Journal of Thrombosis and Haemostasis最新文献

{"title":"Out-of-hospital cardiac arrest associated with venous thromboembolism–a Swedish population-based cohort study","authors":"Emma Bendz ,&nbsp;Anna Oksanen ,&nbsp;Susanna Larsson ,&nbsp;Joel Ohm ,&nbsp;Therese Djärv ,&nbsp;Maria Bruzelius","doi":"10.1016/j.jtha.2024.11.021","DOIUrl":"10.1016/j.jtha.2024.11.021","url":null,"abstract":"<div><h3>Background</h3><div>Venous thromboembolism (VTE) is a common and preventable cardiovascular disease but is potentially fatal if it presents as pulmonary embolism. There are few population-based studies on out-of-hospital cardiac arrest (OHCA) associated with VTE.</div><div>Objectives: We aimed to investigate the prevalence and survival of VTE-associated OHCA in relation to sex, age, and presenting rhythm.</div></div><div><h3>Methods</h3><div>This population-based cohort included all individuals over 15 years registered with a medical OHCA in Sweden 2008-2018. Data from national registers were used. Association with presenting rhythm, 30-day survival, and sex was estimated using adjusted multinomial and binary logistic regression for odds ratios (ORs) with 95% CI.</div></div><div><h3>Results</h3><div>OHCA was associated with VTE in 852 (2.0%) of 41 813 individuals. The median age for VTE-associated OHCA was 69, compared to 73 for the entire cohort, with a higher female prevalence (45% vs 34%). Younger women had a proportionally higher incidence of VTE-associated OHCA than men of the same age. Pulseless electrical activity and asystole had adjusted ORs of 17.2 (95% CI, 11.3-26.0) and 9.59 (95% CI, 6.37-14.4) for VTE-associated OHCA compared with the entire cohort. The 30-day survival was substantially lower in the VTE group compared with the overall medical OHCA group, 2.0% vs 12%, adjusted OR 0.25 (95% CI, 0.13-0.47).</div></div><div><h3>Conclusion</h3><div>This nationwide study confirms that VTE-associated OHCA is uncommon and almost always fatal. Despite fewer women experiencing OHCA, a higher proportion had VTE-associated OHCA, especially younger women. Our findings highlight the need for better prevention and identification of VTE-associated OHCA, particularly in women.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 3","pages":"Pages 968-977"},"PeriodicalIF":5.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intercellular synergy between protease-activated receptors 1 and 4 during mouse development","authors":"Rahul Rajala ,&nbsp;Courtney T. Griffin","doi":"10.1016/j.jtha.2024.11.022","DOIUrl":"10.1016/j.jtha.2024.11.022","url":null,"abstract":"","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 3","pages":"Pages 1117-1119"},"PeriodicalIF":5.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818496","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":"Clinical and genetic characteristics of 40 patients with nonmuscle myosin heavy chain 9-related disease (MYH9-RD) misdiagnosed as immune thrombocytopenia: a retrospective analysis in China","authors":"Abdul Rehman Arif ,&nbsp;Hu Zhou ,&nbsp;Yongjun Fang ,&nbsp;Yunfeng Cheng ,&nbsp;Jieyu Ye ,&nbsp;Wenlan Chen ,&nbsp;Yajie Ding ,&nbsp;Li Cai ,&nbsp;Mei Xue ,&nbsp;Heng Mei ,&nbsp;Yadan Wang","doi":"10.1016/j.jtha.2024.12.001","DOIUrl":"10.1016/j.jtha.2024.12.001","url":null,"abstract":"<div><h3>Background</h3><div>Myosin heavy chain 9-related diseases (MYH9-RDs) are rare autosomal dominant platelet disorders characterized by macrothrombocytopenia and leukocyte inclusion bodies. They can manifest with nonhematological complications, including deafness, nephropathy, or cataracts. Due to its rarity and its similar clinical presentation with immune thrombocytopenia (ITP), MYH9-RD is often misdiagnosed as ITP, leading to inappropriate treatment and delayed management of complications.</div></div><div><h3>Objectives</h3><div>This study aimed to evaluate clinical, therapeutic, and genetic aspects of patients with MYH9-RD misdiagnosed with ITP, comparing differences between Chinese pediatric and adult cases of this condition.</div></div><div><h3>Methods</h3><div>This multicenter retrospective study included data obtained from Chinese patients diagnosed with MYH9-RD between January 2014 and December 2023 at 5 centers.