects with <60% activity in the clot-based assay alone. Unlike the clot-based assay, the FVm cleavage assay was not affected by the presence of rivaroxaban in the plasma.

Conclusion: An assay using the FVm substrate may be less susceptible to interference and provide a more accurate evaluation of plasma PS activity than clot-based assays.

背景:蛋白 S(PS)是一种抗凝剂,是活化蛋白 C(APC)的辅助因子和组织因子通路抑制剂。缺乏 PS 是静脉血栓栓塞症的一个危险因素。PS活性通常使用基于凝块的检测方法进行测量,涉及纤维蛋白和凝血酶的生成,但仍需改进:目的:通过量化被 APC 分解的活化凝血因子 V(FVa)的量,开发一种测量血浆 PS 活性的新测定方法:我们设计了一种模拟 FVa 的重组改良 FV(FVm)。我们分析了从国立脑和心血管中心生物库中有目的地挑选的 160 份血浆样本:结果:使用正常和 PS 缺乏的混合血浆进行的检测发现,FVm 的裂解与 PS 浓度有关。用FVm裂解测定法测得的PS活性与游离PS抗原水平之间的相关性相对较弱。随后,我们对 47 名结论受试者的 PROS1 的所有外显子进行了测序:与基于凝块的检测方法相比,使用 FVm 底物的检测方法可能不易受干扰,并能更准确地评估血浆 PS 活性。
{"title":"Development of an assay using a modified coagulation factor V to measure protein S activity.","authors":"Keiko Maruyama, Koichi Kokame","doi":"10.1016/j.jtha.2024.08.010","DOIUrl":"10.1016/j.jtha.2024.08.010","url":null,"abstract":"<p><strong>Background: </strong>Protein S (PS) is an anticoagulant that functions as a cofactor for activated protein C and the tissue factor pathway inhibitor. PS deficiency is a risk factor for venous thromboembolism. PS activity is commonly measured using clot-based assays involving fibrin and thrombin production, but improvements are needed.</p><p><strong>Objectives: </strong>To develop a new assay for measuring plasma PS activity by quantifying the amount of activated coagulation factor (F)V cleaved by activated protein C.</p><p><strong>Methods: </strong>We designed a recombinant, modified FV (FVm) that mimicked FVa. We analyzed 160 purposively selected plasma samples from the Biobank of the National Cerebral and Cardiovascular Center.</p><p><strong>Results: </strong>The assay using mixed normal and PS-deficient plasma detected FVm cleavage in a PS concentration-dependent manner. The correlation between PS activity, measured using the FVm cleavage assay, and free PS antigen levels was relatively weak. We then sequenced all exons of PROS1 from 47 subjects with <60% activity in either the FVm cleavage assay or the clot-based assay. Nonsynonymous variants were identified in 12 of 24 subjects with <60% activity in both assays and in 2 of 7 subjects with <60% activity in the FVm cleavage assay alone. No variants were identified in 16 subjects with <60% activity in the clot-based assay alone. Unlike the clot-based assay, the FVm cleavage assay was not affected by the presence of rivaroxaban in the plasma.</p><p><strong>Conclusion: </strong>An assay using the FVm substrate may be less susceptible to interference and provide a more accurate evaluation of plasma PS activity than clot-based assays.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145868","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
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。
{"title":"Biomarker-enhanced cardiovascular risk prediction in patients with cancer: a prospective cohort study","authors":"Simon Kraler ,&nbsp;Luca Liberale ,&nbsp;Stephan Nopp ,&nbsp;Cornelia Englisch ,&nbsp;Ella Grilz ,&nbsp;Tetiana Lapikova-Bryhinska ,&nbsp;Alexander Akhmedov ,&nbsp;Federico Carbone ,&nbsp;Davide Ramoni ,&nbsp;Amedeo Tirandi ,&nbsp;Alessandro Scuricini ,&nbsp;Simone Isoppo ,&nbsp;Curzia Tortorella ,&nbsp;Federica La Rosa ,&nbsp;Cristina Michelauz ,&nbsp;Federica Frè ,&nbsp;Aurora Gavoci ,&nbsp;Anna Lisa ,&nbsp;Thomas M. Suter ,&nbsp;Arnold von Eckardstein ,&nbsp;Florian Moik","doi":"10.1016/j.jtha.2024.07.019","DOIUrl":"10.1016/j.jtha.2024.07.019","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Objectives</h3><div>To assess a broad panel of cardiovascular biomarkers and risk factors for the prediction of MACE and cardiovascular death in cancer patients.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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 <em>C</em>-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 <em>C</em>-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.</div></div><div><h3>Conclusion</h3><div>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 <em>first-of-its-kind</em> risk score may provide the basis for personalized cardiovascular risk assessment across cancer entities.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120151","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
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。
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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
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Journal of Thrombosis and Haemostasis
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