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Persistent Splenic-Derived IgM Preferentially Recognize Factor VIIIA2 and C2 Domain Epitopes but Do Not Alter Antibody Production. 持续存在的脾脏衍生 IgM 可优先识别因子 VIIIA2 和 C2 结构域表位,但不会改变抗体的产生。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-28 DOI: 10.1016/j.jtha.2024.10.017
Elizabeth S York, Benjamin D Dratch, Jasmine Ito, Samantha M Horwitz, Sahand Emamian, Joseph A Ambarian, Surinder Gill, Jayre Jones, Satheesh Chonat, Pete Lollar, Shannon L Meeks, Katherine M Davis, Glaivy Batsuli

Background: The most significant treatment complication for patients with hemophilia A is the development of neutralizing immunoglobin G (IgG), termed inhibitors, against factor VIII (FVIII) which prevent FVIII replacement therapy. Low titers of FVIII-specific immunoglobin M (IgM) have been identified in hemophilia A patients with and without inhibitors, as well as healthy individuals. However, the duration and influence of IgM on the immune response to FVIII remains unclear.

Objective: To characterize the binding interactions of persistently secreted FVIII-specific IgM in hemophilia A mice and assess their effect on IgG antibody development.

Methods: Splenic-derived monoclonal antibodies (MAbs) from immunized FVIII knockout mice were isolated and purified using hybridoma technology. Binding interactions were assessed utilizing a novel fluid-phase ELISA and computational modeling with HADDOCK to account for weak IgM binding.

Results: Sixteen porcine cross-reactive and non-inhibitory FVIII-specific IgM MAbs were identified. RNA sequencing of FVIII-specific IgM revealed 13 unique VDJ/VJ sequences indicating derivation from 13 unique B cell clones. IgM demonstrated polyclonal and polyreactive binding to FVIII in vitro and in silico. Molecular docking studies with reconstructed IgM VDJ/VJ regions identified frequent IgM interactions with amino acid residues K376, T381, K437, R2215 or K2249 within the FVIII A2 and C2 domains. Injections of individual IgM prior to FVIII exposure and co-injection of FVIII/IgM immune complexes did not affect de novo FVIII antibody production.

Conclusion: Persistent FVIII-specific IgM are polyclonal but preferentially bind the A2 and C2 domains and FVIII/IgM immune complex formation do not significantly alter inhibitor development.

背景:A 型血友病患者在治疗过程中最主要的并发症是产生针对 VIII 因子 (FVIII) 的中和免疫球蛋白 G (IgG),即抑制剂,从而阻碍 FVIII 替代治疗。在有抑制剂和无抑制剂的 A 型血友病患者以及健康人中都发现了低滴度的 FVIII 特异性免疫球蛋白 M (IgM)。然而,IgM 对 FVIII 免疫反应的持续时间和影响仍不清楚:目的:描述 A 型血友病小鼠体内持续分泌的 FVIII 特异性 IgM 的结合相互作用,并评估其对 IgG 抗体形成的影响:方法:利用杂交瘤技术分离和纯化免疫FVIII基因敲除小鼠脾源性单克隆抗体(MAbs)。利用新型液相酶联免疫吸附试验(ELISA)和 HADDOCK 计算模型对结合相互作用进行评估,以考虑弱 IgM 结合:结果:共鉴定出 16 种猪交叉反应性和非抑制性 FVIII 特异性 IgM MAbs。FVIII特异性IgM的RNA测序发现了13个独特的VDJ/VJ序列,表明其来源于13个独特的B细胞克隆。IgM 与 FVIII 在体外和硅学中表现出多克隆和多反应结合。与重建的 IgM VDJ/VJ 区域进行的分子对接研究发现,IgM 与 FVIII A2 和 C2 结构域内的 K376、T381、K437、R2215 或 K2249 氨基酸残基经常发生相互作用。在暴露于 FVIII 之前注射单个 IgM 和联合注射 FVIII/IgM 免疫复合物不会影响新生 FVIII 抗体的产生:结论:持续存在的 FVIII 特异性 IgM 是多克隆的,但优先结合 A2 和 C2 结构域,FVIII/IgM 免疫复合物的形成不会显著改变抑制剂的产生。
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引用次数: 0
Duration of Anticoagulation for Venous Thromboembolism in Pediatric Patients: Kids-DOTT Trial Outcomes at Two Years. 儿科静脉血栓栓塞症患者抗凝治疗的持续时间:Kids-DOTT 试验两年后的结果。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-24 DOI: 10.1016/j.jtha.2024.09.038
Neil A Goldenberg, Sam Schulman, John M Kittelson, Thomas C Abshire, James F Casella, Rita Dale, Jonathan L Halperin, Jade Hanson, Craig M Kessler, Marilyn J Manco-Johnson, Laurel McDevitt, Robert F Sidonio, Alex C Spyropoulos, P Gabriel Steg, Marc P Bonaca

