Journal of Thrombosis and Haemostasis最新文献

{"title":"Effect of Prothrombin Complex Concentrate versus Frozen Plasma on Divalent Cations and Vitamin K Dependent Factor Function: An Ex Vivo Mechanistic Study.","authors":"Min U Jang, Hung A Nguyen, Amir L Butt, Kofi B Vandyck, Kenneth E Stewart, Vibhudutta Awasthi, Kenichi A Tanaka","doi":"10.1016/j.jtha.2026.10.006","DOIUrl":"https://doi.org/10.1016/j.jtha.2026.10.006","url":null,"abstract":"<p><strong>Background: </strong>Prothrombin complex concentrate (PCC) has demonstrated hemostatic superiority over frozen plasma (FP) in cardiac surgery, yet the mechanism beyond factor concentration remains unclear.</p><p><strong>Objectives: </strong>To test ex vivo whether citrate-mediated depletion of ionized calcium (Ca²⁺) and magnesium (Mg²⁺) by FP impairs vitamin K dependent (VKD) factor function, minimized by PCC.</p><p><strong>Patients/methods: </strong>Heparinized whole blood from healthy volunteers (n=10) was diluted and supplemented with 20% FP or volume-equivalent PCC. Coagulation was assessed by heparinase-modified INTEM (ROTEM) and contact-activated thrombin generation, and validated in cardiopulmonary bypass (CPB) samples (n=6). Factor IX (FIX) and Factor X γ-carboxyglutamate (Gla) domain affinities for Ca²⁺ and Mg²⁺ were measured by MicroScale Thermophoresis (MST).</p><p><strong>Results: </strong>FP reduced Ca²⁺ from 0.94 ± 0.03 to 0.24 ± 0.01 mmol·L^-1 and Mg²⁺ to undetectable levels. Without exogenous calcium, FP abolished clot formation (clotting time, CT >3600 s) whereas PCC maintained CT (105.4 ± 16.9 s). Low-dose calcium (0.4 mmol·L^-1) partially restored CT (1037 ± 575.5 s); adding MgSO₄ (0.6 mmol·L^-1) improved it to 275.2 ± 56.2 s. Findings held in CPB samples. By MST, the FIX Gla domain bound Mg²⁺ ∼6-fold more tightly than Ca²⁺ (Kd 66.1 ± 8.2 vs 381.2 ± 45.3 μM).</p><p><strong>Conclusions: </strong>Lowering ionized calcium with FP-derived citrate revealed a functional interaction between magnesium and the Gla domain of VKD factors: at low calcium, restoring magnesium rather than calcium alone recovered thrombin generation and clot formation. PCC preserved the ionic milieu and thrombin generation. Standard coagulation assays potentially underestimate this magnesium dependence because of supraphysiological recalcification.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224367","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}

{"title":"Plasma protein profiles in Bleeding Disorder of Unknown Cause.","authors":"Ina Kronevska, Dino Mehic, Alette Kooiker, Carmen van der Zwaan, Arie Johan Hoogendijk, Joost C M Meijers, Helmuth Haslacher, Cihan Ay, Ingrid Pabinger, Maartje van den Biggelaar, Johanna Gebhart, Tirsa T van Duijl","doi":"10.1016/j.jtha.2026.10.004","DOIUrl":"https://doi.org/10.1016/j.jtha.2026.10.004","url":null,"abstract":"<p><strong>Background: </strong>In over half of patients with mild to moderate clinically relevant bleeding, the etiology remains unknown, and patients are classified as having bleeding disorders of unknown cause (BDUC).</p><p><strong>Objective: </strong>To identify alterations within and beyond the classical hemostatic system and characterize the plasma proteome in BDUC.</p><p><strong>Methods: </strong>Plasma samples of two blood draws from patients (n=105) with BDUC from the Vienna Bleeding Biobank and a reference population (n=118) were analyzed using targeted and unbiased mass spectrometry-based proteomics. Protein levels were assessed for associations with bleeding phenotype, functional laboratory tests and clinical characteristics, and individual signatures were examined across two blood draws.</p><p><strong>Results: </strong>Targeted and discovery-based proteomics demonstrated similar distributions of coagulation and fibrinolytic proteins in BDUC compared to reference. Plasma proteome profiles were predominantly shaped by female sex and ABO blood group, while only limited associations were observed with bleeding severity. Among hemostatic proteins, tissue factor pathway inhibitor, von Willebrand factor and protein Z exhibited the greatest inter-individual variability, although to a similar extent as in the reference population. Global plasma protein levels were consistent across blood draws, and one-versus-all analysis identified predominantly acute-phase and sex hormone-related proteins, with limited alterations in the hemostatic system.</p><p><strong>Conclusions: </strong>Proteomic profiles in BDUC were within normal ranges at steady state, suggesting that unexplained bleeding is unlikely to result from isolated quantitative alterations in hemostatic plasma proteins. These findings highlight the need for functional omics approaches and multi-compartment analyses beyond plasma to uncover the mechanisms underlying unexplained bleeding.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224370","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}

