Research and Practice in Thrombosis and Haemostasis最新文献

{"title":"Joint effects of atrial fibrillation and prothrombotic genotypes on the risk of venous thromboembolism","authors":"Erin Mathiesen Hald ,&nbsp;Maja–Lisa Løchen ,&nbsp;Kristian Hveem ,&nbsp;Mary Cushman ,&nbsp;Sigrid K. Brækkan ,&nbsp;John–Bjarne Hansen","doi":"10.1016/j.rpth.2025.102880","DOIUrl":"10.1016/j.rpth.2025.102880","url":null,"abstract":"<div><h3>Background</h3><div>Atrial fibrillation (AF) is a risk factor for venous thromboembolism (VTE), but the role of common prothrombotic gene variants in this relationship is unknown.</div></div><div><h3>Objectives</h3><div>We investigated the joint effect of prothrombotic genotypes and AF on the risk of VTE in a population-based case-cohort.</div></div><div><h3>Methods</h3><div>Incident VTE cases (<em>n</em> = 1458) and a subcohort (<em>n</em> = 14,526) randomly sampled from the Tromsø (1994-2012) and Trøndelag Health (1995-2008) cohort studies were included. DNA was genotyped for rs8176719 (ABO), rs6025 (factor V Leiden [FVL]), rs1799963 (prothrombin), rs2066865 (fibrinogen gamma gene), and rs2036914 (F11). Hazard ratios (HRs) with 95% CIs for VTE were estimated by individual single-nucleotide polymorphisms and categories of a genetic risk score (0-1, 2, 3, 4, and ≥5 risk alleles) in subjects with and without AF.</div></div><div><h3>Results</h3><div>Over a median 12.3 years follow-up, 1421 participants were diagnosed with AF, of whom 139 developed subsequent VTE. Overall, participants with AF had a 1.7-fold increased risk of VTE (HR, 1.73; 95% CI, 1.43-2.08). Among those with AF, ≥1 risk allele of FVL was associated with 1.9-fold higher VTE risk (HR, 1.89; 95% CI, 1.13-3.17) compared with 0 risk alleles. None of the other single-nucleotide polymorphisms increased the risk. In participants without AF, the VTE risk increased linearly with increasing genetic risk score. No such association was found for those with AF.</div></div><div><h3>Conclusion</h3><div>We confirmed that AF is a risk factor for VTE and showed that this relationship was augmented for carriers of FVL. Other common prothrombotic genotypes do not add additional risk of VTE to that induced by AF alone.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 4","pages":"Article 102880"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144534564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Probing rare von Willebrand disease–causing mutations in the D4 and C-domains of von Willebrand factor","authors":"Golzar Mobayen ,&nbsp;Sammy El-Mansi ,&nbsp;Alain Chion ,&nbsp;Thomas D. Nightingale ,&nbsp;Thomas A.J. McKinnon","doi":"10.1016/j.rpth.2025.102922","DOIUrl":"10.1016/j.rpth.2025.102922","url":null,"abstract":"<div><h3>Background</h3><div>von Willebrand disease (VWD) is characterized by absence or reduction of plasma von Willebrand factor (VWF) levels or reduced protein function. While the spectrum of causative VWD mutations is vast, there has been limited characterization of variants occurring within the D4-C6 domains of VWF that comprise the C-terminal portion of the molecule.</div></div><div><h3>Objectives</h3><div>In this study, we investigated the impact of 9 putative low-frequency VWD-causing variants on VWF function.</div></div><div><h3>Methods</h3><div>Variants were generated by site-directed mutagenesis and expressed in human embryonic kidney (HEK)293(T) cells and analyzed for expression, intracellular storage, and multimeric profile. The ability of Arg2379Cys to form dimers was assessed using an A2-CK fragment of VWF.