Journal of Thrombosis and Haemostasis最新文献_第5页

Concizumab use in toddlers with hemophilia B and inhibitors real-world data from an international collaboration 康珠单抗用于血友病B患儿和抑制剂的国际合作的真实世界数据。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-01-01 DOI: 10.1016/j.jtha.2025.09.038

Sarina Levy-Mendelovich , Judith Timmermans , Beatrice Nolan , Sabina Heine , Federica Achini-Gutzwiller , Allison P. Wheeler , Gili Kenet

Background

Hemophilia B (HB) with inhibitors presents a treatment challenge, particularly in young children who may also experience allergic reactions to factor (F)IX. Concizumab, an antitissue factor pathway inhibitor monoclonal antibody, is a novel subcutaneous prophylactic agent recently approved for patients aged ≥12 years. However, data on its use in young children remain limited.

Objectives

To assess the safety, efficacy, and dosing of prophylactic concizumab in children under 6 years old with severe HB and inhibitors using data from compassionate or off-label use in Europe, Israel, and the United States.

Methods

This international retrospective cohort study included 5 children aged 0 to 6 years with severe HB (FIX <1%) and inhibitors (Bethesda units >0.6) who were treated with concizumab for at least 12 weeks. Clinical, genetic, laboratory, and thrombin generation data were collected and analyzed. Exclusion criteria included coagulopathies and enrollment in industry-sponsored trials.

Results

All patients experienced allergic reactions to FIX and developed inhibitors at a median age of 15 months. Concizumab prophylaxis began at a median age of 21 months. Annualized bleeding rates after concizumab therapy ranged from 0 to 4, with only 2 patients experiencing spontaneous bleeds, both resolving after dose adjustments. No thrombotic events occurred. Thrombin generation improved significantly posttreatment, and FIX inhibitor levels declined without additional FIX exposure or immune tolerance induction.

Conclusion

Concizumab appears safe and effective in young children with severe HB and inhibitors. It offers a promising, factor-free prophylactic strategy.

背景：血友病B （HB）与抑制剂提出了一个治疗挑战，特别是在幼儿谁也可能经历因子IX过敏反应（FIX）。Concizumab是一种抗tfpi单克隆抗体，是最近批准用于年龄≥12岁患者的新型皮下预防药物。然而，关于其在幼儿中的使用的数据仍然有限。目的：利用欧洲、以色列和美国同情用药或标签外用药的数据，评估6岁以下严重HB患儿预防性concizumab的安全性、有效性和剂量。患者/方法：这项国际回顾性队列研究包括5名0-6岁患有严重HB （FIX 0.6）的儿童，他们接受了concizumab治疗至少12周。收集并分析临床、遗传、实验室和凝血酶生成数据。排除标准包括凝血病变和行业赞助试验的入组。结果：所有患者在中位年龄15个月时出现FIX过敏反应并产生抑制剂。康珠单抗预防开始的中位年龄为21个月。康珠单抗治疗后的年化出血率从0到4不等，只有两名患者出现自发性出血，均在剂量调整后消退。未发生血栓事件。治疗后凝血酶生成显著改善，FIX抑制剂水平下降，无需额外的FIX暴露或免疫耐受诱导。结论：Concizumab对患有严重HB和抑制剂的幼儿安全有效。它提供了一种有希望的、无因素的预防策略。

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引用次数: 0

Defective lymphangiogenesis and iron removal after hemarthrosis in factor VIII-deficient mice are rectified with therapeutic factor VIII administration—implications for joint health 治疗性给药FVIII纠正了FVIII缺陷小鼠关节血肿后淋巴生成缺陷和铁去除-对关节健康的影响。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-01-01 DOI: 10.1016/j.jtha.2025.08.016

Bilgimol Chumappumkal Joseph , Juan Andres De Pablo-Moreno , Nicca Falah , Mia Lora Cacho , Annette von Drygalski

Background

Maladaptive lymphangiogenesis after hemarthrosis in factor(F)VIII-deficient (knockout [KO]) mice facilitates synovial iron accumulation.

Objectives

To investigate the effect of FVIII treatment on lymphangiogenesis, iron clearance, and joint health after hemarthrosis.

