Background Inflammation is an emerging target for stroke prevention, but additional therapeutic candidates are needed. Experimental and observational studies implicate tumor necrosis factor (TNF) in atherosclerotic plaque progression and cardiovascular events. We integrated plasma proteomics from population-based studies and prospective stroke cohorts with single-cell and spatial transcriptomic profiling of human atherosclerotic plaque to investigate TNF signaling in stroke pathogenesis. Methods We assessed associations between 34 TNF-superfamily proteins (Olink Explore) and incident ischemic stroke among 47,529 UK Biobank participants without cardiovascular disease. We performed an individual-participant data (IPD) meta-analysis of four prospective cohorts with ischemic stroke (n=2,180) to examine associations between TNF-? and recurrent vascular events. We characterised plaque-level TNF biology using single-cell RNA sequencing of 259,116 cells (62 donors) and Xenium spatial transcriptomics (12 donors) with human carotid plaques. Results In UK Biobank, higher circulating TNF pathway proteins were independently associated with incident stroke after multivariable adjustment, including TNF, TNFR1, and TNFR2 (Hazard Ratio [HR] per SD increase, 1.14, [95% CI 1.07?1.20], 1.22, [1.14?1.31], and 1.15 [1.09?1.21], respectively. An additional 15 TNF superfamily members were also associated with incident stroke. In the IPD analysis of stroke cohorts, TNF-? was associated with recurrent stroke (risk ratio [RR] 1.50, 95% CI 1.14-1.98; top vs. bottom third of TNF-?) and MACE (RR 1.54, 1.18-2.02) after adjustment for cardiovascular risk factors and secondary prevention medications (537 MACE events, 6793 person-years follow up). In single-cell RNA plaque sequencing, TNF and TNF pathway genes were broadly expressed across immune cell populations. In spatial transcriptomics, TNF detection increased progressively from media to fibrous cap (Odds Ratio 2.32 vs media, 95% CI 1.94?2.78; p<0.001). At the fibrous cap, CD8+ effector T cells demonstrated 4.1-fold enrichment for TNF expression despite comprising only 3% of fibrous cap cells. Conclusions TNF signaling is independently associated with incident ischemic stroke and recurrent MACE after stroke. TNF is enriched in human carotid plaque at the fibrous cap, in macrophages and CD8+ effector T cells. These results support evaluation of TNF-targeted therapies for stroke prevention. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial PROGRESS ClinicalTrials.gov ID: [NCT04889872][1] included as part of IPD Meta-Analysis. ### Funding Statement N/A ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UK Biobank has ethical approval from the North West Multi-Centre Research Ethics Committee (REC reference 11/NW/03820), and all participants provided written informed consent. Analyses using UK Biobank data were conducted under project approval 1282644 and in accordance with the Declaration of Helsinki. The data included in the Meta-Analysis was extracted from previously published work with inbuilt ethical approval and therefore no additional ethical approval was required. For the plaque analysis, the spatial transcriptiomic data is available as open access material. The ethical information for the original study in which Human carotid artery plaque samples were obtained in the Munich Vascular Biobank can be found at the following DOI https://doi.org/10.1038/s41467-025-67679-4. The collection process adhered to the ethical principles of the Declaration of Helsinki and was approved by the local ethics committee at the Technical University of Munich (approval numbers: 2799/10 and 2023-297). Informed written consent was obtained from all participants, and clinical data were retrieved from electronic patient records. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Individual-level UK Biobank data are available to eligible researchers through the UK Biobank application process. This study was conducted under UK Biobank application number 1282644. The integrated single-cell RNA sequencing atlas is publicly available through CELLxGENE (https://cellxgene.cziscience.com/collections/db70986c-7d91-49fe-a399-a4730be394ac.), and the spatial transcriptomic dataset is publicly available via Zenodo (https://zenodo.org/records/17526248). [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04889872&atom=%2Fmedrxiv%2Fearly%2F2026%2F05%2F01%2F2026.04.29.26352088.atom