Background: The Kids-DOTT multinational randomized clinical trial (RCT) revealed non-inferiority of a six-week versus three-month duration of anticoagulation for the treatment of provoked venous thromboembolism (VTE) in patients <21 years old, in regard to net clinical benefit at one year.

Objective: To evaluate non-inferiority at two years.

Patients/methods: Patients whose repeat imaging six weeks after VTE diagnosis did not show complete veno-occlusion were randomized to discontinue anticoagulation versus receive a total three-month course and followed for two years for the occurrence of symptomatic recurrent (SR-) VTE (efficacy outcome) and clinically-relevant bleeding (CRB, safety outcome). Outcomes were centrally adjudicated and net clinical benefit was compared between treatment arms via a pre-specified bivariate non-inferiority boundary, using 95% confidence intervals (CIs) in absolute risk differences (ARDs) between treatment arms.

Results: Kaplan-Meier estimates of two-year cumulative incidences in the six-week and three-months arms of the intention-to-treat (ITT) population (n=417) were 1.7% (95% CI: 0%, 3.7%) and 2.9% (95% CI: 0.3%, 5.4%) for SR-VTE and 1.1% (95% CI: 0%, 2.5%) and 3.2% (95% CI: 0.6%, 5.7%) for CRB. Bivariate analysis of the ARDs in the ITT population demonstrated that a six-week anticoagulation duration was non-inferior to a three-month course.

Conclusions: These findings support durability of the Kids-DOTT RCT findings of net clinical benefit at two years.

背景:Kids-DOTT多国随机临床试验(RCT)显示,在治疗诱发静脉血栓栓塞症(VTE)患者时,抗凝时间为六周与三个月相比并无劣效:评估两年后的非劣效性:患者/方法: VTE 诊断六周后重复成像未显示完全静脉闭塞的患者被随机分为停止抗凝与接受为期三个月的疗程,并随访两年,以观察有症状复发 (SR-) VTE 的发生情况(疗效结果)和临床相关出血(CRB,安全性结果)。结果由中央裁定,并通过预先指定的双变量非劣效界值比较各治疗臂之间的净临床获益,采用各治疗臂之间绝对风险差异(ARD)的95%置信区间(CI):在意向治疗(ITT)人群(n=417)中,六周组和三个月组的两年累积发病率卡普兰-梅耶估计值分别为:SR-VTE为1.7%(95% CI:0%,3.7%)和2.9%(95% CI:0.3%,5.4%);CRB为1.1%(95% CI:0%,2.5%)和3.2%(95% CI:0.6%,5.7%)。对ITT人群的ARD进行的双变量分析表明,6周的抗凝疗程不劣于3个月的疗程:这些研究结果表明,Kids-DOTT RCT 研究发现的两年净临床获益具有持久性。
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引用次数: 0
The molecular background of quantitative defects of von Willebrand factor von Willebrand因子定量缺陷的分子背景。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-24 DOI: 10.1016/j.jtha.2024.07.035
Ferdows Atiq
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引用次数: 0
A new track for KDELivery of designer cargo by platelets 血小板运送设计货物的 KDEL 新路径。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-24 DOI: 10.1016/j.jtha.2024.09.005
Yvonne X. Kong, Jose S. Perdomo, Freda H. Passam
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引用次数: 0
Annoucements 公告
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-24 DOI: 10.1016/S1538-7836(24)00608-1
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引用次数: 0
Pregnancy loss in individuals with von Willebrand disease and unspecified mucocutaneous bleeding disorders: A multicentre cohort study. 冯-威廉氏病和不明皮肤黏膜出血性疾病患者的妊娠损失:一项多中心队列研究。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-23 DOI: 10.1016/j.jtha.2024.09.037
Leslie Skeith, Paula James, Peter Kouides, Kelsey Uminski, Lisa Duffett, Shannon Jackson, Michelle Sholzberg, Margaret V Ragni, Adam Cuker, Maeve O'Beirne, Julia Hews-Girard, Natalia Rydz, Dawn M Goodyear, Jill Baxter, Andra James, David Garcia, Sara K Vesely, Man-Chiu Poon

Background: While bleeding around pregnancy is well described in von Willebrand disease (VWD), risk of pregnancy loss is less certain. We aimed to describe the frequency of pregnancy loss in females with VWD, compared with those with a similar mucocutaneous bleeding phenotype and no VWD, or compared with non-bleeding disorder controls.