Methods

Two days after knee injury/bleed (subpatellar needle puncture) FVIII-KO mice were separated into 3 groups receiving (1) intravenous saline, (2) recombinant human FVIII for 2 days, or (3) murine (m)FcFVIII for 14 days. FVIII activity levels were measured repeatedly (peak/trough) for 14 days. Joint tissues were processed at 2 and 4 weeks postbleed for Prussian blue staining (iron), CD68 (macrophage), αSMA (vascular remodeling), and LYVE1 (lymphangiogenesis) immunohistochemistry, and Safranin-O-Green staining (cartilage health).

Results

Joint injury caused profound hemarthrosis. Mice treated with mFcFVIII maintained stable FVIII activity levels for 14 days (troughs 29%-38%). Pronounced synovial iron accumulation colocalizing with macrophages, along with severely impaired lymphangiogenesis and joint health parameters, were present in saline-treated mice at 2 and 4 weeks when compared with baseline. Short-term recombinant human FVIII administration resulted in partially impaired lymphangiogenesis and iron clearance with delayed recovery of joint health parameters. In contrast, mice treated with mFcFVIII experienced rapid iron clearance alongside normal lymphangiogenesis, associated with fast and effective normalization of joint health parameters, particularly with respect to cartilage health.

Conclusion

Prolonged FVIII availability in the “mild hemophilia range” (± Fc-mediated effects) after hemarthrosis seem critical for lymphangiogenesis, rapid iron removal, and joint repair, including glycosaminoglycan-dependent cartilage restoration. Intensified courses of FVIII treatment in patients may therefore be beneficial for postbleed management.

背景：因子(F)VIII缺乏症（KO）小鼠关节血肿后的不适应淋巴管生成促进滑膜铁积聚。目的：探讨FVIII治疗对血肿后淋巴管生成、铁清除和关节健康的影响。方法：膝关节损伤/出血（髌骨下针穿刺）2 d后，将FVIII- ko小鼠分为3组，分别给予(1)静脉注射生理盐水，(2)重组人（rh）FVIII 2 d,(3)小鼠(m)FcFVIII 14 d。连续14天反复测定FVIII活性水平（峰/谷）。在出血后2周和4周对关节组织进行普鲁士蓝染色（铁）、CD68（巨噬细胞）、αSMA（血管重塑）、LYVE1（淋巴管生成）和红花素- o -绿（组织学、软骨健康）。结果：关节损伤引起深度关节积血。经mFcFVIII处理的小鼠在14天内保持稳定的FVIII活性水平（波幅为29-38%）。与基线相比，盐水处理小鼠在2周和4周时出现了明显的滑膜铁积累与巨噬细胞共定位，以及严重受损的淋巴管生成和关节健康参数。短期给药导致部分淋巴管生成和铁清除受损，关节健康参数恢复延迟。相比之下，用mFcFVIII治疗的小鼠在正常淋巴管生成的同时经历了快速的铁清除，与关节健康参数的快速有效正常化有关，特别是在软骨健康方面。结论：关节血肿后，延长FVIII在“轻度血友病范围”（+/- fc介导作用）的可用性似乎对淋巴管生成、快速铁清除和关节修复（包括糖胺聚糖依赖性软骨修复）至关重要。因此，患者强化FVIII治疗可能有利于出血后的处理。

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引用次数: 0

Macrophage Plg-RKT expression promotes diet-induced obesity and metabolic dysfunction-associated steatotic liver disease 巨噬细胞Plg-RKT表达促进饮食诱导的肥胖和代谢功能障碍相关的脂肪变性肝病。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-01-01 DOI: 10.1016/j.jtha.2025.09.020

Lindsey A. Miles , Hongdong Bai , Sagarika Chakrabarty , Nagyung Baik , Yuqing Zhang , Robert J. Parmer , Fahumiya Samad

Background

Plg-R_KT is a transmembrane plasminogen receptor that enhances the activation of plasminogen to plasmin and localizes proteolytic activity of plasmin on the cell surface.

Objectives

We investigated the role of Plg-R_KT in high-fat diet (HFD)-induced obesity and metabolic dysfunction-associated steatotic liver disease (MASLD).