Obesity is a global health concern driven by excessive lipid accumulation and adipocyte dysfunction, requires therapeutic strategies that both inhibit fat formation and promote lipid degradation. This study investigated the dual anti-adipogenic and pro-lipolytic effects of Pseuderanthemum palatiferum leaf extract (PPE) in 3T3-L1 adipocytes. The phytochemical analysis of PPE performed by using gas chromatography-mass spectrometry (GC-MS) and Liquid chromatography-mass spectrometry (LC-MS). The findings revealed that GC-MS analysis of PPE identified 35 volatile compounds, with benzofuran (29.94%) as the major constituent. LC-MS detected 27 non-volatiles phytochemicals, including chlorogenic acid and p-coumaric acid. PPE exhibited no significant cytotoxic effects on 3T3-L1 preadipocytes at doses ranging from 50 - 150 μg/mL. At 150 μg/mL, PPE reduced lipid accumulation by 37.84% and increased glycerol release by 60.46%, indicating both an anti-adipogenic and a lipolytic properties. Gene expression analysis revealed that pre-treatment with 150 μg/mL of PPE promoted the upregulation of early adipogenic markers (C/EBPα, ACC1, FAS, and GLUT4) while downregulating markers associated with mature adipocytes (Adiponectin, AP2, and CD36), indicating interference with adipocyte differentiation and lipid synthesis. Additionally, PPE lowered intracellular reactive oxygen species, suggesting an antioxidative contribution to its anti-obesity action. Collectively, this study provides the first evidence that P. palatiferum exerts complementary regulation of adipogenesis and lipolysis in 3T3-L1 cells, offering new insight into its multi-target mechanisms and potential as a natural therapeutic candidate for obesity management. HIGHLIGHTS Abnormal lipid metabolism contributes to obesity, accompanied by oxidative stress and inflammation. PPE modulates key pathways regulating fat storage and breakdown, leading to reduced lipid accumulation. PPE may influence adipose cells to reduce the release of inflammatory factors and subsequently to diminish oxidative stress. PPE may serve as a natural candidate for dietary or therapeutic strategies targeting obesity. GRAPHICAL ABSTRACT

Background Associations of plasma levels of coagulation factors FVIII and FIX with incident cardiovascular disease (CVD) and mortality remain uncertain. Objective To clarify associations of FVIII and FIX with CVD and mortality in a meta-analysis of general population prospective studies. Methods We conducted a systematic literature review up to 19 July 2024, of PubMed and Cochrane databases, reporting estimates (and measures of variability) of associations of plasma levels of FVIII or FIX with risks of incident CVD. Pooled risk ratios (RRs), adjusted for age, sex, systolic blood pressure, total cholesterol, smoking, and diabetes, were estimated in a random effects meta-analysis for effects of FVIII and FIX levels on incident CVD and CVD and total mortality. Results In 7 studies (8888 cases in 32 123 participants) for FVIII and 4 studies (2273 cases in 6951 participants) for FIX the pooled RRs (95% CI) for incident CVD per 1 SD higher were 1.12 (1.09-1.14) and 1.05 (1.00-1.12), respectively. Corresponding CVD mortality and total mortality RRs for FVIII were 1.17 (1.07-1.28) and 1.16 (1.12-1.19), and for FIX;1.14 (1.06-1.22) and 1.13 (1.07-1.18), respectively. Comparing factor levels above vs below the 90th percentile, pooled RRs were 1.34 (1.25-1.44) for FVIII; and 1.02 (0.85-1.22) for FIX. Conclusion Risks of CVD, CVD mortality, and total mortality increase across higher population distributions of FVIII levels. Risks of CVD mortality and total mortality also increase across FIX levels, but no evidence of an independent effect for incident CVD risk.

AimsAssociations of plasma viscosity and plasma Ig levels (a determinant of viscosity) with incident coronary heart disease (CHD) events; and with CHD, cardiovascular disease (CVD: CHD and stroke) and all-cause mortalities.MethodsMeta-analysis of plasma viscosity levels from the MONitoring of trends and determinants of CArdiovascular (MONICA)/Cooperative Health Research in the Region of Augsburg, MONICA Glasgow and Speedwell Studies; and five other published studies. Meta-analysis of IgA, IgG and IgM levels from the Augsburg, Glasgow and Speedwell studies; and one other published study.ResultsOver median follow-up periods of 14–26 years, there were 2270 CHD events, and 4220 all cause deaths in 28 605 participants with baseline plasma viscosity measurements. After adjustment for major risk factors, (HRs; 95% CIs) for a 1 SD increase in viscosity were 1.14 (1.09 to 1.20) for CHD events; and 1.21 (1.17 to 1.25) for all-cause mortality. 821 CHD events and 2085 all-cause deaths occurred in 8218 participants with baseline Ig levels. For CHD events, adjusted HRs for 1 SD increases in IgA, IgG and IgM were, respectively, 0.97 (0.89 to 1.05); 0.95(0.76 to 1.17) and 0.90 (0.79 to 1.03). Corresponding adjusted HRs for all-cause mortality were 1.08 (95% CI 1.02 to 1.13), 1.03 (95% CI 0.94 to 1.14) and 1.01 (95% CI 0.96 to 1.06).ConclusionsAfter risk factor adjustment, plasma viscosity was significantly associated with risks of CHD events; and with CHD, CVD and all-cause mortalities. We found no significant association of IgA, IgG or IgM levels with incident CHD events or mortality, except for a borderline association of IgA with all-cause mortality.

