Thrombosis and haemostasis最新文献

{"title":"Landscape and Spectrum of VWF Variants in Type 2 Von Willebrand Disease: Insights from a German Patient Cohort.","authors":"Hamideh Yadegari, Susan Halimeh, Alexander Krahforst, Anna Pavlova, Behnaz Pezeshkpoor, Jens Müller, Bernd Pötzsch, Arijit Biswas, Natascha Marquardt, Ute Scholz, Heinrich Richter, Heiner Trobisch, Karin Liebscher, Martin Olivieri, Karolin Trautmann-Grill, Oliver Tiebel, Ralf Knöfler, Johannes Oldenburg","doi":"10.1055/a-2616-5161","DOIUrl":"10.1055/a-2616-5161","url":null,"abstract":"<p><p>von Willebrand disease (VWD) type 2 arises from variants in von Willebrand factor (VWF) that disrupt its essential hemostatic functions. As per ISTH guidelines, it is classified as type 2A, 2B, 2M, and 2N based on the affected VWF roles.This population-based study aims to uncover the genotype and laboratory phenotypes in type 2 VWD, providing insights into underlying genetics and genotype-phenotype associations.Our cohort included 247 patients from 196 families. Patients were characterized through multiple VWF phenotypic assays and genetic analyses, including DNA sequencing, copy number variation evaluations, and bioinformatic assessments.A total of 86 index patients (IPs, 44%) were diagnosed with type 2A, the most prevalent subtype. Additionally, 27 IPs (14%) were diagnosed with type 2N, 24 IPs (12%) with type 2B, 17 IPs (9%) with type 2M, and 42 IPs categorized as type U VWD carried VWD-associated variants but could not be assigned to a specific subtype. VWF variants were detected in 187 out of 196 (95%) individuals. A total of 222 VWF variants were identified: 187 missense (84%), 22 null alleles (10%), 5 regulatory (2%), 6 gene conversions (3%), and 2 silent variants (1%). Many variants were recurrent in our cohort, resulting in 114 distinct variants. Of these, 45 (39%) were novel.Our data expands the spectrum of disease-associated variants in VWF, including many newly identified variants. This provides valuable insights for accurate diagnosis and personalized treatment. Additionally, the significant genetic heterogeneity among type 2 patients highlights the challenges in sub-classification.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111976","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":"Gut microbiota-platelet axis and thrombosis in advanced chronic liver disease.","authors":"Francesco Violi, Vittoria Cammisotto, Pasquale Pignatelli, Emanuele Valeriani","doi":"10.1055/a-2628-4143","DOIUrl":"https://doi.org/10.1055/a-2628-4143","url":null,"abstract":"<p><p>Advanced chronic liver disease is characterized by metabolic-associated liver disease, metabolic-associated steatohepatitis and cirrhosis. This clinical setting is associated with platelets' activation, that has been suggested to play a role in the progression of liver disease; thus, platelet activation has been detected in portal circulation as well within liver sinusoids. Experimental studies with antiplatelet drugs and observational studies in human suggested a role for platelet activation in the mechanism of the disease. Furthermore, advanced chronic liver disease may be complicated by atherosclerotic complications, where the role of platelet activation is well consolidated. Platelets' activation may represent a unique mechanism leading to liver disease on one hand and to atherosclerotic complications on the other hand. Several studies pointed to the role of gut dysbiosis as key step for eliciting platelets' activation via the production of pro-aggregating metabolites such as Trimethylamine N-oxide or translocation of bacterial products such as lipopolysaccharide into the systemic circulation. The aims of this narrative review are 1) to show experimental and clinical evidence relating platelets with advanced chronic liver disease, 2) to explore the role of gut microbiota as mechanism for platelets' activation, and 3) to suggest novel therapeutic strategy to inhibit gut microbiota-platelet axis.