Methods: Female patients were consecutively approached in 8 specialty bleeding disorder clinics between 2014-2023. The VWD group was defined as having VWF:Antigen (Ag) and VWF:Activity (Act) levels, each <0.50 IU/mL on ≥2 occasions, and a Condensed MCMDM-1 score of ≥4. The non-VWD mucocutaneous bleeding disorder group had VWF levels ≥0.50 IU/mL on ≥2 occasions and a MCMDM-1 score ≥4. A non-bleeding disorder control group was recruited in pregnancy from a low-risk maternity clinic.

Results: There were 150 females in the VWD group, 145 in the non-VWD mucocutaneous bleeding disorder group, and 137 in the control group. There was a similar frequency of individuals with ≥1 loss in the VWD group (45.3%, 68/150), the non-VWD group (56.6%, 82/145) (-11.2%, 97.5% CI -24.2, 1.8%), and the non-bleeding disorder control group (37.2%, 51/137) (8.1%, 97.5% CI -4.9%, 21.1%). Using a logistic regression, the odds ratio of pregnancy losses in the VWD group versus non-VWD group was 0.94 (95% CI 0.65, 1.36). All groups experienced more recurrent losses compared to the literature.

Conclusions: There was no statistically significant difference in risk of pregnancy loss between females with VWD, females with a similar mucocutaneous bleeding phenotype, and with non-bleeding disorder controls.

背景:von-Willebrand病(VWD)患者妊娠期出血的情况已得到充分描述,但妊娠失败的风险却不太确定。我们旨在描述 VWD 女性患者的妊娠损失频率,并与具有相似粘膜出血表型但无 VWD 的女性患者进行比较,或与非出血性疾病对照组进行比较:2014-2023年间,8家出血性疾病专科门诊连续接诊了女性患者。VWD组被定义为具有VWF:抗原(Ag)和VWF:活性(Act)水平的患者:VWD组有150名女性,非VWD粘膜出血性疾病组有145名女性,对照组有137名女性。在 VWD 组(45.3%,68/150)、非 VWD 组(56.6%,82/145)(-11.2%,97.5% CI -24.2,1.8%)和非出血性疾病对照组(37.2%,51/137)(8.1%,97.5% CI -4.9%,21.1%)中,≥1 项损失的人数频率相似。通过逻辑回归,VWD 组与非 VWD 组的妊娠损失几率比为 0.94(95% CI 0.65,1.36)。与文献相比,所有组别都经历了更多的复发性流产:患有 VWD 的女性、具有相似粘膜出血表型的女性以及非出血障碍对照组的女性在妊娠损失风险方面没有明显的统计学差异。
{"title":"Pregnancy loss in individuals with von Willebrand disease and unspecified mucocutaneous bleeding disorders: A multicentre cohort study.","authors":"Leslie Skeith, Paula James, Peter Kouides, Kelsey Uminski, Lisa Duffett, Shannon Jackson, Michelle Sholzberg, Margaret V Ragni, Adam Cuker, Maeve O'Beirne, Julia Hews-Girard, Natalia Rydz, Dawn M Goodyear, Jill Baxter, Andra James, David Garcia, Sara K Vesely, Man-Chiu Poon","doi":"10.1016/j.jtha.2024.09.037","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.09.037","url":null,"abstract":"<p><strong>Background: </strong>While bleeding around pregnancy is well described in von Willebrand disease (VWD), risk of pregnancy loss is less certain. We aimed to describe the frequency of pregnancy loss in females with VWD, compared with those with a similar mucocutaneous bleeding phenotype and no VWD, or compared with non-bleeding disorder controls.</p><p><strong>Methods: </strong>Female patients were consecutively approached in 8 specialty bleeding disorder clinics between 2014-2023. The VWD group was defined as having VWF:Antigen (Ag) and VWF:Activity (Act) levels, each <0.50 IU/mL on ≥2 occasions, and a Condensed MCMDM-1 score of ≥4. The non-VWD mucocutaneous bleeding disorder group had VWF levels ≥0.50 IU/mL on ≥2 occasions and a MCMDM-1 score ≥4. A non-bleeding disorder control group was recruited in pregnancy from a low-risk maternity clinic.</p><p><strong>Results: </strong>There were 150 females in the VWD group, 145 in the non-VWD mucocutaneous bleeding disorder group, and 137 in the control group. There was a similar frequency of individuals with ≥1 loss in the VWD group (45.3%, 68/150), the non-VWD group (56.6%, 82/145) (-11.2%, 97.5% CI -24.2, 1.8%), and the non-bleeding disorder control group (37.2%, 51/137) (8.1%, 97.5% CI -4.9%, 21.1%). Using a logistic regression, the odds ratio of pregnancy losses in the VWD group versus non-VWD group was 0.94 (95% CI 0.65, 1.36). All groups experienced more recurrent losses compared to the literature.</p><p><strong>Conclusions: </strong>There was no statistically significant difference in risk of pregnancy loss between females with VWD, females with a similar mucocutaneous bleeding phenotype, and with non-bleeding disorder controls.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502860","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
Mechanistic basis of activation and inhibition of protein disulfide isomerase by allosteric antithrombotic compounds. 异位抗血栓化合物激活和抑制蛋白二硫异构酶的机制基础
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-23 DOI: 10.1016/j.jtha.2024.09.036
Nathan Ponzar, Mathivanan Chinnaraj, Anna Pagotto, Vincenzo De Filippis, Robert Flaumenhaft, Nicola Pozzi