Methods

Mice deficient in Plg-R_KT in macrophages (mPlg-R_KT^−/−) or hepatocytes (hPlg-R_KT^−/−) and control mice (Plg-R_KT^flox/flox) were fed a HFD to determine the cell-specific role of this receptor in obesity and MASLD. Glucose homeostasis, hepatic lipogenesis, fatty acid oxidation pathways, adipose macrophage phenotypes, and inflammation were analyzed. RNA sequencing analysis of liver was performed to identify differentially expressed genes and functional pathways impacted by the loss of myeloid Plg-R_KT.

Results

Plg-R_KT levels were significantly elevated in the liver of HFD-fed mice with MASLD. HFD-fed mPlg-R_KT^−/− mice were protected from obesity, MASLD, and liver dysfunction. mPlg-R_KT^−/− mice exhibited reduced liver fat, lower plasma alanine aminotransferase levels, and improved glucose homeostasis. In contrast, HFD-fed hPlg-R_KT^−/− mice were not protected from obesity and MASLD. Mechanistically, mPlg-R_KT deficiency reduced hepatic Akt activation, lowered fatty acid synthase expression, and activated the PPARα fatty acid oxidation pathway. In adipose tissue, mPlg-R_KT deficiency shifted macrophage polarization from proinflammatory M1-like to anti-inflammatory M2-like, enhancing insulin sensitivity, decreasing lipolysis, and lowering plasma free fatty acids available for liver uptake. RNA sequencing revealed significant gene expression changes in lipid metabolism, fibrosis, and inflammation.

Conclusion

These findings underscore the critical role of macrophage Plg-R_KT signaling in the pathogenesis of obesity and MASLD.

背景：Plg-RKT是一种跨膜的纤溶酶原受体，它可以增强纤溶酶原对纤溶酶的激活，并使纤溶酶的蛋白水解活性定位在细胞表面。方法：在巨噬细胞（mPlg-RKT-/-）或肝细胞（hPlg-RKT-/-）和对照小鼠（Plg-RKTflox/flox）中缺乏Plg-RKT的小鼠喂食HFD，以确定该受体在肥胖和MASLD中的细胞特异性作用。分析了葡萄糖稳态、肝脏脂肪生成、脂肪酸氧化途径、脂肪巨噬细胞表型和炎症。对肝脏进行RNA-seq分析，以鉴定受髓系Plg-RKT缺失影响的差异表达基因（DEGs）和功能途径。结果：hfd喂养的MASLD小鼠肝脏中Plg-RKT水平显著升高。hfd喂养的mPlg-RKT-/-小鼠可避免肥胖、MASLD和肝功能障碍。mPlg-RKT-/-小鼠表现出肝脏脂肪减少，血浆丙氨酸转氨酶（ALT）水平降低，葡萄糖稳态改善。相比之下，hfd喂养的hPlg-RKT-/-小鼠没有受到肥胖和MASLD的保护。机制上，mPlg-RKT缺乏可降低肝脏Akt活化，降低脂肪酸合成酶（FAS）表达，激活PPARα脂肪酸氧化途径。在脂肪组织中，mPlg-RKT缺乏将巨噬细胞极化从促炎m1样转变为抗炎m2样，增强胰岛素敏感性，减少脂肪分解，降低可用于肝脏摄取的血浆游离脂肪酸。RNA-seq显示在脂质代谢、纤维化和炎症中显著的基因表达变化。结论：这些发现强调了巨噬细胞Plg-RKT信号在肥胖和MASLD发病机制中的关键作用。

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引用次数: 0

A closer look at the GPIbM assay: unraveling unexpected discrepancies in von Willebrand factor activity testing GPIbM检测的进一步研究：揭示VWF活性检测中意想不到的差异。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-01-01 DOI: 10.1016/j.jtha.2025.09.025

Emily Helm , Daniel E. Sabath , Theingi Tun , Maryam Asif

引用次数: 0

Diagnostic accuracy of computed tomography venography compared with ultrasonography for detection of peripherally inserted central venous catheter–related thrombosis in patients with cancer: the DETECT study CT静脉造影与超声检测癌症患者外周中心静脉导管相关血栓的诊断准确性：DETECT研究

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-01-01 DOI: 10.1016/j.jtha.2025.08.008