</div></div><div><h3>Results</h3><div>Arg2379Cys, Ser2497Pro, and Cys2639Tyr had significantly reduced secretion from HEK293T cells, while the other mutations all failed to be secreted. While cotransfection with wild-type VWF appeared to rescue expression, cotransfection with a deletion A1 construct demonstrated that only the Gly2044Asp, Glu2343Val, Ser2497Pro, and Cys2693Tyr variants could be rescued. All the variants failed to form appreciable pseudo–Weibel-Palade bodies in HEK293 cells and showed abnormal multimers in cell lysates. The Arg2379Cys variant could be overexpressed by only formed monomers and some dimers. Analysis with a VWF-A2CK protein demonstrated that in the homozygous state Arg2379Cys behaves likes a type 2A variant, while it is likely to be a type 1 variant in the heterozygous state.</div></div><div><h3>Conclusion</h3><div>These data show that variants within the C-terminal region of VWF can dramatically impact proper VWF expression and can different impacts on VWF depending on homozygosity or heterozygosity.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 4","pages":"Article 102922"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144522486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SARS-CoV-2 ORF7a activates the endothelium to release von Willebrand factor that promotes thrombosis","authors":"Quan Zhang ,&nbsp;Xiaohu Huang ,&nbsp;Hangnoh Lee ,&nbsp;Jin-Gu Lee ,&nbsp;Szumam Liu ,&nbsp;Shiwani Limbu ,&nbsp;Malay K. Basu ,&nbsp;Joyce van de Leemput ,&nbsp;Felice D’Agnillo ,&nbsp;Zhe Han ,&nbsp;X. Long Zheng","doi":"10.1016/j.rpth.2025.102947","DOIUrl":"10.1016/j.rpth.2025.102947","url":null,"abstract":"<div><h3>Background</h3><div>Patients with severe and critical COVID-19 frequently exhibit thromboembolic complications, a significant cause of mortality and morbidity. Increased plasma levels of von Willebrand factor (VWF) following SARS-CoV-2 infection have been extensively reported, which links to thrombosis and increased mortality. However, the mechanism underlying SARS-CoV-2–associated thrombotic complications is not fully understood.</div></div><div><h3>Objectives</h3><div>To determine the mechanism of SARS-CoV-2–associated thrombosis.</div></div><div><h3>Methods</h3><div><em>Drosophila</em> genetic screening and molecular, cellular, and biochemical approaches were used.</div></div><div><h3>Results</h3><div>Genetic screening identified a SARS-CoV-2 accessory protein, Orf7a, as a crucial factor promoting agglutination of hemolymph, the circulatory fluid of flies, which is functionally comparable to the blood and lymph of vertebrates. Further studies using cultured murine splenic vascular endothelial cells and human umbilical cord endothelial cells demonstrated that overexpression of ORF7a in these cells significantly activated and stimulated the release of VWF, leading to an increased rate and final coverage of <em>Adamts-13</em>^<em>-/-</em> murine platelets on activated endothelial surfaces under arterial shear. Moreover, a soluble recombinant ORF7a could also activate human endothelial cells and trigger the release of VWF from Weibel–Palade bodies.</div></div><div><h3>Conclusion</h3><div>We demonstrate for the first time that SARS-CoV-2 ORF7a may be one of the pathogenic factors contributing to COVID-19–associated thrombosis by activating the vascular endothelium to release ultralarge VWF, which promotes platelet adhesion and agglutination, and thrombus formation. Thus, a strategy specifically targeting VWF-platelet interaction, such as recombinant a disintegrin and metalloprotease with thrombospondin type 1 repeats, 13 (ADAMTS-13) and/or caplacizumab, may be efficacious in reducing COVID-19–associated thrombosis and mortality.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 4","pages":"Article 102947"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144632047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploration of biomarkers for inhibitor development in persons with hemophilia A","authors":"Meng-Ni Fan ,&nbsp;Tangliang Shen ,&nbsp;Barbara A. Konkle ,&nbsp;Xiaohe Cai ,&nbsp;Ting-Yen Chao ,&nbsp;Marilyn Manco-Johnson ,&nbsp;Anna V. Faino ,&nbsp;Junping Zhang ,&nbsp;Shumin Bao ,&nbsp;Weidong Xiao ,&nbsp;Lei Li ,&nbsp;Carol H. Miao","doi":"10.1016/j.rpth.2025.102877","DOIUrl":"10.1016/j.rpth.2025.102877","url":null,"abstract":"<div><h3>Background</h3><div>Inhibitor development remains a significant challenge for hemophilia A (HA) treatment. Cytokines and glycosylation play crucial roles in inducing and regulating immune responses. Cytokine and altered N-glycan profiles have the potential to be biomarkers in association with the presence of inhibitors in persons with HA.