Background: Protein disulfide isomerase (PDI) is a promising target for combating thrombosis. Extensive research over the past decade has identified numerous PDI-targeting compounds. However, limited information exists regarding how these compounds control PDI activity, which complicates further development.

Objectives: To define the mechanism of action of 2 allosteric antithrombotic compounds of therapeutic interest, quercetin-3-O-rutinoside and bepristat-2a.

Methods: A multipronged approach that integrates single-molecule spectroscopy, steady-state kinetics, single-turnover kinetics, and site-specific mutagenesis.

Results: PDI is a thiol isomerase consisting of 2 catalytic a domains and 2 inactive b domains arranged in the order a-b-b'-a'. The active sites CGHC are located in the a and a' domains. The binding site of quercetin-3-O-rutinoside and bepristat-2a is in the b' domain. Using a library of 9 Förster resonance energy transfer sensors, we showed that quercetin-3-O-rutinoside and bepristat-2a globally alter PDI structure and dynamics, leading to ligand-specific modifications of its shape and reorientation of the active sites. Combined with enzyme kinetics and mutagenesis of the active sites, Förster resonance energy transfer data reveal that binding of quercetin-3-O-rutinoside results in a twisted enzyme with reduced affinity for the substrate. In contrast, bepristat-2a promotes a more compact conformation of PDI, in which a greater enzymatic activity is achieved by accelerating the nucleophilic step of the a domain, leading to faster formation of the covalent enzyme-substrate complex.

Conclusion: This work reveals the mechanistic basis underlying PDI regulation by antithrombotic compounds quercetin-3-O-rutinoside and bepristat-2a and points to novel strategies for furthering the development of PDI-targeting compounds into drugs.