{"title":"Reported items and methods for analysis in diagnostic management studies evaluating venous thromboembolism: a systematic review: Communication from the ISTH SSC Subcommittee on Diagnosis and Prediction in Thrombotic Disease.","authors":"Vicky Mai, Noémie Kraaijpoel, Shaima Kaka, Marie-Eve Matthieu, Kerstin de Wit, Helia Robert-Ebadi, Marc Righini, Grégoire Le Gal, Tobias Tritschler","doi":"10.1016/j.jtha.2026.09.045","DOIUrl":"https://doi.org/10.1016/j.jtha.2026.09.045","url":null,"abstract":"<p><strong>Introduction: </strong>Reporting of venous thromboembolism (VTE) diagnostic management studies is not standardized, which contributes to incomplete and variable description of study methods and results. This variability hampers interpretation and appraisal of study results. The aim of this study was to evaluate the reporting of key methodology items in recent VTE diagnostic management studies.</p><p><strong>Methods: </strong>A systematic search was conducted in Embase and MEDLINE from January 1^st, 2005, to August 6^th, 2024, to identify prospective diagnostic management studies that included adult patients with suspected VTE with follow-up of patients in whom VTE was excluded at baseline. The primary outcome was the reporting of predefined study items. Secondary outcomes were definitions and analysis of diagnostic failure rates and efficiency.</p><p><strong>Results: </strong>Fifty-nine studies were included. Reporting varied: study design, inclusion criteria, follow-up and overall VTE prevalence were consistently reported, whereas location of confirmed PE and reasons for loss to follow-up were poorly reported. Fifty-four studies (92%) reported a definition of the diagnostic failure rate, of which 45 (83%) defined it as the incidence of VTE in all patients in whom VTE had been excluded at baseline. Predefined upper safety margin for the diagnostic failure rate was reported in 34 studies (63%), and varied widely, ranging between 1.5% and 8.0%. Only 8 studies (14%) defined diagnostic efficiency.</p><p><strong>Conclusion: </strong>Reporting of key study items, as well as definitions and analysis of diagnostic failure rates varied among VTE diagnostic management studies. Standardization of the reporting and analysis of VTE diagnostic management studies is needed.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149216418","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}

{"title":"Plasma Neutrophil Gelatinase-Associated Lipocalin levels and risk of future incident venous thromboembolism.","authors":"Nikolai Hagensen Eide, Vania Maris Morelli, Thor Ueland, Pål Aukrust, Sigrid Kufaas Brækkan, John-Bjarne Hansen","doi":"10.1016/j.jtha.2026.10.005","DOIUrl":"https://doi.org/10.1016/j.jtha.2026.10.005","url":null,"abstract":"<p><strong>Background: </strong>Although neutrophils are suggested to play a role in the pathogenesis of venous thromboembolism (VTE), no study has investigated whether neutrophil gelatinase-associated lipocalin (NGAL), a marker of neutrophil activation, is associated with future VTE risk in the general population.</p><p><strong>Aim: </strong>To investigate the association between plasma NGAL levels and the risk of future VTE.</p><p><strong>Methods: </strong>Plasma NGAL levels were measured in 416 VTE cases and 848 age- and sex-matched controls in a nested case-control study derived from the Tromsø study cohort (1994-2007). Logistic regression models were used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for VTE according to quartiles of plasma NGAL adjusted for age, sex, body mass index, arterial cardiovascular disease, cancer, and C-reactive protein. Separate analyses with follow-up restricted to the first 2- and 5 years after cohort inclusion were conducted to investigate potential short-term associations.</p><p><strong>Results: </strong>We found no association between NGAL levels and risk of future VTE when analyzing the entire study period (OR for highest vs. lowest quartile of NGAL: 1.02, 95% CI: 0.70-1.51). However, when follow-up was restricted to 2 years, higher NGAL levels were associated with increased risk of future VTE (OR 3.87, 95% CI 1.15-13.03). The association was attenuated when follow-up was extended to 5 years (OR: 1.51, 95% CI: 0.82-2.80).</p><p><strong>Conclusion: </strong>Higher plasma NGAL levels were associated with a transiently increased risk of future VTE.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149216410","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}