</div></div><div><h3>Objectives</h3><div>We investigated the association of cytokine and plasma N-glycan profiles with inhibitor presence.</div></div><div><h3>Methods</h3><div>In 60 persons with HA and 23 controls, we analyzed 10 cytokines and used multivariable regression to assess their association with inhibitor presence. Given the challenges of validating these findings in previously untreated patients, we employed an HA mouse model to explore the association between cytokine levels and inhibitors. We also examined the correlation between plasma N-glycan profiles and inhibitors in persons with HA, analyzing adult and pediatric groups separately due to age-dependent glycosylation.</div></div><div><h3>Results</h3><div>Elevated granulocyte colony-stimulating factor and interleukin (IL) 6 levels, coupled with decreased IL-10, were significantly associated with inhibitor presence in multivariable regression analysis. High-titer inhibitor was observed in factor (F)VIII-treated mice experiencing chronic inflammation with increased levels of granulocyte colony-stimulating factor, IL-6, and macrophage inflammatory protein-1β, a murine IL-8 homolog, but not in those receiving FVIII alone, consistent with our clinical observations. Inhibitor-positive adult patients exhibited higher biantennary <em>N</em>-glycan and reduced multiantennary <em>N</em>-glycan ratios compared with inhibitor-negative adults. Conversely, inhibitor-positive pediatric patients displayed decreased sialic acid ratios.</div></div><div><h3>Conclusion</h3><div>These findings highlight the association of inhibitor presence with altered plasma cytokine levels and <em>N-</em>glycosylation patterns. Prospective validation is crucial to confirm these associations, develop robust biomarkers, and improve inhibitor risk assessment for persons with HA.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 4","pages":"Article 102877"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Halo fluorescence fibrinolysis test: a novel quantitative assay to evaluate fibrinolysis on established plasma clots","authors":"Zikou Liu ,&nbsp;Orr Zaacks ,&nbsp;Be’eri Niego ,&nbsp;Robert L. Medcalf","doi":"10.1016/j.rpth.2025.102874","DOIUrl":"10.1016/j.rpth.2025.102874","url":null,"abstract":"<div><h3>Background</h3><div>Fibrinolysis is essential for dissolving blood clots and maintaining hemostasis. This process is primarily mediated by tissue-type plasminogen activator, which converts plasminogen into plasmin, thereby breaking down fibrin clots. Traditional amidolytic assays often measure plasmin generation without directly assessing fibrin degradation, while thromboelastography frequently overlooks clot maturation, which significantly influences fibrinolysis resistance.</div></div><div><h3>Objectives</h3><div>To address these limitations, we present a novel quantitative assay for analyzing fibrinolysis on established clots, termed the halo fluorescence fibrinolysis (HoFF) test.</div></div><div><h3>Methods</h3><div>The HoFF test used fluorophore-conjugated fibrinogen to form halo-shaped plasma clots. Fibrinolysis was induced with tissue-type plasminogen activator or its variant tenecteplase, and clot breakdown was monitored via real-time fluorescence detection by a microplate reader. The fluorescence signal was analyzed to calculate a fibrinolysis index, indicating fibrinolytic capacity. Its specificity for fibrinolysis over plasmin generation was validated against traditional amidolytic assays using a plasmin substrate.