</div></div><div><h3>Results</h3><div>Adults exhibited significantly longer median misdiagnosis (9 years vs 0.2 years, <em>P</em> &lt; .001) and treatment durations (1.5 years vs 0.1 years, <em>P</em> &lt; .001) than children. Nonhematological manifestations were exclusive to adults (10/21). All patients received inappropriate ITP treatments, with adults receiving more different treatments. Genetic analysis revealed 21 spontaneous mutations (52.5%), 12 familial mutations, and 7 mutations with unknown inheritance patterns. Two novel mutations (p.G1517V and p.K1674Q) were identified. Patients with the p.R702C mutation demonstrated early-stage kidney injury and hearing loss.</div></div><div><h3>Conclusion</h3><div>Adult patients with MYH9-RD have greater risk of misdiagnosis, prolonged inappropriate treatment, and nonhematological complications than pediatric patients. Enhanced awareness, consideration of mean platelet volume, family history, and genetic screening are crucial for accurate MYH9-RD diagnosis and management. The incidence of spontaneous mutations and identified genotype–phenotype correlations warrant further investigation in the Chinese population.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 3","pages":"Pages 1043-1051"},"PeriodicalIF":5.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822211","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":"Transfusion biomaterials for hemostasis","authors":"Ethan Pozy ,&nbsp;Ashley C. Brown","doi":"10.1016/j.jtha.2024.11.030","DOIUrl":"10.1016/j.jtha.2024.11.030","url":null,"abstract":"<div><div>Bleeding is a leading cause of trauma deaths and surgical complications. Excessive bleeding has traditionally been treated with the transfusion of donated blood. However, the complicated logistics of sourcing and storing donated blood increases the cost and reduces the accessibility of treatment, particularly as rates of blood donation decline. Advances in biomaterials for targeted drug delivery have presented the opportunity for alternative synthetic injectable hemostats. Among these leading technologies are lipid and polymeric particles and polymer platforms that bind to ligands present at wound sites and amplify hemostatic pathways. As leading hemostatic biomaterials advance toward clinical application, we review current preclinical research models and findings as well as future research directions for next-generation biomaterial injectable hemostatic technologies.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 3","pages":"Pages 790-803"},"PeriodicalIF":5.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829158","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":"Hemophilia B Leyden: characteristics and natural history in the International Pediatric Network of Hemophilia Management Registry","authors":"Mutlu Kartal-Kaess ,&nbsp;Fernando Pinto ,&nbsp;Veerle Labarque ,&nbsp;Marloes de Kovel ,&nbsp;Beatrice Nolan ,&nbsp;Manuel Carcao ,&nbsp;Roseline d’Oiron ,&nbsp;Torben Stamm Mikkelsen ,&nbsp;Rolf Ljung ,&nbsp;Nadine G. Andersson","doi":"10.1016/j.jtha.2024.12.020","DOIUrl":"10.1016/j.jtha.2024.12.020","url":null,"abstract":"<div><h3>Background</h3><div>A unique form of hemophilia B (HB) is HB Leyden. We evaluated the international Pediatric Network on Hemophilia Management Registry (PedNet) database to explore the natural history of HB Leyden, investigate genotype-phenotype associations, and guide clinical decision-making.</div></div><div><h3>Objectives</h3><div>To assess the association between genetic variants, endogenous factor (F)IX levels over time, treatment, and bleeding phenotype in children with HB Leyden.</div></div><div><h3>Methods</h3><div>Data on genetic variants, FIX levels at diagnosis and over time, bleeding, and treatment details were extracted from the international PedNet in children with hemophilia born since 2000.</div></div><div><h3>Results</h3><div>Of 457 individuals with HB, 24 showed an HB Leyden genotype. The most frequent <em>F9</em> variant was c.-35G&gt;A, affecting 14 individuals, followed by c.-35G&gt;C (<em>n</em> = 4), c.-49T&gt;A (<em>n</em> = 2), and c.-52C&gt;T, c.-34A&gt;G, and c.-22delT (<em>n</em> = 1 each). Major clinical differences in bleeding and treatment modality were observed when comparing c.-35G&gt;A with non-c.-35G&gt;A genotypes. For all children with a c.-35G&gt;A genotype, FIX levels increased before the age of 4 years but did not normalize over time, irrespective of initial severity. In children with non-c.-35G&gt;A genotypes, an increase in FIX was less common (4/9) and occurred later.</div></div><div><h3>Conclusion</h3><div>HB Leyden is caused by the variant c.