背景:蛋白二硫异构酶(PDI)是一个很有希望的抗血栓靶点。过去十年的广泛研究发现了许多 PDI 靶向化合物。然而,关于这些化合物如何控制 PDI 活性的信息却很有限,这使得进一步开发变得复杂:明确两种具有治疗意义的异位抗血栓化合物--槲皮素-3-O-芸香糖苷和贝普利司他-2a--的作用机制:方法:采用多管齐下的方法,将单分子光谱学、稳态动力学、单一周转动力学和位点特异性诱变结合起来:PDI是一种硫醇异构酶,由两个催化a域和两个非活性b域组成,其排列顺序为a-b-b'-a'。活性位点 CGHC 位于 a 和 a'结构域中。槲皮素-3-O-芸香糖苷和贝普利司他-2a的结合位点位于b'结构域。利用九种 FRET 传感器库,我们发现槲皮素-3-O-芸香糖苷和贝普利司他-2a 会全面改变 PDI 的结构和动力学,导致配体特异性地改变其形状和活性位点的重新定向。结合酶动力学和活性位点的诱变,FRET 数据显示,与槲皮素-3-O-芸香糖苷结合会导致酶扭曲,对底物的亲和力降低。相比之下,贝普利司他-2a 能促进 PDI 形成更紧凑的构象,在这种构象中,通过加速 a 结构域的亲核步骤,使酶与底物的共价复合物更快地形成,从而获得更高的酶活性:这项研究揭示了抗血栓化合物槲皮素-3-O-芸香糖苷和贝普利司他-2a调控PDI的机理基础,并为进一步将PDI靶向化合物开发成药物指出了新的策略。
{"title":"Mechanistic basis of activation and inhibition of protein disulfide isomerase by allosteric antithrombotic compounds.","authors":"Nathan Ponzar, Mathivanan Chinnaraj, Anna Pagotto, Vincenzo De Filippis, Robert Flaumenhaft, Nicola Pozzi","doi":"10.1016/j.jtha.2024.09.036","DOIUrl":"10.1016/j.jtha.2024.09.036","url":null,"abstract":"<p><strong>Background: </strong>Protein disulfide isomerase (PDI) is a promising target for combating thrombosis. Extensive research over the past decade has identified numerous PDI-targeting compounds. However, limited information exists regarding how these compounds control PDI activity, which complicates further development.</p><p><strong>Objectives: </strong>To define the mechanism of action of 2 allosteric antithrombotic compounds of therapeutic interest, quercetin-3-O-rutinoside and bepristat-2a.</p><p><strong>Methods: </strong>A multipronged approach that integrates single-molecule spectroscopy, steady-state kinetics, single-turnover kinetics, and site-specific mutagenesis.</p><p><strong>Results: </strong>PDI is a thiol isomerase consisting of 2 catalytic a domains and 2 inactive b domains arranged in the order a-b-b'-a'. The active sites CGHC are located in the a and a' domains. The binding site of quercetin-3-O-rutinoside and bepristat-2a is in the b' domain. Using a library of 9 Förster resonance energy transfer sensors, we showed that quercetin-3-O-rutinoside and bepristat-2a globally alter PDI structure and dynamics, leading to ligand-specific modifications of its shape and reorientation of the active sites. Combined with enzyme kinetics and mutagenesis of the active sites, Förster resonance energy transfer data reveal that binding of quercetin-3-O-rutinoside results in a twisted enzyme with reduced affinity for the substrate. In contrast, bepristat-2a promotes a more compact conformation of PDI, in which a greater enzymatic activity is achieved by accelerating the nucleophilic step of the a domain, leading to faster formation of the covalent enzyme-substrate complex.</p><p><strong>Conclusion: </strong>This work reveals the mechanistic basis underlying PDI regulation by antithrombotic compounds quercetin-3-O-rutinoside and bepristat-2a and points to novel strategies for furthering the development of PDI-targeting compounds into drugs.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502857","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
Pazopanib in treatment of Hereditary Hemorrhagic Telangiectasia-related epistaxis and gastrointestinal bleeding. 帕唑帕尼(Pazopanib)用于治疗遗传性出血性远端血管扩张症相关的鼻衄和消化道出血。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-23 DOI: 10.1016/j.jtha.2024.10.014
Magdalena D Lewandowska, Shelby Gordon, Anthony Betbadal, Amy D Shapiro

Background: Hereditary hemorrhagic telangiectasia (HHT) is a bleeding disorder characterized by arteriovenous malformations (AVMs), commonly presenting with epistaxis and gastrointestinal bleeding. Bleeding symptoms may be difficult to manage and may become life-threatening, with many patients developing dependence on parenteral iron and/or blood transfusion. There is a growing body of evidence that antiangiogenic therapies may be effective in management of bleeding symptoms, presumably targeting pathogenic HHT pathways such as vascular endothelial growth factor (VEGF) receptor.

Objectives: To report single-center, retrospective real-world use of pazopanib, an orally administered tyrosine kinase inhibitor that blocks VEGF receptors, in six patients with HHT-associated epistaxis and/or gastrointestinal (GI) bleeding.

Patient/methods: A retrospective observational analysis was performed to assess the safety/efficacy of pazopanib use in patients with confirmed HHT-associated epistaxis and/or GI bleeding between 01 January 2019 and 14 June 2023 The Indiana Hemophilia and Thrombosis (IHTC) institutional EMR was queried for HHT patients who were treated with pazopanib for >3 months. Patient data were obtained from patient documentation, physician/nursing notes, and on-call documentation Institutional IRB approval was obtained for data pull as an exempt study RESULTS AND CONCLUSIONS: Our observations on the real-world use of pazopanib in six HHT patients with moderate to severe bleeding showed improvement in hemoglobin levels, with reduction in iron infusions and red blood cell transfusion requirement. Pazopanib may be a reasonable option for patients with HHT with epistaxis or gastrointestinal bleeding that are refractory to standard treatment.