Noori A.M. Guman , Bart M. van Dooremaal , Ludo F. Beenen , Maeke J. Scheerder , Anne-Marie Becking , Michiel F. Lagerweij , IJsbrand A.J. Zijlstra , Martijn R. Meijerink , Hanneke W.M. van Laarhoven , Patrick M. Bossuyt , Peter Verhamme , Harry R. Büller , Michiel Coppens , Nick van Es

Background

Ultrasonography is the primary diagnostic imaging modality for upper extremity deep vein thrombosis related to peripherally inserted central venous catheters (PICCs). Computed tomography (CT) venography may offer higher sensitivity while additionally providing information about the superior vena cava and central pulmonary arteries.

Objectives

We compared the diagnostic accuracy of CT venography with ultrasonography for screen-detected PICC-related venous thromboembolism (VTE).

Methods

Consecutive adult patients with cancer were enrolled before PICC placement. On day 20 ± 5, screening was performed by compression ultrasonography and duplex of the neck and upper extremity and CT venography of the neck, upper extremity, and chest. The primary outcome included upper extremity deep vein thrombosis, vena cava and right atrial thrombosis, and pulmonary embolism. CT scans were adjudicated by 2 radiologists blinded to initial readings. The sensitivity of CT and ultrasonography was estimated using VTE on either test as a combined standard.

Results

Forty one patients participated (median age 61 years, 51% female), of whom 18 (44%) were diagnosed with PICC-related VTE, including 15 asymptomatic detected at screening and 3 symptomatic VTE prior to screening. Screening CT venography missed 6 events (sensitivity, 60%; 95% CI, 36-80) and ultrasonography missed 3 (sensitivity, 80%; 95% CI, 55-93). Thrombi missed by CT venography were located across cannulated upper extremity deep veins, while ultrasonography missed thrombi in the brachiocephalic and more central veins.

Conclusion

Both CT venography and ultrasonography missed VTE at screening. Results indicate that it is unlikely that the sensitivity of CT venography alone exceeds that of ultrasonography in detection of asymptomatic PICC-related VTE.

背景：超声检查是上肢深静脉血栓形成（DVT）的主要诊断成像方式，与周围中心静脉导管（PICCs）有关。计算机断层扫描（CT）静脉造影可以提供更高的灵敏度，同时还可以提供有关上腔静脉和中央肺动脉的信息。目的：比较CT静脉造影与超声对筛查picc相关静脉血栓栓塞（VTE）的诊断准确性。方法：连续入组PICC植入前的成年癌症患者。在第20±5天，通过(1)颈部和上肢压迫超声和双工，(2)颈部、上肢和胸部CT静脉造影进行筛查。主要结局包括上肢深静脉血栓、腔静脉和右心房血栓以及肺栓塞。CT扫描是由两名不知道初始读数的放射科医生裁决的。CT和超声的敏感性估计使用VTE在任何一个测试作为联合标准。结果：41例患者（中位年龄61岁，51%为女性），其中18例（44%）诊断为picc相关性静脉血栓栓塞，其中15例在筛查时无症状，3例筛查前有症状。CT静脉造影筛查遗漏6个事件（敏感性60%，95%-CI 36-80），超声检查遗漏3个事件（敏感性80%，95%-CI 55-93）。CT静脉造影未发现的血栓位于空腔上肢深静脉，而超声未发现的血栓位于头臂静脉和更多的中心静脉。结论：CT和超声检查均未发现静脉血栓栓塞。结果表明，在检测无症状的picc相关静脉血栓栓塞时，单独CT静脉造影的灵敏度不太可能超过超声。