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144235264","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":"Association of Fibrinogen Variants with Severity of Obesity and Metabolic Liver Disease: 2-Year Follow-up after Bariatric Surgery.","authors":"Nadja B Pedersen, Anna-Marie Bloch Münster, Mette Munk Lauridsen, Yaseelan Palarasah, Charlotte W Wernberg, Lea Ladegaard Grønkjær, Birgitte G Jacobsen, Elise Jonasson, Moniek P M de Maat, Else-Marie Bladbjerg","doi":"10.1055/a-2615-4682","DOIUrl":"10.1055/a-2615-4682","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the hepatic manifestation of obesity. Studies in mice link fibrinogen variation to obesity and MASLD, but how naturally occurring fibrinogen variants associate with obesity and MASLD in humans is unknown.To investigate associations of fibrinogen variants (fibrinogen γ', fibrinogen α_E, and sialylated fibrinogen) with obesity, MASLD, and fibrosis severity and examine changes in variants 2 years after bariatric surgery.We included 195 individuals with a body mass index (BMI) > 35 kg/m². A subgroup of 93 individuals, who underwent bariatric surgery (<i>n</i> = 35) or served as nonsurgical control group (<i>n</i> = 58), were followed for 2 years. Hepatic tissue samples were scored for MASLD and fibrosis. Fibrinogen variants were measured using enzyme-linked immunosorbent assay.Absolute levels of fibrinogen variants tended to be higher in individuals with BMI > 45 kg/m² compared with BMI < 40 kg/m² (Δγ': 70 [95% confidence interval: -19, 160] µg/mL; Δα_E: 0.85 [-0.36, 2.06] µg/mL; Δsialylated: 0.09 [-0.05, 0.24] arbitrary units [AU]). Absolute and relative fibrinogen α_E levels increased with MASLD (Δα_E: 2.04 [0.74, 3.35] µg/mL; Δα_E ratio: 0.05 [0.02, 0.08] %) and fibrosis (Δα_E: 1.79 [0.48, 3.11] µg/mL; Δα_E ratio: 0.05 [0.02, 0.07] %), whereas relative fibrinogen γ' levels decreased with fibrosis (Δγ' ratio: -2.52 [-4.70, -0.35] %). After bariatric surgery, sialylated fibrinogen levels were lower (Δsialylated: -0.22 [-0.32, -0.11] AU), but relative levels of the fibrinogen variants were higher (Δγ': 1.7 [0.03, 3.30] %; Δα_E: 0.03 [0.001, 0.06] %; Δsialylated: 0.02 [0.002, 0.04] AU/g/L) compared with the control group.Obesity, MASLD, and fibrosis alter fibrinogen variant profiles in plasma suggesting that fibrinogen variation plays a role in these inflammatory conditions.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144102443","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":"Major Bleeding Risk Assessment in Patients with Cancer-Associated Venous Thromboembolism Treated with DOACs: Data from a Multicenter Cohort.","authors":"Maria Cristina Vedovati, Rosa Talerico, Clara Sacco, Matteo Mazzetti, Elena Campello, Simone Birocchi, Sofia Beccatini, Angelo Porfidia, Rachele Caprari, Corrado Lodigiani, Paolo Simioni, Gian Marco Podda, Isabella Mastandrea, Cecilia Becattini, Roberto Pola","doi":"10.1055/a-2605-9015","DOIUrl":"https://doi.org/10.1055/a-2605-9015","url":null,"abstract":"<p><p>In cancer-associated venous thromboembolism (CAT), extended anticoagulation should be considered when the risk-benefit profile is favorable. However, optimal predictors of major bleeding (MB) remain unclear.This multicenter observational study included CAT patients treated with direct oral anticoagulants (DOACs). Study objectives were: (i) assess the performance of nine bleeding risk scores (ATRIA, CAT-BLEED, CHAP, DOAC, HAS-BLED, Kuijer, ORBIT, RIETE, VTE-BLEED), (ii) identify predictors of MB (ISTH definition), and (iii) propose an improved bleeding risk model (Perform score).Overall, 823 patients were followed (mean 1.6 years). MB occurred in 44 cases (3.4% per patient-year). The predictive performance of bleeding risk scores was modest (c-statistics range 0.513-0.606). Risk factors included increasing age (HR 1.04, 95% CI 1.00-1.07), use of steroids (HR 2.69, 95% CI 1.34-5.40), antimetabolites (HR 2.51, 95% CI 1.28-4.93), and unresected gastrointestinal cancer (HR 7.30, 95% CI 1.70-31.30). Conversely, prior cancer surgery (HR 0.41, 95% CI 0.20-0.82) and anticancer hormones (HR 0.22, 95% CI 0.05-0.92) showed a possible protective effect toward MB risk. The Perform score provided a slight enhancement in risk prediction (c-statistics 0.678), but remained suboptimal.In this real-world cohort of CAT patients treated with DOACs, unresected gastrointestinal cancer and use of steroids or antimetabolites were associated with increased MB risk, while prior cancer surgery and anticancer hormones were linked to a lower risk. These factors, not considered in current bleeding risk scores, may refine bleeding prediction. Further studies should clarify their role in guiding anticoagulation decisions and improving personalized risk assessment.