Thrombosis Research Institute

The incidence of cancer-associated venous thromboembolism (CAT) has risen in recent decades, underscoring the need for novel risk biomarkers and mechanistic insights. MicroRNAs (miRNAs) have emerged as promising biomarkers for various diseases, with elevated miRNA-145-5p (miR-145-5p) levels linked to reduced venous thromboembolism (VTE) risk. We aimed to investigate the association between plasma miR-145-5p levels and risk of future VTE related to (CAT) and unrelated to cancer (non-CAT). Plasma miR-145-5p levels were measured in a case cohort derived from the Trøndelag Health Study (HUNT3; N = 50 807). The study included 455 VTEs (95 CATs), occurring during 9 years of follow-up, and 1740 randomly sampled age-weighted subcohort participants. VTEs were classified as CAT if they occurred within 1 year before or 2 years after a cancer diagnosis. Multivariable adjusted hazard ratios (HRs) for CAT and non-CAT were estimated using weighted Cox regression, with cancer modeled as a time-varying covariate. Increasing miR-145-5p levels were associated with lower risk of CAT (HR per 1 SD, 0.70; 95% CI, 0.52-0.96) and non-CAT (HR, 0.81; 95% CI, 0.72-0.91). Individuals in the highest miR-145-5p quartile had lower risk of both CAT (HR, 0.55; 95% CI, 0.25-1.20) and non-CAT (HR, 0.48; 95% CI, 0.33-0.69) than those in the lowest quartile. High plasma miR-145-5p levels were associated with lower risk of CAT and non-CAT, suggesting that miR-145-5p has the potential to serve as a risk biomarker for CAT.

Preeclampsia is a hypertensive disorder affecting 2% to 8% of pregnancies. Women with a history of preeclampsia have an increased risk of cardiovascular disease. The long noncoding RNA MALAT1 is shown to regulate inflammatory responses linked to cardiovascular disease. MALAT1 is decreased in preeclampsia placentas and may have a cis-regulatory function on neighboring RNAs. Expression of MALAT1, NEAT1, mascRNA, SCYL1, and FRMD8 was assessed in peripheral blood mononuclear cells, and MALAT1 in plasma and extracellular vesicles, at 22 to 24 and 36 to 38 weeks of gestation in healthy (n=214) and preeclampsia (n=37) women from the STORK cohort study (STORe barn og Komplikasjoner, translated as Large Babies and Complications) and at 5-year follow-up in women with and without history of preeclampsia (n=29; n=271). We investigated their associations with established markers of disease activity and later cardiometabolic risk. MALAT1 was silenced in lipopolysaccharide-stimulated THP-1 differentiated macrophages in vitro. MALAT1, NEAT1, mascRNA, and FRMD8 are decreased in peripheral blood mononuclear cells during preeclampsia development. At follow-up in women with a previous preeclampsia diagnosis, MALAT1 and NEAT1 are decreased in peripheral blood mononuclear cells and show associations with cardiometabolic markers. Silencing MALAT1 in macrophages increased secretion of IL (interleukin)-6 and reduced MMP9 (matrix metalloproteinase-9) and VEGF (vascular endothelial growth factor) A levels. Given the association of MALAT1 and neighboring RNAs with preeclampsia during pregnancy and at follow-up, as well as with cardiometabolic markers and results from silencing experiments, these transcripts may be potential targets for preeclampsia development and cardiometabolic risk in women with previous preeclampsia.