背景:遗传性出血性毛细血管扩张症(HHT)是一种以动静脉畸形(AVM)为特征的出血性疾病,通常表现为鼻衄和消化道出血。出血症状可能难以控制,并可能危及生命,许多患者开始依赖肠外铁剂和/或输血。越来越多的证据表明,抗血管生成疗法可有效控制出血症状,可能是针对血管内皮生长因子(VEGF)受体等 HHT 致病途径:报告帕唑帕尼(一种阻断血管内皮生长因子受体的口服酪氨酸激酶抑制剂)在6例HHT相关性鼻衄和/或胃肠道(GI)出血患者中的单中心、回顾性实际应用情况:对2019年1月1日至2023年6月14日期间确诊的HHT相关性鼻衄和/或消化道出血患者使用帕唑帕尼的安全性/有效性进行了回顾性观察分析,并查询了印第安纳州血友病和血栓症(IHTC)机构的EMR,以了解接受帕唑帕尼治疗超过3个月的HHT患者的情况。患者数据来自患者文档、医生/护理记录和值班文档。作为一项豁免研究,数据拉取已获得机构 IRB 批准。 结果与结论:我们观察到帕唑帕尼在现实世界中的使用情况:我们对 6 名中重度出血的 HHT 患者实际使用帕唑帕尼的观察结果显示,血红蛋白水平有所改善,铁剂输注和红细胞输注需求减少。对于标准治疗难治的鼻衄或消化道出血 HHT 患者,帕唑帕尼可能是一个合理的选择。
{"title":"Pazopanib in treatment of Hereditary Hemorrhagic Telangiectasia-related epistaxis and gastrointestinal bleeding.","authors":"Magdalena D Lewandowska, Shelby Gordon, Anthony Betbadal, Amy D Shapiro","doi":"10.1016/j.jtha.2024.10.014","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.10.014","url":null,"abstract":"<p><strong>Background: </strong>Hereditary hemorrhagic telangiectasia (HHT) is a bleeding disorder characterized by arteriovenous malformations (AVMs), commonly presenting with epistaxis and gastrointestinal bleeding. Bleeding symptoms may be difficult to manage and may become life-threatening, with many patients developing dependence on parenteral iron and/or blood transfusion. There is a growing body of evidence that antiangiogenic therapies may be effective in management of bleeding symptoms, presumably targeting pathogenic HHT pathways such as vascular endothelial growth factor (VEGF) receptor.</p><p><strong>Objectives: </strong>To report single-center, retrospective real-world use of pazopanib, an orally administered tyrosine kinase inhibitor that blocks VEGF receptors, in six patients with HHT-associated epistaxis and/or gastrointestinal (GI) bleeding.</p><p><strong>Patient/methods: </strong>A retrospective observational analysis was performed to assess the safety/efficacy of pazopanib use in patients with confirmed HHT-associated epistaxis and/or GI bleeding between 01 January 2019 and 14 June 2023 The Indiana Hemophilia and Thrombosis (IHTC) institutional EMR was queried for HHT patients who were treated with pazopanib for >3 months. Patient data were obtained from patient documentation, physician/nursing notes, and on-call documentation Institutional IRB approval was obtained for data pull as an exempt study RESULTS AND CONCLUSIONS: Our observations on the real-world use of pazopanib in six HHT patients with moderate to severe bleeding showed improvement in hemoglobin levels, with reduction in iron infusions and red blood cell transfusion requirement. Pazopanib may be a reasonable option for patients with HHT with epistaxis or gastrointestinal bleeding that are refractory to standard treatment.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A gain of function variant in RGS18 candidate for a familial mild bleeding syndrome. 候选家族性轻度出血综合征的 RGS18 功能增益变异。
IF 8.3 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-23 DOI: 10.1016/j.jtha.2024.10.016
Caroline Vayne, Maguelonne Roux, Yves Gruel, Marjorie Poggi, Claire Pouplard, Franck Peiretti, David-Alexandre Trégouët, Paquita Nurden, Marie-Christine Alessi

Background: Inherited platelet diseases are bleeding disorders characterized by either defects in platelet count or platelet function, the latter being less common and very heterogeneous. Numerous gene variants associated with abnormal receptors, granules, and signaling pathways have been reported. Despite significant advancements in our understanding, many patients still lack a precise diagnosis.