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216942","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":"Ticagrelor Therapy Modifications after Acute Coronary Syndrome: An Ever-Evolving Issue.","authors":"Felice Gragnano, Dominick J Angiolillo","doi":"10.1055/a-2448-7029","DOIUrl":"10.1055/a-2448-7029","url":null,"abstract":"","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":"607-609"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142508515","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":"Treatment Modifications in Acute Coronary Syndrome Patients Treated with Ticagrelor: Insights from the FORCE-ACS Registry.","authors":"Niels M R van der Sangen, Jaouad Azzahhafi, Dean R P P Chan Pin Yin, Lucas J G Zaaijer, Wout W A van den Broek, Ronald J Walhout, Melvyn Tjon Joe Gin, Ron Pisters, Deborah M Nicastia, Jorina Langerveld, Georgios J Vlachojannis, Rutger J van Bommel, Yolande Appelman, José P S Henriques, Wouter J Kikkert, Jurriën M Ten Berg","doi":"10.1055/a-2421-8866","DOIUrl":"10.1055/a-2421-8866","url":null,"abstract":"<p><p>Patients presenting with acute coronary syndrome (ACS) are frequently treated with the P2Y₁₂-inhibitor ticagrelor. Some patients prematurely discontinue ticagrelor, but the incidence of reasons for and clinical implications of treatment modification are relatively unknown.Data from 4,278 ACS patients (mean age: 63.6 years, 26.1% women) who were discharged on ticagrelor and enrolled in the FORCE-ACS registry between 2015 and 2020 were used. Treatment modifications were categorized as physician-recommended discontinuation, alteration, interruption, or disruption and occurred in 26.7, 20.1, 2.8, and 3.1% of patients within 12 months of follow-up (VISUAL SUMMARY: ). Underlying reasons for treatment modification differed per type of modification. Overall, the rate of ischemic events defined as all-cause death, myocardial infarction, or stroke was 6.6% at 12 months of follow-up. Cox regression analysis using time-updated modification variables as independent variables showed that treatment interruption (adjusted hazard ratio [HR]: 2.93, 95% confidence interval [CI]: 1.48-5.79, <i>p</i> < 0.01) and disruption (adjusted HR: 2.33, 95% CI: 1.07-5.07, <i>p</i> = 0.03) were associated with an increased risk of ischemic events even after adjustment for relevant confounders. Discontinuation and alteration were not associated with increased ischemic risk.In clinical practice, treatment modifications in ACS patients discharged on ticagrelor are common, although type and reasons for modification are heterogeneous. Treatment interruption and disruption are associated with excess cardiovascular risk.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":"597-606"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12115549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547628","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":"Relationship Between Screening-Detected Atrial Fibrillation and Blood Pressure Levels in Elderly Hypertensive Patients: The OMRON Heart Study.","authors":"Keitaro Senoo, Mitsuko Nakata, Arito Yukawa, Kohei Kawai, Jun Munakata, Masahiro Makino, Nobunari Tomura, Hibiki Iwakoshi, Tetsuro Nishimura, Satoshi Shimoo, Hirokazu Shiraishi, Satoshi Teramukai, Satoaki Matoba","doi":"10.1055/a-2484-0641","DOIUrl":"10.1055/a-2484-0641","url":null,"abstract":"<p><p>Hypertension is a well-known risk factor for atrial fibrillation (AF) and strokes, but studies assessing screening-detected AF in hypertensive populations and its relationship to the blood pressure (BP) are scarce.We prospectively recruited hypertensive patients (aged ≥60 years) from all over Japan in a decentralized clinical trial. Participants were asked to measure their electrocardiogram (ECG) and BP at home for 3 months with a BP monitor equipped with ECG.Between