Introduction The associations of plasma factor VIII (FVIII) and factor IX (FIX) levels with risk of venous thromboembolism (VTE) are not well defined. We performed a systematic review and meta-analysis of these associations. Methods Random effects inverse-variance weighted meta-analysis was used to estimate pooled odds ratios for comparisons across equal quartiles of the distributions and 90 % thresholds (higher versus lower), and for testing linear trends. Results Among 15 studies (5327 cases) the pooled odds ratio of VTE for the fourth versus first quarter was 3.92 (95 % confidence interval 1.61, 5.29) for FVIII level; and among 7 studies (3498 cases) 1.57 (1.32, 1.87) for FIX level. Comparing factor levels above, versus below, the 90th percentile, the estimated pooled odds ratios were 3.00 (2.10, 4.30) for FVIII; 1.77 (1.22, 2.56) for FIX; and 4.56 (2.73, 7.63) for both FVIII and FIX considered jointly. Conclusions We confirm increases in risk of VTE across population distributions of FVIII and FIX levels. Levels above the 90th percentile have almost twice the risk for FIX level compared to levels below; three-fold risk for FVIII level; and almost five-fold risk for both FVIII and FIX levels elevated.

We examined the associations between haematological and inflammatory variables with future venous thromboembolism (VTE), in 3494 men aged 60-79 years, with no previous history of VTE or myocardial infarction, who were not receiving oral anticoagulants. After a mean follow-up period of 18 years, there were 149 confirmed cases of fatal or non-fatal VTE (deep vein thrombosis and/or pulmonary embolism). Among classical cardiovascular risk factors, only obesity and cigarette smoking were associated with VTE risk. After adjustment for age, obesity and smoking, VTE risk was associated with coagulation factor VIII, factor IX, von Willebrand factor (VWF), activated partial thromboplastin time (APTT), and fibrin D-dimer. Hazard ratios (95% CI) for top to bottom quarters (bottom to top for APTT), were respectively 2.17 (1.37, 3.44), 2.15 (1.30, 3.53), 2.02 (1.27, 3.22), 2.43 (1.47, 4.02) and 3.62 (2.18, 6.08). The 11% of men with both the shortest APTT and highest D-dimer combined had a 5.02 (2.37, 10.62) higher risk of VTE. VTE risk was not associated with fibrinogen, factor VII or activated protein C resistance; full blood count variables or with inflammatory markers, plasma viscosity, C-reactive protein or interleukin-6. The combination of D-dimer and APTT merits evaluation as an adjunct to VTE risk prediction scores.

From 1800, arterial thrombosis and venous thrombosis were increasingly recognised as causes of sudden death. By 1960, they had replaced infections as the commonest cause of death in Scotland and the UK, as in many developed countries. The important contributions of Scotland’s doctors between 1800 and 1960 to the knowledge of thrombosis, and to its treatment and prevention by anticoagulant drugs, are reviewed.

The associations of plasma levels of hemostatic factors, other than fibrinogen, with risks of cardiovascular disease (CVD) and all-cause mortality are not well defined. In two phases of the Glasgow MONICA study, we assayed coagulation factors (VII, VIII, IX, and von Willebrand factor), coagulation inhibitors (antithrombin, protein C, protein S), coagulation activation markers (prothrombin fragment 1 + 2, thrombin–antithrombin complexes, D-dimer), and the fibrinolytic factors, tissue plasminogen activator (t-PA) antigen and plasminogen activator inhibitor type 1. Over 15 to 20 years, we followed up between 382 and 1,123 men and women aged 30 to 74 years, without baseline CVD, for risks of CVD and mortality. Age- and sex-adjusted hazard ratios (HRs) for CVD (top third vs bottom third) were significant only for factor VIII (1.30; 95% confidence interval [CI], 1.06–1.58) and factor IX (1.18; 95% CI, 1.01–1.39); these HRs were attenuated by further adjustment for CVD risk factors: 1.17 (95% CI, 0.94–1.46) and 1.07 (95% CI, 0.92–1.25), respectively. In contrast, factor VIII (HR, 1.63; 95% CI, 1.35–1.96), D-dimer (HR, 2.34; 95% CI, 1.26–4.35), and t-PA (HR, 2.81; 95% CI, 1.43–5.54) were strongly associated with mortality after full risk factor adjustment. Further studies, including meta-analyses, are required to assess the associations of these hemostatic factors with the risks of stroke and heart disease and causes of mortality.