Objectives: To identify the genetic basis of a novel mild bleeding syndrome in a family exhibiting a selective defect of platelet aggregation.

Methods: Our study included 6 family members across 3 generations who displayed reduced platelet aggregation in response to adenosine diphosphate, protease-activated receptor 1-activating peptide, arachidonic acid, and epinephrine but not collagen. Platelet morphology, granule content, and expression of major surface glycoproteins were all found to be normal. Whole exome sequencing was performed for affected and nonaffected family members.

Results: We identified RGS18, which encodes the regulator of G protein signaling (RGS) 18, as a candidate gene for the platelet function defect observed in this family. The RGS18 protein serves as a crucial negative regulator of G protein-coupled receptor signaling and coordinates the signaling pathways of natural platelet inhibitors. The heterozygous RGS18 c.643C>T, p.Arg215∗ variant was found to cosegregate among all 6 affected subjects.

Conclusion: Truncation at Arg215 removes the S216 and S218 phosphorylation sites, which are crucial regulatory domains for RGS18 activation. The impaired platelet function is thought to arise from excessive platelet downregulation due to constitutive activation of RGS18, resulting from a loss of association of the truncated form with the 14-3-3 protein.

背景:遗传性血小板疾病(IPDs)是一种以血小板数量或血小板功能缺陷为特征的出血性疾病,后者较少见,且异质性很强。与受体、颗粒和信号通路异常相关的基因变异已被大量报道。尽管我们对这种疾病的认识有了很大的进步,但许多患者仍然无法得到准确的诊断:患者/方法:我们的研究包括三个世代的 6 名家庭成员,他们对 ADP、PAR1-AP、花生四烯酸和肾上腺素的血小板聚集反应减弱,但对胶原蛋白的反应不减弱。血小板形态、颗粒含量和主要表面糖蛋白的表达均正常。对受影响和未受影响的家庭成员进行了全外显子组测序:我们发现编码 G 蛋白信号调节器(RGS)18 的 RGS18 是该家族中血小板功能缺陷的候选基因。RGS18 蛋白是 G 蛋白偶联受体(GPCR)信号传导的重要负调控因子,并协调天然血小板抑制剂的信号传导途径。在所有六名受影响的受试者中都发现了杂合子 RGS18 c.643C>T、p.Arg215* 变异。Arg215 的截断去除了 S216 和 S218 磷酸化位点,而这两个位点是 RGS18 激活的关键调节域。血小板功能受损的原因被认为是由于 RGS18 构成性激活导致血小板过度下调,而截短形式与 14-3-3 蛋白质失去结合。
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引用次数: 0
Risk assessment and management strategies in older patients with acute pulmonary embolism. 老年急性肺栓塞患者的风险评估和管理策略。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-23 DOI: 10.1016/j.jtha.2024.10.015
Dieuwke Luijten, Denise Abbel, Suzanne C Cannegieter, Jeroen Eikenboom, Paul L den Exter, Jacobijn Gussekloo, Menno V Huisman, Thijs E van Mens, Lara Tahir, Stella Trompet, Simon P Mooijaart, Frederikus A Klok

Introduction: Managing older patients with acute pulmonary embolism (PE) is challenging due to their underrepresentation in clinical trials, comorbidities and increased complication risk. This study evaluates risk assessment and management outcomes in older PE patients focussing on home and reperfusion treatment.

Methods: A retrospective analysis was conducted on patients aged ≥70 years diagnosed with acute PE at an academic medical centre (2015-2022).

Results: 242 patients with a mean age of 77 years were included. All 59 patients with negative Hestia criteria were discharged ≤24h, and in total 81 patients (35%) received home treatment. Among these 14-day mortality and recurrent venous-thromboembolism were 0% and major bleeding occurred in 1.3% (one patient, 95%CI 0.11-6.1). European Society of Cardiology (ESC) risk-classification showed 9 low-risk PE (3.9%), 199 intermediate-risk (87%), and 20 high-risk PE patients (8.8). In 5 of the 20 high-risk patients, hypotension was mainly caused by another condition, i.e. sepsis. Eight high-risk patients received reperfusion therapy. Fourteen-day mortality was 51% in high-risk patients (95%CI 27-71); 5 out of 8 patients receiving reperfusion treatment died within 5 days. Patients with an Acute Presenting Older Patient (APOP) score of ≥45% had higher 14-day mortality (28%; 95%CI 12-46) compared to <45% (3.2%; 95%CI 0.85-8.3; HR 10.2; 95%CI 2.6-39).