{"title":"Incidence of thrombosis and bleeding in patients with JAK2- positive myeloproliferative neoplasms receiving low-dose aspirin: a systematic review and meta-analysis.","authors":"Kristina Vrotniakaite-Bajerciene, Caterina E Marx, Tobias Tritschler, Risa Shorr, Marc Carrier, Dean A Fergusson, Aurélien Delluc, Miriam Kimpton","doi":"10.1016/j.jtha.2026.09.044","DOIUrl":"https://doi.org/10.1016/j.jtha.2026.09.044","url":null,"abstract":"<p><strong>Background: </strong>Patients with JAK2V617F-positive myeloproliferative neoplasms (MPNs) are at increased thrombotic risk and commonly receive low-dose aspirin, yet its net clinical benefit is uncertain.</p><p><strong>Objectives: </strong>We estimated the incidence of thrombotic and bleeding events in patients with JAK2-positive MPNs treated with low-dose aspirin.</p><p><strong>Methods: </strong>A systematic review was performed for studies evaluating thrombotic and hemorrhagic events in patients with JAK2V617F-positive MPNs while taking low-dose aspirin. Study-level incidence rates (IR) per 100 person-years (PY) and incidence rate ratios (IRR) comparing aspirin use versus no aspirin were calculated and pooled using random-effects meta-analysis. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.</p><p><strong>Results: </strong>We included 3 randomized clinical trials and 7 observational studies (n=1,760 with aspirin, n=367 without aspirin). The pooled IR of thrombotic events in JAK2V617F-positive MPN patients receiving low-dose aspirin prophylaxis was 2.72 per 100 PY (95% confidence interval (CI) 1.59 - 4.65; I²=93%) with pooled IRR receiving aspirin versus no aspirin of 0.59 (95% CI 0.40 - 0.86, I²=16%). The pooled IR of major and non-major bleeding on low-dose aspirin prophylaxis was 1.97 (95% CI 1.06 - 3.65; I²=90%) per 100 PY with pooled IRR of 2.43 (95% CI 1.15 - 5.11; I²=43%). The GRADE level of confidence for the investigated risks was low.</p><p><strong>Conclusions: </strong>Aspirin was associated with a 40% reduction in thrombosis but a 2.5-fold increase in bleeding risk with low certainty of evidence. More studies are needed to gain high-quality evidence the better define the role of aspirin in JAK2V617F-positive MPNs.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149216446","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}