{"title":"Diagnostic accuracy of computed tomography venography compared with ultrasonography for detection of peripherally inserted central venous catheter–related thrombosis in patients with cancer: the DETECT study","authors":"Noori A.M. Guman , Bart M. van Dooremaal , Ludo F. Beenen , Maeke J. Scheerder , Anne-Marie Becking , Michiel F. Lagerweij , IJsbrand A.J. Zijlstra , Martijn R. Meijerink , Hanneke W.M. van Laarhoven , Patrick M. Bossuyt , Peter Verhamme , Harry R. Büller , Michiel Coppens , Nick van Es","doi":"10.1016/j.jtha.2025.08.008","DOIUrl":"10.1016/j.jtha.2025.08.008","url":null,"abstract":"<div><h3>Background</h3><div>Ultrasonography is the primary diagnostic imaging modality for upper extremity deep vein thrombosis related to peripherally inserted central venous catheters (PICCs). Computed tomography (CT) venography may offer higher sensitivity while additionally providing information about the superior vena cava and central pulmonary arteries.</div></div><div><h3>Objectives</h3><div>We compared the diagnostic accuracy of CT venography with ultrasonography for screen-detected PICC-related venous thromboembolism (VTE).</div></div><div><h3>Methods</h3><div>Consecutive adult patients with cancer were enrolled before PICC placement. On day 20 ± 5, screening was performed by compression ultrasonography and duplex of the neck and upper extremity and CT venography of the neck, upper extremity, and chest. The primary outcome included upper extremity deep vein thrombosis, vena cava and right atrial thrombosis, and pulmonary embolism. CT scans were adjudicated by 2 radiologists blinded to initial readings. The sensitivity of CT and ultrasonography was estimated using VTE on either test as a combined standard.</div></div><div><h3>Results</h3><div>Forty one patients participated (median age 61 years, 51% female), of whom 18 (44%) were diagnosed with PICC-related VTE, including 15 asymptomatic detected at screening and 3 symptomatic VTE prior to screening. Screening CT venography missed 6 events (sensitivity, 60%; 95% CI, 36-80) and ultrasonography missed 3 (sensitivity, 80%; 95% CI, 55-93). Thrombi missed by CT venography were located across cannulated upper extremity deep veins, while ultrasonography missed thrombi in the brachiocephalic and more central veins.</div></div><div><h3>Conclusion</h3><div>Both CT venography and ultrasonography missed VTE at screening. Results indicate that it is unlikely that the sensitivity of CT venography alone exceeds that of ultrasonography in detection of asymptomatic PICC-related VTE.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 1","pages":"Pages 180-189"},"PeriodicalIF":5.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958883","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

TET2 mutations in myeloproliferative neoplasms: potential mediation of atrial fibrillation by interleukin-1β and impact on stroke risk in clinical cohorts 骨髓增生性肿瘤中的TET2突变：IL-1β对房颤的潜在介导作用及其对卒中风险的影响

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-01-01 DOI: 10.1016/j.jtha.2025.09.015

Guangshuai Teng , Minghui Duan , Ke Shang , Yuhui Zhang , Xiaojing Wei , Lan Peng , Gary Tse , Yuan Zhou , Gregory Y.H. Lip , Tong Liu , Jie Bai

Background

The role of clonal hematopoiesis of indeterminate potential (CHIP) related gene mutations in atrial fibrillation (AF) and stroke in patients with myeloproliferative neoplasms (MPNs) remains insufficiently investigated.

Objectives

To investigate the role of CHIP related gene mutations in AF and stroke in patients with MPNs and explore the role of cytokines.

Methods

A retrospective cohort of 465 MPN patients (mean age 61; range, 10-89; 49% male) and an additional validation cohort (n = 196) were analyzed using multivariable Cox regression, Firth-corrected Cox regression, and competing risks models, adjusting for confounders. Propensity score matching (PSM) balanced confounders. Mediation analysis assessed the role of IL-1β in the link between TET2 and AF/stroke.

Results

CHIP-related mutations increased the risk of AF in all 3 models, both before and after PSM. TET2 independently increased the risk of AF (Cox, hazard ratio [HR] = 3.13; 95% CI, 1.62, 6.06; P = .001; Firth, HR = 3.03; 95% CI, 1.55, 5.74; P = .002; Fine-Gray, subdistribution HR = 2.98; 95% CI, 1.46, 6.08; P = .003). Sensitivity analysis in the JAK2 subgroup and PSM cohort, as well as the validation cohort, all confirmed that TET2 remained associated with AF (all P < .05). Interleukin (IL)-1β partially mediated the association between TET2 and AF (P = .034). AF predicted the occurrence of stroke (P < .05) and partially mediated the relationship between TET2 and stroke. No direct association between CHIP/TET2 and stroke was observed, and IL-1β did not play a role in the association between TET2 and stroke.