We thank Dr Fustes and Dr Rodriguez for their valuable comments on our paper.1 We read with interest the case history they share, providing support for our fi ndings. As they point out, isolated oculomotor nerve palsy is an aetiologically diverse condition, partly related to its neuroanatomical pathway originating in the midbrain and ending in the extraocular muscles. Damage at any point in the nerve’s course, divided broadly into the regions of brainstem nucleus, fascicles, subarachnoid space, cavernous sinus and orbital apex,2 for any number of different reasons can lead to clinical manifestations.

Background Oral anticoagulation reduces the rate of systemic embolism for patients with atrial fibrillation by two-thirds, but its benefits for patients with previous intracranial haemorrhage are uncertain. In the Start or STop Anticoagulants Randomised Trial (SoSTART), we aimed to establish whether starting is non-inferior to avoiding oral anticoagulation for survivors of intracranial haemorrhage who have atrial fibrillation. Methods SoSTART was a prospective, randomised, open-label, assessor-masked, parallel-group, pilot phase trial done at 67 hospitals in the UK. We recruited adults (aged >= 18 years) who had survived at least 24 h after symptomatic spontaneous intracranial haemorrhage, had atrial fibrillation, and had a CHA2DS2-VASc score of at least 2. Web-based computerised randomisation incorporating a minimisation algorithm allocated participants (1:1) to start or avoid long-term (>= 1 year) full treatment dose open-label oral anticoagulation. The participants assigned to start oral anticoagulation received either a direct oral anticoagulant or vitamin K antagonist, and the group assigned to avoid oral anticoagulation received standard clinical practice (antiplatelet agent or no antithrombotic agent). The primary outcome was recurrent symptomatic spontaneous intracranial haemorrhage, and was adjudicated by an individual masked to treatment allocation. All outcomes were ascertained for at least 1 year after randomisation and assessed in the intention-to-treat population of all randomly assigned participants, using Cox proportional hazards regression adjusted for minimisation covariates. We planned a sample size of 190 participants (one-sided p=0.025, power 90%, allowing for non-adherence) based on a non-inferiority margin of 12% (or adjusted hazard ratio [HR] of 3.2). This trial is registered with ClinicalTrials.gov (NCT03153150) and is complete. Findings Between March 29, 2018, and Feb 27, 2020, consent was obtained at 61 sites for 218 participants, of whom 203 were randomly assigned at a median of 115 days (IQR 49-265) after intracranial haemorrhage onset. 101 were assigned to start and 102 to avoid oral anticoagulation. Participants were followed up for median of 1.2 years (IQR 0.97-1.95; completeness 97.2%). Starting oral anticoagulation was not non-inferior to avoiding oral anticoagulation: eight (8%) of 101 in the start group versus four (4%) of 102 in the avoid group had intracranial haemorrhage recurrences (adjusted HR 2.42 [95% CI 0.72-8.09]; p=0.152). Serious adverse events occurred in 17 (17%) participants in the start group and 15 (15%) in the avoid group. 22 (22%) patients in the start group and 11 (11%) patients in the avoid group died during the study. Interpretation Whether starting oral anticoagulation was non-inferior to avoiding it for people with atrial fibrillation after intracranial haemorrhage was inconclusive, although rates of recurrent intracranial haemorrhage were lower than expected. In view of weak evidence from analyses of three composite secondary outcomes, the possibility that oral anticoagulation might be superior for preventing symptomatic major vascular events should be investigated in adequately powered randomised trials.

Over 70 years, the West of Scotland Haemophilia Centre in the UK has played a leading role in research, education and training. Its staff studied the natural history of haemophilias, their complications, and their treatment complications, pioneered the use of fibrinolytic inhibitors to reduce the risk of receiving a blood transfusion and developed national audit. Collaborations across Scotland with other haemophilia centres and the Scottish National Blood Transfusion Service progressed self-sufficiency in NHS-produced factor concentrates, heat treatments to prevent HIV and hepatitis transmission, and finally, replacement of human by recombinant factor concentrates.