Conclusion: Selecting for home treatment using Hestia was safe for older PE patients in our cohort. Mortality in the high-risk group was high also when receiving reperfusion treatment. The ESC risk-classification and APOP score identified patients at higher mortality risk, suggesting their potential utility in clinical decision-making.

简介:由于老年急性肺栓塞(PE)患者在临床试验中的代表性不足、合并症和并发症风险增加,管理老年急性肺栓塞患者具有挑战性。本研究评估了老年肺栓塞患者的风险评估和管理结果,重点是家庭治疗和再灌注治疗:结果:共纳入 242 例患者,平均年龄 77 岁。所有59名Hestia标准阴性的患者均在24小时内出院,共有81名患者(35%)接受了家庭治疗。其中,14 天死亡率和复发性静脉血栓栓塞率均为 0%,大出血发生率为 1.3%(一名患者,95%CI 0.11-6.1)。欧洲心脏病学会(ESC)的风险分类显示,低风险 PE 患者为 9 人(3.9%),中风险患者为 199 人(87%),高风险 PE 患者为 20 人(8.8%)。在这 20 名高风险患者中,有 5 名患者的低血压主要是由败血症等其他疾病引起的。8 名高风险患者接受了再灌注治疗。高危患者的 14 天死亡率为 51%(95%CI 27-71);8 名接受再灌注治疗的患者中有 5 人在 5 天内死亡。与结论相比,急性发病老年患者(APOP)评分≥45%的患者14天死亡率更高(28%;95%CI 12-46):在我们的队列中,选择使用 Hestia 进行家庭治疗对老年 PE 患者是安全的。在接受再灌注治疗时,高风险组的死亡率也很高。ESC风险分级和APOP评分可识别死亡率风险较高的患者,这表明它们在临床决策中具有潜在的实用性。
{"title":"Risk assessment and management strategies in older patients with acute pulmonary embolism.","authors":"Dieuwke Luijten, Denise Abbel, Suzanne C Cannegieter, Jeroen Eikenboom, Paul L den Exter, Jacobijn Gussekloo, Menno V Huisman, Thijs E van Mens, Lara Tahir, Stella Trompet, Simon P Mooijaart, Frederikus A Klok","doi":"10.1016/j.jtha.2024.10.015","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.10.015","url":null,"abstract":"<p><strong>Introduction: </strong>Managing older patients with acute pulmonary embolism (PE) is challenging due to their underrepresentation in clinical trials, comorbidities and increased complication risk. This study evaluates risk assessment and management outcomes in older PE patients focussing on home and reperfusion treatment.</p><p><strong>Methods: </strong>A retrospective analysis was conducted on patients aged ≥70 years diagnosed with acute PE at an academic medical centre (2015-2022).</p><p><strong>Results: </strong>242 patients with a mean age of 77 years were included. All 59 patients with negative Hestia criteria were discharged ≤24h, and in total 81 patients (35%) received home treatment. Among these 14-day mortality and recurrent venous-thromboembolism were 0% and major bleeding occurred in 1.3% (one patient, 95%CI 0.11-6.1). European Society of Cardiology (ESC) risk-classification showed 9 low-risk PE (3.9%), 199 intermediate-risk (87%), and 20 high-risk PE patients (8.8). In 5 of the 20 high-risk patients, hypotension was mainly caused by another condition, i.e. sepsis. Eight high-risk patients received reperfusion therapy. Fourteen-day mortality was 51% in high-risk patients (95%CI 27-71); 5 out of 8 patients receiving reperfusion treatment died within 5 days. Patients with an Acute Presenting Older Patient (APOP) score of ≥45% had higher 14-day mortality (28%; 95%CI 12-46) compared to <45% (3.2%; 95%CI 0.85-8.3; HR 10.2; 95%CI 2.6-39).</p><p><strong>Conclusion: </strong>Selecting for home treatment using Hestia was safe for older PE patients in our cohort. Mortality in the high-risk group was high also when receiving reperfusion treatment. The ESC risk-classification and APOP score identified patients at higher mortality risk, suggesting their potential utility in clinical decision-making.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502861","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
期刊
Journal of Thrombosis and Haemostasis
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