-35G&gt;A in &gt;50% of cases in whom a FIX increase occurs at very young ages, which is associated with low bleeding rates. This contrasts with the phenotype of individuals with HB Leyden due to a non-c.-35G&gt;A variant. Our study may thus help guide clinical decision-making in this rare HB entity.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 3","pages":"Pages 921-927"},"PeriodicalIF":5.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915239","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":"High risk of long-term recurrence after a first episode of venous thromboembolism during pregnancy or postpartum: the REcurrence after a PrEgnAncy related Thrombosis (REPEAT) Study","authors":"Manal Ibrahim-Kosta ,&nbsp;Sarah El Harake ,&nbsp;Barbara Leclercq ,&nbsp;Céline De Mari ,&nbsp;Jean-François Secondi ,&nbsp;Emilie Paoletti ,&nbsp;Pierre Suchon ,&nbsp;Yasmine Benredouane ,&nbsp;Dominique Brunet ,&nbsp;Marie-Christine Barthet ,&nbsp;Maria Bruzelius ,&nbsp;Gaëlle Munsch ,&nbsp;David-Alexandre Trégouët ,&nbsp;Pierre-Emmanuel Morange ,&nbsp;Louisa Goumidi ,&nbsp;Gabrielle Sarlon-Bartoli","doi":"10.1016/j.jtha.2024.09.039","DOIUrl":"10.1016/j.jtha.2024.09.039","url":null,"abstract":"<div><h3>Background</h3><div>The long-term recurrence risk after a pregnancy-associated venous thromboembolism (VTE) is sparsely assessed.</div></div><div><h3>Objectives</h3><div>To determine the rate of recurrence after a pregnancy-associated VTE and identify associated risk factors.</div></div><div><h3>Methods</h3><div>Five hundred eighty-seven women with a history of first VTE occurring during pregnancy or up to 3 months after delivery were referred to La Timone Hospital, Marseille, France. Women were consecutively included between 2000 and 2015. VTE characteristics and biological parameters were collected upon inclusion. During the 2016-2019 period, patients were recontacted to gather information on postinclusion VTE. A weighted Cox model, adapted to the study’s ambispective design, was used to analyze pre- and postinclusion VTE recurrences.</div></div><div><h3>Results</h3><div>After quality controls, 583 women were analyzed. The incidence of recurrent VTE was 2.4% person-years. The cumulative risk of VTE recurrence was 38% (<em>n</em> = 221), with a median follow-up of 31 years (95% CI: 27-35); 6%, 13%, 17%, and 30% at 2, 5, 10, and 30 years respectively. Pulmonary embolism at first event was associated with a 2-fold increased risk of pulmonary embolism at recurrence compared with isolated deep venous thrombosis (DVT, hazard ratio [HR]: 2.63; 95% CI: 1.44-4.82). Risk factors significantly associated with recurrence were interrupted pregnancies (HR: 1.85; 95% CI: 1.18-2.90), lower limb DVT (HR: 2.95; 95% CI: 1.16-7.49), and AB blood group (HR: 1.71; 95% CI: 1.06-2.77).</div></div><div><h3>Conclusion</h3><div>Although the recurrence risk is low within the first 10 years after a pregnancy-associated VTE, one-third of patients experienced a new event over a 30-year period. Interrupted pregnancies, lower limb DVT, and AB blood group were associated with higher risk of recurrence.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 3","pages":"Pages 937-946"},"PeriodicalIF":5.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564310","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":"Impact of diagnostic coding schemas on major bleeding risk assessment for oral anticoagulants in patients with atrial fibrillation using administrative claims data","authors":"Hsiu-Ting Chien ,&nbsp;Tze-Fan Chao ,&nbsp;Rosa Wang ,&nbsp;Chia-Jui Chang ,&nbsp;Shin-Yi Lin ,&nbsp;Fang-Ju Lin","doi":"10.1016/j.jtha.2024.12.010","DOIUrl":"10.1016/j.jtha.2024.12.010","url":null,"abstract":"<div><h3>Background</h3><div>Reliable diagnostic coding schemas are essential for accurately assessing bleeding risks in patients on oral anticoagulants, particularly in observational studies.</div></div><div><h3>Objectives</h3><div>This study evaluated how different published diagnostic coding schemas impact the assessment of major bleeding risks associated with direct oral anticoagulants (DOACs) and warfarin.