Conclusion

TET2 mutations increase the risk of AF, which may be associated with the IL-1β-mediated inflammatory pathway. AF serves as a critical intermediary for CHIP-associated ischemic stroke. Integrating TET2 status into AF surveillance and anticoagulation strategies may reduce thrombosis.

目的：探讨不确定电位克隆造血（CHIP）相关基因突变在骨髓增生性肿瘤（MPN）患者心房颤动（AF）和脑卒中中的作用，并探讨细胞因子在其中的作用。方法：采用多变量Cox回归、firth校正Cox回归和竞争风险模型对465例MPN患者（平均年龄61岁，范围：10-89岁，49%为男性）和另外一个验证队列（n=196）进行回顾性分析，并对混杂因素进行调整。倾向评分匹配（PSM）平衡混杂因素。中介分析评估了IL-1β在TET2与AF/卒中之间的联系中的作用。结果：芯片相关突变增加了三种模型在PSM前后发生房颤的风险。TET2独立增加AF的风险(Cox: HR=3.13 (95% CI: 1.62-6.06， P=0.001), Firth: HR=3.03 (95% CI: 1.55-5.74， P=0.002), Fine-Gray: sHR=2.98 （95% CI: 1.46-6.08， P=0.003）。JAK2亚组和PSM队列以及验证队列的敏感性分析均证实TET2仍与房颤相关（均为p2）。结论：TET2突变增加房颤的风险，这可能与il -1β介导的炎症途径有关。房颤是chip相关缺血性脑卒中的重要中介。将TET2状态纳入房颤监测和抗凝策略可减少血栓形成。

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引用次数: 0

“Thromboembolism in transplant-ineligible multiple myeloma patients on triplet/quadruplet therapy: a post hoc analysis of BENEFIT”: comment from Galarza Fortuna et al. “不适合移植的多发性骨髓瘤患者接受三胞胎/四胞胎治疗的血栓栓塞：对BENEFIT的事后分析”：来自Galarza Fortuna等人的评论。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-01-01 DOI: 10.1016/j.jtha.2025.09.017

Gliceida M. Galarza Fortuna , Kian J. Rahbari , Muhamed Baljevic , Douglas W. Sborov

引用次数: 0

WE-thrombin induces cytoprotective signaling in endothelial cells by cleavage of Arg46 of protease-activated receptor 1. 凝血酶通过裂解蛋白酶激活受体1的Arg46诱导内皮细胞的细胞保护信号。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2025-12-31 DOI: 10.1016/j.jtha.2025.11.034

Indranil Biswas, Alireza R Rezaie

Background: The thrombin mutant, W215A/E217A (WE-thrombin), is currently undergoing clinical trials for determining its therapeutic potential as an anti-thrombotic and cytoprotective drug. Mechanistically, it is thought that WE-thrombin exerts its protective effects indirectly through thrombomodulin (TM)-dependent activation of protein C (APC). APC exerts protective effects by both enzymatic inactivation of procoagulant cofactors Va and VIIIa in the anticoagulant and cleavage of Arg46 of protease-activated receptor 1 (PAR1) in the anti-inflammatory pathways. We recently discovered that upon binding TM, thrombin can cleave PAR1-Arg46 with ∼10-fold higher efficiency than APC to elicit cytoprotective signaling effects in endothelial cells.

Objective: In this study, we investigated the hypothesis that WE-thrombin may have direct PAR1-dependent cytoprotective signaling function.

Methods: We evaluated the direct signaling and PAR1-Arg46 cleavage functions of WE-thrombin by transfecting PAR1-knockout endothelial cells or HEK-293 cells with a PAR1 construct which has an intact Arg46, but its Arg41 has been replaced with an Ala (PAR1-R41A).

Results: We discovered that WE-thrombin elicits direct cytoprotective signaling in transfected endothelial cells through cleavage of PAR1-Arg46. This conclusion was supported by a PAR1-Arg46 cleavage-reporter assay using HEK-293 cells transfected with both TM and NanoLuc-luciferase labeled PAR1-R41A constructs.

Conclusion: These results suggest that a direct WE-thrombin activation of PAR1 through cleavage of Arg46 may primarily be responsible for the cytoprotective signaling function of WE-thrombin independent of its function as a protein C activator.