</div></div><div><h3>Results</h3><div>Fluorescence-labeled fibrinogen was confirmed as a reliable marker of fibrin degradation. The HoFF test exhibited strong linear correlations between the fibrinolysis index and plasminogen activator concentrations, with robust reproducibility. It also effectively evaluated tenecteplase-induced fibrinolysis and demonstrated versatility across clot types, including mouse plasma and human whole-blood models. Furthermore, the test distinguished fibrinolysis from plasmin generation, demonstrated by the differential effects of tranexamic acid inhibition.</div></div><div><h3>Conclusion</h3><div>The HoFF test offers a sensitive, reliable, and high-throughput tool for quantitatively evaluating fibrinolysis on established human and mouse plasma and whole blood clots.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 4","pages":"Article 102874"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144166401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to ‘Preemptive anticoagulation during antenatal pulmonary embolism diagnostics in a community setting: retrospective cohort study’","authors":"Aidan R. Campbell ,&nbsp;Cole J. Florio ,&nbsp;Grace V. Heringer ,&nbsp;Sara T. Woldemariam ,&nbsp;Scott D. Casey ,&nbsp;William B. Stubblefield ,&nbsp;Lauren M. Westafer ,&nbsp;Edward Qiao ,&nbsp;Cydney E. Middleton ,&nbsp;Lara Zekar ,&nbsp;Nachiketa Gupta ,&nbsp;Madeline J. Somers ,&nbsp;Mary E. Reed ,&nbsp;Nareg H. Roubinian ,&nbsp;Ashok P. Pai ,&nbsp;Jeffrey D. Sperling ,&nbsp;David R. Vinson","doi":"10.1016/j.rpth.2025.102892","DOIUrl":"10.1016/j.rpth.2025.102892","url":null,"abstract":"","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 4","pages":"Article 102892"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144166402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"177 The Current Landscape of Anticoagulation (AC) Stewardship Implementation Around the World: An International Survey","authors":"Nancy L. Shapiro ,&nbsp;Grace A. McGee ,&nbsp;Allison E. Burnett","doi":"10.1016/j.rpth.2025.102761","DOIUrl":"10.1016/j.rpth.2025.102761","url":null,"abstract":"","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 ","pages":"Article 102761"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144203241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"98 Derivation and Validation of a Pharmacogenetic-guided Warfarin Dosing Algorithm in an Arab Population Residing in Qatar","authors":"Amr Fahmi ,&nbsp;Ahmed El Bardissy ,&nbsp;Mohamed Saad ,&nbsp;Mohamed Nabil ,&nbsp;Loulia Bader ,&nbsp;Mohamed Kassem ,&nbsp;Ahmed Mahfouz ,&nbsp;Osama Abdelsamad ,&nbsp;Abdelnasser Elzouki ,&nbsp;Hazem Elewa","doi":"10.1016/j.rpth.2025.102778","DOIUrl":"10.1016/j.rpth.2025.102778","url":null,"abstract":"","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 ","pages":"Article 102778"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144203342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"93 Adherence to Direct Oral Anticoagulants among U.S. Veterans with Atrial Fibrillation in the Era of the Veteran Health Administration DOAC Population Management Tool","authors":"Arthur Allen ,&nbsp;Shardool Patel ,&nbsp;Brian Sauer ,&nbsp;Bishoy Ragheb","doi":"10.1016/j.rpth.2025.102749","DOIUrl":"10.1016/j.rpth.2025.102749","url":null,"abstract":"","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 ","pages":"Article 102749"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144203520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"85 Developing an Innovative Clinical Decision Support App for Enhanced Peripheral Artery Disease Management","authors":"Kelly M. Rudd ,&nbsp;Jennifer Glen ,&nbsp;Tim Michalski","doi":"10.1016/j.rpth.2025.102797","DOIUrl":"10.1016/j.rpth.2025.102797","url":null,"abstract":"","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 ","pages":"Article 102797"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144203532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}