</div></div><div><h3>Methods</h3><div>This retrospective cohort study included patients with atrial fibrillation who initiated DOACs or warfarin between 2012 and 2019 using Taiwan’s national claims database. Major bleeding events, including gastrointestinal bleeding, intracranial hemorrhage (ICH), and other major bleeding events, were identified using coding schemas from Cunningham et al., the Mini-Sentinel protocol, and Yao et al. Propensity score matching was performed to ensure covariate balance. Incidence rates and hazard ratios (HRs) were estimated to evaluate the bleeding risks.</div></div><div><h3>Results</h3><div>After matching, each cohort comprised 20 704 patients. The number of reported major bleeding events was influenced by the strictness of the coding schema, with Cunningham yielding the most events, followed by the Mini-Sentinel and Yao schemas. DOACs were associated with a consistently lower risk of composite major bleeding (HR range across different coding schemas, 0.73-0.76; all <em>P</em> &lt; .05) and ICH (HR range, 0.43-0.63; all <em>P</em> &lt; .05) but not gastrointestinal bleeding (HR range, 0.87-0.90; all <em>P</em> &gt; .05), regardless of the coding schema applied. Restricting ICH definitions to primary diagnosis or spontaneous cases revealed a more pronounced reduction in ICH risk associated with DOACs.</div></div><div><h3>Conclusion</h3><div>While the choice of coding schemas has a negligible impact on overall bleeding risk comparisons between DOACs and warfarin, it significantly affects ICH risk assessment. This underscores the importance of careful coding schema selection in observational studies evaluating major bleeding risks.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 3","pages":"Pages 877-887"},"PeriodicalIF":5.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872469","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":"Importance of individual residues in hydrophobic patch PLVIVGL (1481-1487) in FV-Short for synergistic TFPIα cofactor activity with protein S, an alanine-scanning study: AlphaFold-mediated prediction of FV-Short/TFPIα/protein S trimolecular complex structure","authors":"Björn Dahlbäck ,&nbsp;Sinh Tran ,&nbsp;Piotr Draczkowski","doi":"10.1016/j.jtha.2024.11.013","DOIUrl":"10.1016/j.jtha.2024.11.013","url":null,"abstract":"<div><h3>Background</h3><div>In the splice variant factor (F)V-Short, 702 residues are deleted from the B domain, resulting in exposure of an acid region (AR2; 1493-1537) that binds TFPIα. FV-Short and protein S serve as synergistic TFPIα cofactors in inhibition of FXa. In the preAR2 region, a hydrophobic patch PLVIVGL (1481-1487) is crucial for synergistic TFPIα-cofactor activity and assembly of FV-Short, TFPIα, and protein S.</div></div><div><h3>Objectives</h3><div>To elucidate the importance of individual residues in the PLVIVGL patch for synergism between FV-Short and protein S as TFPIα cofactors.</div></div><div><h3>Methods</h3><div>An alanine scanning of the hydrophobic patch was performed in which 7 FV-Short variants were created. The synergistic TFPIα-cofactor activity was analyzed by FXa inhibition and a microtiter-based assay tested binding between the proteins. AlphaFold 3 was used to predict protein–protein interactions between FV-Short, protein S, and TFPIα.</div></div><div><h3>Results</h3><div>Five of the 7 variants (V1483A, I1484A, V1485A, G1486A, and L1487A) demonstrated decreased synergistic TFPIα cofactor activity; in particular, G1486A and L1487A were severely affected. Neither wild-type FV-Short nor any of the mutants bound protein S in the absence of TFPIα. In the presence of TFPIα, wild-type FV-Short, P1481A, L1482A, and V1485A bound protein S, whereas V1483A, I1484A, G1486A, and L1487A did not. AlphaFold predicted an interaction between the hydrophobic patch in FV-Short and a hydrophobic patch in protein S involving residues 268-276 and 422-426.</div></div><div><h3>Conclusion</h3><div>Individual residues (V1483, I1484, G1486, and L1487) in the hydrophobic patch are demonstrated to be important for the synergistic TFPIα-cofactor activity and for the assembly of a trimolecular FXa-inhibitory complex.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 3","pages":"Pages 849-862"},"PeriodicalIF":5.