背景：凝血酶突变体W215A/E217A （we -凝血酶）目前正在进行临床试验，以确定其作为抗血栓和细胞保护药物的治疗潜力。从机制上讲，我们认为凝血酶是通过凝血调节蛋白（TM）依赖性激活蛋白C （APC）间接发挥其保护作用的。APC通过促凝辅助因子Va和viia的酶灭活在抗凝和蛋白酶激活受体1 (PAR1) Arg46的裂解中发挥保护作用。我们最近发现，在结合TM后，凝血酶可以以比APC高10倍的效率切割PAR1-Arg46，从而在内皮细胞中引发细胞保护信号效应。目的：在本研究中，我们探讨了we -凝血酶可能具有直接依赖par1的细胞保护信号功能的假设。方法：我们通过转染PAR1敲除内皮细胞或HEK-293细胞，用具有完整Arg46，但其Arg41已被Ala （PAR1- r41a）取代的PAR1构建物来评估We -凝血酶的直接信号传导和PAR1-Arg46切割功能。结果：我们发现We -凝血酶通过裂解PAR1-Arg46在转染的内皮细胞中引发直接的细胞保护信号。通过转染TM和nanoluc荧光素酶标记的PAR1-R41A构建物的HEK-293细胞，进行PAR1-Arg46切割报告基因实验，支持了这一结论。结论：这些结果表明，we -凝血酶通过切割Arg46直接激活PAR1可能主要负责we -凝血酶的细胞保护信号功能，而不是其作为蛋白C激活剂的功能。

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引用次数: 0

Screening, Diagnosis, and Management of Pediatric Post-Thrombotic Syndrome Following Extremity Thrombosis. 儿童肢体血栓形成后血栓形成综合征的筛查、诊断和治疗。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2025-12-23 DOI: 10.1016/j.jtha.2025.11.031

Avila Laura, Betensky Marisol, Klaassen Ilm, Rajpurkar Madhvi, Zia Ayesha

Pediatric post-thrombotic syndrome (PTS) is the most common long-term complication of deep vein thrombosis (DVT) in children, which is in turn the most common thrombotic event in childhood. Diagnosis and severity rating of PTS are based on the findings of signs and symptoms in the DVT-affected extremity. The lack of objective methods to diagnose or monitor for PTS and the consequent need to rely on symptoms can be an additional challenge in the pediatric population. Although the importance of long-term PTS monitoring in children with upper and lower extremity DVT is increasingly being recognized, the implementation of long-term follow-up in clinical practice is still suboptimal. Similarly, the management of pediatric PTS is inconsistent, in part due to the limited number of studies in this population to guide practice. The rising recognition of pediatric DVT is expected to lead to more cases of PTS in the near future and, therefore, efforts to further disseminate current knowledge on pediatric PTS among treaters are relevant. In this manuscript, we present two representative cases of children with extremity DVT to address key aspects of PTS diagnosis related to patient follow-up and family counselling. This manuscript complements the guidance developed by Post-Thrombotic Sequelae Working Party of the Scientific and Standardization Subcommittee on Pediatric and Neonatal Thrombosis of the International Society on Thrombosis and Haemostasis to optimize the clinical care of children with or at risk of PTS.

儿童血栓形成后综合征（PTS）是儿童深静脉血栓形成（DVT）最常见的长期并发症，而深静脉血栓形成又是儿童时期最常见的血栓事件。PTS的诊断和严重程度分级是基于深静脉血栓影响肢体的体征和症状的发现。缺乏客观的方法来诊断或监测PTS，因此需要依赖症状，这对儿科人群来说是一个额外的挑战。尽管长期PTS监测对儿童上下肢深静脉血栓的重要性越来越被认识到，但在临床实践中长期随访的实施仍然不够理想。同样，儿童PTS的管理也不一致，部分原因是在该人群中指导实践的研究数量有限。随着对儿科深静脉血栓的认识不断提高，预计在不久的将来会出现更多的PTS病例，因此，在治疗人员中进一步传播儿科PTS的现有知识是有意义的。在这篇文章中，我们提出了两个具有代表性的儿童下肢深静脉血栓的病例，以解决与患者随访和家庭咨询相关的PTS诊断的关键方面。该手稿补充了国际血栓与止血学会儿科和新生儿血栓形成科学与标准化小组委员会血栓后后遗症工作组制定的指导方针，以优化患有或有PTS风险的儿童的临床护理。