April 2022 and July 2023, 4,078 hypertensive patients from across the country participated in this study. The mean age was 66.3 ± 5.5 years, and the male proportion was 80.3%. After excluding those with no measurement data (<i>n</i> = 258), AF detection was 5.8% (<i>n</i> = 220/3,820), and the time to AF detection was 3 to 109 days (median 28 days). The mean BP at baseline was 133 ± 14/85 ± 9 mmHg in the morning and 125 ± 14/79 ± 9 mmHg in the evening. AF detection did not significantly differ between the baseline BP categories (log rank test, <i>p</i> = 0.54), with hazard ratios (95% confidence interval) of 0.83 (0.57-1.19), 0.79 (0.55-1.14), and 0.99 (0.59-1.68) for systolic BP (SBP) 135 to 144 and/or diastolic BP (DBP) 85 to 89, SBP 145 to 159 and/or DBP 90 to 99, and SBP ≥ 160 and/or DBP ≥ 100, respectively (SBP ≤ 134 and DBP ≤ 84 as a reference). The results did not change when taking into account the impact of the measurement rates and antihypertensive drugs on AF detection during the observation period.Detection of undiagnosed AF was 5.8% in elderly hypertensives, with no significant differences between the baseline BP categories and no effect of the measurement rate or antihypertensive drugs.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":"545-552"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12115540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717150","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":"Blood Loss in Women of Childbearing Potential Taking Oral Anticoagulants for Venous Thromboembolism (The BLEED Study).","authors":"Elvira Grandone, Mario Mastroianno, Gabriella Pacilli, Donatella Colaizzo, Alessandra Margaglione, Behnood Bikdeli, Gregory Piazza","doi":"10.1055/a-2461-6822","DOIUrl":"10.1055/a-2461-6822","url":null,"abstract":"<p><p>Oral anticoagulants (OAC) may exacerbate menstrual bleeding in women of childbearing age; however, the existing literature on this issue has several limitations.This study investigates abnormal uterine bleeding in women of childbearing age taking OAC-vitamin K antagonists or direct oral anticoagulants-for venous thromboembolism through a retrospective analysis of prospectively collected data. Uterine bleeding was assessed using the Pictorial Blood Assessment Chart (PBAC) and hemoglobin (Hb) values during anticoagulation compared with prior therapy. The number of unplanned medical visits for bleeding complications was also calculated.From June 2014 to November 2023, 110 women were recruited (median age, 36 years). PBAC scores correlated with Hb values at baseline and during therapy (analysis of variance [ANOVA], <i>p</i> < 0.01), with a significant difference in Hb values before and during anticoagulant therapy (delta Hb) among groups (ANOVA, p.0.034). Seventeen women (15.5%) reported uterine fibroids, experiencing a greater reduction in Hb values during anticoagulant administration than women without uterine fibroids (delta 0.3, interquartile range [IQR]: 0.8, 2.9 vs. 0.5, IQR 1.2, 0.3; p.0.012). Women with selfreported uterine fibroids required more frequent unplanned medical consultations for bleeding (mean visits 5 vs. 4, respectively; Poisson regression, <i>p</i> < 0.05). Among women with uterine fibroids, those taking apixaban showed smaller Hb changes than those on other oral anticoagulants (ANOVA, p.0.047). This difference persisted even after adjusting for potential confounders (multiple ANOVA, p.0.004).Women of childbearing age taking OAC frequently experience changes in Hb values and PBAC scores during treatment, with uterine fibroids playing a significant role.