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic potential of DNases in immunothrombosis: promising succor or uncertain future?","authors":"Sara Zalghout ,&nbsp;Kimberly Martinod","doi":"10.1016/j.jtha.2024.11.028","DOIUrl":"10.1016/j.jtha.2024.11.028","url":null,"abstract":"<div><div>Sepsis, a life-threatening condition characterized by systemic inflammation and multiorgan dysfunction, is closely associated with the excessive formation of neutrophil extracellular traps (NETs) and the release of cell-free DNA. Both play a central role in sepsis progression, acting as major contributors to immunothrombosis and associated complications. Endogenous DNases play a pivotal role in degrading NETs and cell-free DNA, yet their activity is often dysregulated during thrombotic disease. Although exogenous DNase1 administration has shown potential in reducing NET burden and mitigating the detrimental effects of immunothrombosis, its therapeutic efficacy upon intravenous administration remains uncertain. The development of engineered DNase formulations and combination therapies may further enhance its therapeutic effectiveness by modifying its pharmacodynamic properties and avoiding the adverse effects associated with NET degradation, respectively. Although NETs are well-established targets of DNase1, it remains uncertain whether the positive effects of DNase1 on immunothrombosis are exclusively related to it’s targeting of NETs or if other components contributing to immunothrombosis are also affected. This review examines the endogenous regulation of NETs in circulation and the therapeutic potential of DNases in immunothrombosis, underscoring the necessity for further investigation to optimize their clinical application.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 3","pages":"Pages 760-778"},"PeriodicalIF":5.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818467","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":"Molecular signatures associated with venous thromboembolism in children with acute lymphoblastic leukemia","authors":"Marie-Claude Pelland-Marcotte ,&nbsp;Anas Belaktib ,&nbsp;Arnaud Droit ,&nbsp;Meredith Michelle Remy ,&nbsp;Jeyani George Clement ,&nbsp;Stéphanie Bianco ,&nbsp;Yan Ma ,&nbsp;Jessica Liu ,&nbsp;Lara Herrmann ,&nbsp;Virgile Raufaste-Cazavieille ,&nbsp;Charles Joly-Beauparlant ,&nbsp;Loïc Mangnier ,&nbsp;Mickael Leclercq ,&nbsp;Thomas Sontag ,&nbsp;Maxime Caron ,&nbsp;Pascal St-Onge ,&nbsp;Sylvie Langlois ,&nbsp;Victoria Koch ,&nbsp;Yael Flamand ,&nbsp;Daniel Sinnett ,&nbsp;Raoul Santiago","doi":"10.1016/j.jtha.2024.12.007","DOIUrl":"10.1016/j.jtha.2024.12.007","url":null,"abstract":"<div><h3>Background</h3><div>Venous thromboembolism (VTE) is a frequent complication of childhood acute lymphoblastic leukemia (ALL).</div></div><div><h3>Objectives</h3><div>We aimed to identify molecular markers and signatures of the leukemia microenvironment associated with VTE in childhood ALL by the dual-omics approach of gene expression and DNA methylation profiling.</div></div><div><h3>Methods</h3><div>Eligible children aged 1 to 21 years old with newly diagnosed ALL were enrolled in the Dana-Farber Cancer Institute 16-001 trial with available RNA sequencing data from bone marrow at diagnosis. The primary outcome was VTE requiring medical intervention, divided between early events (ETs), within 6 weeks from ALL diagnosis, or late events otherwise. We compared differential gene expression and DNA methylation in children with and without VTE and in the subgroup of children with ETs. The DNA methylation <em>cis</em>-regulation was explored by dual-omics integration. Functional gene set enrichment analyses were performed to assess dysregulated pathways associated with thrombosis. Gene expression profiling-based signature for the thrombosis-free interval was determined using the Kaplan–Meier estimator and log-rank tests.</div></div><div><h3>Results</h3><div>We included 248 patients (median age, 7.5 years; 78% precursor B-cell ALL), of whom 56 (23%) developed VTE. Genes and metabolic pathways involved in coagulation, platelet activation, and neutrophil extracellular trap formation were associated with ETs. Dual-omics analysis indicated that methylation reprogramming might be responsible for the overexpression of genes involved in neutrophil extracellular trap formation and coagulation in patients with ETs. A prothrombotic gene signature, based on <em>VWF</em>, <em>PF4,</em> and <em>CXCL8</em> expression, predicted a thrombosis-free interval.</div></div><div><h3>Conclusion</h3><div>This suggests that gene markers and epigenetic regulation of the leukemic microenvironment are drivers of VTE, notably ETs in childhood ALL.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 3","pages":"Pages 1009-1022"},"PeriodicalIF":5.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}