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引用次数: 0

Hyperfibrinolysis in Trauma-Induced Coagulopathy: Exploring the Role of Inflammatory Cytokines. 创伤性凝血病中的高纤溶：炎性细胞因子的作用探讨。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2025-12-23 DOI: 10.1016/j.jtha.2025.11.026

Kyosuke Takahashi, Kazuma Yamakawa, Anaar E Siletz, Morihiro Katsura, John B Holcomb, Bryan A Cotton, Charles E Wade, Jessica C Cardenas, Matthew Martin, Kenji Inaba, Kazuhide Matsushima

Background: Hyperfibrinolysis is the excessive fibrinolytic activity observed in severely injured patients with trauma-induced coagulopathy(TIC). Previous studies suggest that inflammatory cytokines initiate inflammatory responses triggered by trauma and could impact on the coagulation cascade; however, the association between inflammatory cytokines and the development of hyperfibrinolysis has not been fully evaluated.

Objectives: The aim of this study was to identify the characteristics of the inflammatory cytokines dynamics in TIC, particularly hyperfibrinolysis.

Methods: This is a secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios trial. Study patients were stratified into the hyperfibrinolysis and non-hyperfibrinolysis groups using TEG LY30 values and plasmin-antiplasmin complex. Serial values of inflammatory cytokine level(0-24 hours post-admission) were compared between the hyperfibrinolysis and non-hyperfibrinolysis groups. Subgroup analysis investigated the cytokines comparing the traumatic brain injury patients with hyperfibrinolysis and those without hyperfibrinolysis RESULTS: A total of 477 patients were included(hyperfibrinolysis:45, non-hyperfibrinolysis:432). The levels of interleukin-6(IL-6), interleukin 1 receptor antagonist(IL-1Ra), major vault protein 1(MVP-1), were significantly higher in the hyperfibrinolysis group compared to those in the non-hyperfibrinolysis group across the time points within 24 hours after presentation. The level of platelet derived growth factor subunit B(PDFG-B) upon arrival was significantly higher in the hyperfibrinolysis group. The IL-6, IL-1Ra, and MVP-1 levels peaked at 4 hours post-admission and PDGF-B peaked upon arrival and downtrended thereafter.

Conclusion: The current study revealed that that IL-6, IL-1Ra, and MVP-1 trended upward for 4 hours post-admission, and PDGF-B peaked upon arrival and downtrended thereafter in severely injured patients with hyperfibrinolysis.

背景：高纤溶是在创伤性凝血病（TIC）严重损伤患者中观察到的过度纤溶活性。先前的研究表明，炎症细胞因子启动创伤引发的炎症反应，并可能影响凝血级联；然而，炎症细胞因子与高纤溶发展之间的关系尚未得到充分评估。目的：本研究的目的是确定TIC中炎症细胞因子动力学的特征，特别是高纤溶。方法：这是对实用的随机最佳血小板和血浆比率试验的二次分析。根据TEG LY30值和纤溶蛋白-抗纤溶蛋白复合物将患者分为高纤溶组和非高纤溶组。比较高纤溶组和非高纤溶组的炎性细胞因子水平序列值（入院后0-24小时）。结果：共纳入477例外伤性脑损伤患者（高纤溶患者45例，非高纤溶患者432例）。在发病后24小时内，与非高纤溶组相比，高纤溶组的白细胞介素-6（IL-6）、白细胞介素-1受体拮抗剂（IL-1Ra）、主要拱顶蛋白1（mps -1）的水平显著高于非高纤溶组。血小板衍生生长因子亚单位B（PDFG-B）水平在到达时在高纤溶组显著升高。IL-6、IL-1Ra和MVP-1水平在入院后4小时达到峰值，PDGF-B在入院后达到峰值，此后呈下降趋势。结论：本研究显示，在严重损伤的高纤溶患者中，IL-6、IL-1Ra和MVP-1在入院后4小时呈上升趋势，PDGF-B在到达时达到峰值，随后呈下降趋势。

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