{"title":"Heparin-PEAR-1 interaction contributes to platelet activation by HIT antibodies.","authors":"Richard J Buka, Jovita Manickam, Hugo Lagonotte, Eleyna M Martin, Rachel E Lamerton, Nithya Radjaramin, Tatianna Fernandes, Yves Gruel, Anthony Calvert, Anthony Poles, Jérôme Rollin, Steve P Watson, Phillip L R Nicolson, Samantha J Montague","doi":"10.1016/j.jtha.2026.10.002","DOIUrl":"https://doi.org/10.1016/j.jtha.2026.10.002","url":null,"abstract":"<p><strong>Background: </strong>Heparin is a negatively charged, polysaccharide used as an anticoagulant. In 0.5-1% of patients receiving unfractionated heparin, heparin-induced thrombocytopenia (HIT) occurs 5-10 days after exposure. In HIT, heparin binds to platelet factor 4 (PF4), exposing PF4 neoepitopes, allowing binding of heparin-dependent anti-PF4 antibodies, forming immune complexes that activate platelets through FcγRIIA. Recently, we showed that heparin mediates weak/slow aggregation of platelets via platelet endothelial aggregation receptor-1 (PEAR1).</p><p><strong>Objectives: </strong>To investigate the role of the heparin-PEAR1 interaction in platelet activation in HIT.</p><p><strong>Methods: </strong>Activation of washed platelets from multiple responsive donors to 5B9 (HIT-like mAb) and eight HIT sera in the presence of heparin, and in the presence or absence of the inhibitory PEAR1 nanobody, Nb138, was assessed. Light transmission aggregometry over 30 minutes was used to measure the kinetics of platelet activation for three sera, whilst flow cytometry for P-selectin expression gave an end read-out after 60 minutes for all eight sera.</p><p><strong>Results: </strong>Aggregation and activation to heparin (0.5 IU/mL) was blocked by Nb138 (100 nM). 5B9 and HIT patient sera in the presence of heparin induced full platelet aggregation within 15 minutes, which was blocked or delayed by Nb138 in most donors. P-selectin expression was increased with 5B9 and HIT sera in the presence of heparin and was reduced by Nb138 in all donors.</p><p><strong>Conclusions: </strong>Our results demonstrate that PEAR1 blockade reduces/blocks platelet activation to a HIT-like monoclonal antibody and HIT sera in the presence of heparin suggesting the heparin-PEAR1 axis may contribute to the pathophysiology in HIT.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149167396","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}

{"title":"Heparin Management and Coagulation in Acute Aortic Dissection Surgery: A Randomised Controlled Trial.","authors":"Jens Toft Eschen, Julie Brogaard Larsen, Andreas Ruelykke Damsted, Michael Kremke, Peter Fast Nielsen, Mariann Tang, Ivy Susanne Modrau","doi":"10.1016/j.jtha.2026.09.036","DOIUrl":"https://doi.org/10.1016/j.jtha.2026.09.036","url":null,"abstract":"<p><strong>Background: </strong>Acute type A aortic dissection remains a life-threatening condition characterised by profound consumptive coagulopathy and perioperative transfusion requirements. The optimal anticoagulation strategy during cardiopulmonary bypass remains uncertain.</p><p><strong>Objectives: </strong>To assess baseline coagulation and compare the impact of two standard anticoagulation strategies on thrombin generation and clinical outcomes in patients undergoing emergent surgery for acute type A aortic dissection.</p><p><strong>Patients/methods: </strong>In this single-centre, partially blinded, randomised controlled trial, patients were allocated 1:1 to heparin-dose response (HDR) or activated clotting time (ACT) guided anticoagulation. Randomisation was stratified by organ dysfunction and preoperative anticoagulation. Primary endpoint was change in prothrombin fragment 1+2 (F1+2) from baseline to heparin reversal after cardiopulmonary bypass. Secondary endpoints included coagulation markers, bleeding, transfusion, and clinical outcomes up to 90 days.</p><p><strong>Results: </strong>Between December 2022 and September 2024, 26 patients were randomised (HDR= 14; ACT= 12). Both groups demonstrated marked baseline consumptive coagulopathy with ongoing intraoperative thrombin generation. Despite baseline differences in F1+2, the primary endpoint did not differ significantly (median change HDR: 333 [IQR 654] vs. ACT: -92 pmol/L [IQR 1984], p = 0.31). Post hoc baseline-adjusted ANCOVA sensitivity analysis of log-transformed change (n = 25) showed a 14% lower fold-increase in HDR compared with ACT (HDR/ACT ratio 0.86, 95% CI 0.63-1.17; p = 0.32). Secondary endpoints were comparable, except for a lower protamine-to-heparin ratio in HDR group (0.51 vs 0.75; p < 0.001).</p><p><strong>Conclusions: </strong>Thrombin generation was insufficiently suppressed by either anticoagulation protocol. Exacerbation of preoperative consumptive coagulopathy highlights the insufficiency of current anticoagulation strategies in acute aortic dissection.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111322","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}

{"title":"Obituary: Professor Björn Wiman.","authors":"Håkan Wallén, Désiré Collen, Tomas L Lindahl","doi":"10.1016/j.jtha.2026.09.042","DOIUrl":"https://doi.org/10.1016/j.jtha.2026.09.042","url":null,"abstract":"","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111354","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}