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":"523-532"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142591167","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":"Unraveling the Molecular Pathogenesis of Protein C Deficiency-Associated VTE: Insights from Protein C Mutations C238G and R189W in Thai Patients.","authors":"Pansakorn Tanratana, Karnsasin Seanoon, Panwajee Payongsri, Praguywan Kadegasem, Ampaiwan Chuansumrit, Nongnuch Sirachainan","doi":"10.1055/a-2408-9529","DOIUrl":"10.1055/a-2408-9529","url":null,"abstract":"<p><p>Protein C (PC) deficiency is a well-established risk factor for thromboembolism (TE), commonly manifesting in pediatric patients. This study aimed to elucidate the pathogenic mechanisms of two novel PC mutations, C238G and R189W, identified in Thai children with both venous and arterial TE.The effects of wild-type (WT), C238G, and R189W PC variants were investigated through transient transfection of HEK293T cells. PC secretion levels were measured, and immunofluorescence analysis was performed to assess intracellular localization. ER stress-related gene expression and UPR activation were evaluated. Structural analysis was conducted to explore the significance of the C238 and R189W residue in PC functionality.The C238G mutation led to a severe 95% reduction in PC secretion, while R189W showed a 30% decrease compared with WT. Immunofluorescence revealed that C238G-PC was predominantly retained in the ER, indicating protein misfolding. C238G-expressing cells exhibited significant upregulation of ER stress-related genes and UPR activation. In contrast, R189W resulted in only a modest increase in UPR gene expression, suggesting a less pronounced impact on protein folding and secretion. Structural analysis demonstrated the critical role of the C238 residue in maintaining PC's disulfide bond and overall conformation.This study reveals distinct molecular mechanisms by which the C238G and R189W mutations contribute to PC deficiency and increased thrombotic risk. The findings emphasize the essential role of the C238 residue in preserving PC structure and secretion, enhancing the understanding of PC deficiency-associated TE in pediatric patients.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":"533-544"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12115538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142126723","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":"The Plasma Proteome and Risk of Future Venous Thromboembolism-Results from the HUNT Study.","authors":"Sigrid K Brækkan, Asbjørn L Onsaker, Therese H Nøst, Weihong Tang, Kristian D Hindberg, Vania M Morelli, Weihua Guan, Christian Jonasson, Aaron R Folsom, Kristian Hveem, John-Bjarne Hansen","doi":"10.1055/a-2484-0836","DOIUrl":"10.1055/a-2484-0836","url":null,"abstract":"<p><p>This study aimed to identify novel plasma proteins associated with first-lifetime venous thromboembolism (VTE) and molecular pathways involved in VTE pathogenesis.A case-cohort comprising incident VTE cases (<i>n</i> = 294) and a randomly sampled age- and sex-weighted subcohort (<i>n</i> = 1,066) was derived from the Trøndelag Health Study (HUNT3, n = 50,800). Blood samples were collected and stored at cohort inclusion (2006-2008), and participants were followed up to 5 years. Proteome-wide analyses was performed using the 7k SomaScan® proteomics platform, and weighted Cox-regression models adjusted for age, sex, and sample batch were conducted, with the Bonferroni method applied to account for multiple testing. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were applied on the top-ranked 200 proteins associated with VTE.Out of 7,288 human proteins, 7 proteins were significantly associated with higher VTE risk with <i>p</i>-value <6.9 × 10^-6 (hazard ratios per 1 standard deviation increase in protein levels ranging from 1.39 to 1.86). Except for coagulation factor VIII and tumor necrosis factor soluble receptor II, these proteins were novel associations and included collagen alpha-3(VI):BPTI/Kunitz inhibitor, histo-blood group ABO system transferase, peroxidasin, human epididymis protein 4, and regulator of G protein signaling 3. KEGG analyses of the top-ranked 200 proteins revealed significant pathway enrichment of nine proteins in the complement (mainly lectin pathway) and coagulation (mainly intrinsic pathway) cascades.Our proteome-wide analysis led to discovery of five novel protein candidates associated with 5-year risk of future VTE. KEGG analyses supported an interplay between the complement and coagulation pathways in the pathogenesis of VTE.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":"574-584"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717178","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}