BACKGROUND:Venous thromboembolism (VTE) is a leading cardiovascular disease, yet its etiology is incompletely understood. This study used large-scale, high-throughput aptamer-based proteomics to identify new circulating protein biomarkers and biological pathways for incident VTE.METHODS:We included 4 longitudinal cohorts (the ARIC study [Atherosclerosis Risk in Communities], CHS [Cardiovascular Health Study], MESA [Multi-Ethnic Study of Atherosclerosis], and the HUNT study [Trøndelag Health]) that identified 1371 incident noncancer VTEs among 20 737 participants followed for a maximum of 10 to 29 years. We used the SomaScan to measure baseline plasma levels of ≈5000 to 7000 proteins and examined the prospective relationships between the protein biomarkers and noncancer VTE. We then conducted an external replication of top VTE proteins in 783 incident noncancer VTEs among 39 097 participants in the UKB study (UK Biobank) based on the Olink proteomics platform. We used Cox proportional hazards regression to estimate the association between each protein biomarker and VTE risk. Mendelian randomization (MR) analysis was used to assess the possible causal associations between identified proteins and VTE risk.RESULTS:There were 23 proteins that exceeded a false discovery rate–adjusted P<0.05 (unadjusted P<6.5×10-4) in the discovery meta-analysis of ARIC, CHS, and MESA and were replicated in HUNT at (unadjusted) P<0.05. Of these, 15 are new to VTE, and 3 of the 15 (transgelin, sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1, and TIMP4 [metalloproteinase inhibitor 4]) exceeded the Bonferroni corrected significance threshold in HUNT. Sixteen of the 23 top VTE proteins were available on the UKB Olink panel, of which 11 were replicated in the UKB study after Bonferroni correction. MR analysis of the 15 new proteins provided significant evidence for a possible causal role of TIMD4 (T-cell immunoglobulin and mucin domain-containing protein 4) (Bonferroni-corrected P<0.05) and suggestive evidence for TIMP4 and CST3 (cystatin-c) (unadjusted P<0.05) in VTE risk. The direction of association from the MR analyses was opposite of that from the VTE proteomics analysis for TIMP4 and TIMD4 but was consistent for CST3.CONCLUSIONS:We identified several novel plasma proteins for VTE that reflect biological processes outside established VTE pathophysiology, including extracellular matrix regulation, immunity, immune–vascular endothelium interactions, and vascular senescence. Results may provide new modifiable targets to improve VTE risk stratification, prevention, or treatment.

Management of acute pulmonary embolism (PE) during pregnancy or post-partum is challenging especially in women at intermediate or high-risk of adverse outcomes. Catheter-directed therapies (CDTs) are increasingly used given their potential efficacy and relatively low complication rates. We systematically reviewed the evidence on CDTs use in pregnancy and post-partum PE. Literature search was conducted in bibliographic databases, reference lists, and review articles until 2 July 2025, without restrictions. Main efficacy and safety outcomes were maternal all-cause and PE-related mortality, fetal mortality, improved right ventricle dysfunction (RVD) and/or pulmonary artery (PA) pressures, improved lung perfusion/clot burden reduction, and maternal major bleeding (MB). We identified 65 case reports, 4 case series and 1 cohort study for a total of 76 patients. Maternal all-cause mortality within 7 days from CDT was 2.8% (2/72; 95% confidence interval [CI], 0.3-9.7%) with no PE-related deaths. In-hospital fetal mortality was 12.5% (5/40; 95% CI, 4.2-26.8%). Within 72h from CDT were observed: an improvement of RVD and/or PA pressures in 96.2% (25/26; 95% CI, 80.4-99.9%), and in lung perfusion/reduction in clot burden in 94.4% of cases (34/36; 95% CI, 81.3-99.3%); maternal MB in 17.2% of cases (11/64; 95% CI, 8.9-28.7%), with 10 out of 11 events (90.9%) reported in the post-partum period. Current evidence is limited and of low quality. CDTs should be considered only after a multidisciplinary evaluation of selected cases, balancing potential benefits and bleeding risks, the latter being mainly observed in the post-partum.

ABSTRACTThe EmDia trial, designed to study the effects of the sodium glucose cotransporter‐2 (SGLT2) inhibitor empagliflozin on cardiovascular comorbidities in type 2 diabetes mellitus (T2DM) patients, has been investigated for short‐term metabolic alterations by a limited set of clinical assays. To expand on this data, we report on the development of a liquid chromatography‐mass spectrometry (LC‐MS)‐based metabolomics approach employing an optimized metabolite separation by pentafluorophenyl chromatography. High‐confidence metabolite annotation based on reference standards allows for fast and robust metabolic characterization of large plasma cohorts due to scalability. Applied to EmDia, we show the high predictive power of our methodology for several clinical parameters, including a near‐perfect prediction of fasting blood glucose (R2 = 0.97), and demonstrate how empagliflozin leads to reduced plasma levels of deoxyhexoses, such as 1,5‐anhydroglucitol, a short‐term biomarker for glycemic control.SummaryClinical metabolomics studies continue to gain interest due to their comprehensive metabolite coverage, offering insights into metabolic alterations in health and disease.In this study, we present a robust data‐independent acquisition liquid chromatography‐mass spectrometry‐based metabolomics workflow employing an optimized metabolite separation by pentafluorophenyl chromatography that showcases a comprehensive coverage of plasma metabolites.Applied to characterize plasma metabolite profiles in samples of EmDia, a placebo controlled study investigating the effect of the SGLT2 inhibitor empagliflozin, we assess the predictive power of metabolite signals for clinical parameters describing organ physiologies and pathophysiologies.Descriptive statistics are applied to the metabolite profiles to identify empagliflozin intake‐associated metabolite markers.