{"title":"Pathogenic mechanisms and novel experimental anti-inflammatory therapies in hemophilic arthropathy.","authors":"Padmavathi Kavadipula, L Vijaya Mohan Rao","doi":"10.1016/j.jtha.2026.09.038","DOIUrl":"https://doi.org/10.1016/j.jtha.2026.09.038","url":null,"abstract":"<p><p>Hemophilic arthropathy (HA) is a chronic, progressive, and debilitating joint disorder resulting from recurrent hemarthroses in individuals with hemophilia. Despite major advances in prophylactic clotting factor replacement and the introduction of non-factor therapies that have markedly reduced bleeding frequency, HA remains a significant unmet clinical challenge. Accumulating evidence indicates that synovial inflammation is a key driver of HA progression, promoting synovial hyperplasia, macrophage infiltration, pathological angiogenesis, and cartilage destruction. Consequently, anti-inflammatory interventions have emerged as a promising strategy to prevent or limit joint deterioration following bleeding episodes. Recent preclinical studies have focused on targeting inflammatory pathways activated after joint bleeding, including cytokine- and immune cell-mediated signaling networks. These investigations have identified several therapeutic targets that can attenuate disease progression, although their efficacy has been variable and often limited by the complexity of HA pathogenesis. More recently, limited preclinical studies suggest that extracellular vesicles (EVs) exhibit promising therapeutic potential in attenuating the progression of HA in experimental murine models by simultaneously modulating multiple pathological processes, including inflammation, angiogenesis, vascular dysfunction, and cartilage degeneration. Unlike therapies directed against a single inflammatory mediator, EVs possess pleiotropic biological activities and can be engineered to enhance therapeutic efficacy and tissue targeting. Although anti-inflammatory therapies for HA remain largely in the preclinical stage, growing evidence supports their translation potential. Continued advances in EV biology, cargo engineering, manufacturing, and delivery technologies may establish EV-based therapeutics as a novel and effective adjunct to current treatment strategies for preventing or slowing HA progression.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111383","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}

{"title":"Coactivators YAP and TAZ Contribute Differently to the Transcriptional Regulation of VWF in Endothelial Cells.","authors":"Meaghan O'Donnell, Anthony Guglya, Elham Ghorbanpour, Nathalie Tijet, Colleen Notley, Emily Bucciol, Taha Azad, Helena Janse van Rensburg, Xiaolong Yang, David Lillicrap","doi":"10.1016/j.jtha.2026.09.034","DOIUrl":"https://doi.org/10.1016/j.jtha.2026.09.034","url":null,"abstract":"<p><strong>Background: </strong>Upstream signals and associated signalling axes that contribute to the differential VWF expression observed across various vascular beds remain unclear. Transcriptional coactivators YAP and TAZ, through transcription factors including TEAD, may contribute distinctly to this heterogeneity in response to external mechanical stimuli.</p><p><strong>Objectives: </strong>Investigate the role of YAP/TAZ in the transcriptional regulation of VWF in endothelial cells (ECs).</p><p><strong>Methods: </strong>Human umbilical vein ECs (HUVECs) and human aortic ECs (HAECs) were assessed for levels of VWF mRNA and VWF:Ag following YAP/TAZ gene silencing by siRNA. VWF promoter activity was measured in HUVECs using luciferase reporter constructs, both before and after inactivating the promoter's single TEAD site. Changes in VWF mRNA and VWF:Ag were measured in ECs exposed to shear stress (5-30 dynes/cm²), and immunofluorescent microscopy was used to visualise and quantify intracellular TAZ localisation.</p><p><strong>Results: </strong>YAP and TAZ assumed different roles between EC subtypes. In HUVECs, we observed a TAZ-dominant contribution to VWF expression across siRNA and shear stress experiments. In HAECs, our results are consistent with a negative regulatory role of YAP on TAZ. Modifications to the TEAD sequence reduced VWF expression in HUVECs, indicating mechanistic convergence of YAP/TAZ on this site, further supported by chromatin immunoprecipitation (ChIP) and in silico ChIP-seq analysis. Immunocytochemistry displayed cytoplasmic TAZ localisation under high laminar flow, implicating shear stress as a negative regulator of VWF expression.</p><p><strong>Conclusion: </strong>YAP and TAZ are novel contributors to the transcriptional regulation of VWF in ECs through a TEAD-dependent mechanism, acting independently and distinctly in various EC subtypes.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111333","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}