Background Oroxylum indicum fruit extract (OIE) has been reported to inhibit the development of adipocytes. However, the exact mechanism of its metabolic activity is not clearly defined. This study attempted to investigate whether OIE was involved in disrupting the cell cycle, glucose metabolism, and mitochondrial function in 3 T3-L1 cells. Methods The effect of the OIE on cell cycle progression was measured by flow cytometry along with observing the expression of the cycle regulator by immunoblotting. The effect of the OIE on glucose metabolism was investigated. The amount of glucose uptake (2-NBDG) influenced by insulin was determined as well as the protein tyrosine phosphorylation (PY20), and glucose transporter4 (GLUT4) expression was determined by immunoblotting assay. Mitochondria are also essential to metabolic processes. This study investigated mitochondrial activity using fluorescent lipophilic carbocyanine dye (JC-1) and mitochondria mass by MitoTracker Green (MTG) staining fluorescence dyes. Finally, cellular ATP concentration was measured using an ATP chemiluminescence assay. Results Treatment with OIE plus adipogenic stimulators for 24 h arrested cell cycle progression in the G2/M phase. Moreover, 200 μg/mL of OIE significantly diminished the expression of the insulin receptor (IR) and GLUT4 protein compared to the untreated-adipocytes ( P < 0.05). The mitochondrial membrane potential (MMP) was significantly reduced (24 h) and increased (day 12) by OIE compared to untreated-adipocytes ( P < 0.05). However, OIE maintained MMP and ATP at a similar level compared to the pre-adipocytes (day 12). Transmission electron microscope (TEM) results demonstrated that OIE could protect mitochondria deformation compared to the untreated-adipocytes. Conclusion These results suggest that the inhibitory effect of the OIE on adipogenesis may potentially inhibit the cell cycle and phosphorylation of IR, leading to a decrease in glucose uptake to the cells. The OIE also slows down the mitochondrial activity of the early phase of cell differentiation, which can also inhibit the development of fat cells.

Background Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (>= 18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1: 1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2.0 years (IQR [1.0-3.0]; completeness 99.3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0.51 [95% CI 0.25-1.03]; p= 0.060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0.71 [0.39-1.30]; p= 0.27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1.02 [0.65-1.60]; p= 0.92). Interpretation These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd.

Importance It is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE). Objective To estimate the associations of major cardiovascular risk factors with VTE, ie, deep vein thrombosis and pulmonary embolism. Design, Setting, and Participants This study included individual participant data mostly from essentially population-based cohort studies from the Emerging Risk Factors Collaboration (ERFC; 731 728 participants; 75 cohorts; years of baseline surveys, February 1960 to June 2008; latest date of follow-up, December 2015) and the UK Biobank (421 537 participants; years of baseline surveys, March 2006 to September 2010; latest date of follow-up, February 2016). Participants without cardiovascular disease at baseline were included. Data were analyzed from June 2017 to September 2018. Exposures A panel of several established cardiovascular risk factors. Main Outcomes and Measures Hazard ratios (HRs) per 1-SD higher usual risk factor levels (or presence/absence). Incident fatal outcomes in ERFC (VTE, 1041; coronary heart disease [CHD], 25 131) and incident fatal/nonfatal outcomes in UK Biobank (VTE, 2321; CHD, 3385). Hazard ratios were adjusted for age, sex, smoking status, diabetes, and body mass index (BMI). Results Of the 731 728 participants from the ERFC, 403 396 (55.1%) were female, and the mean (SD) age at the time of the survey was 51.9 (9.0) years; of the 421 537 participants from the UK Biobank, 233 699 (55.4%) were female, and the mean (SD) age at the time of the survey was 56.4 (8.1) years. Risk factors for VTE included older age (ERFC: HR per decade, 2.67; 95% CI, 2.45-2.91; UK Biobank: HR, 1.81; 95% CI, 1.71-1.92), current smoking (ERFC: HR, 1.38; 95% CI, 1.20-1.58; UK Biobank: HR, 1.23; 95% CI, 1.08-1.40), and BMI (ERFC: HR per 1-SD higher BMI, 1.43; 95% CI, 1.35-1.50; UK Biobank: HR, 1.37; 95% CI, 1.32-1.41). For these factors, there were similar HRs for pulmonary embolism and deep vein thrombosis in UK Biobank (except adiposity was more strongly associated with pulmonary embolism) and similar HRs for unprovoked vs provoked VTE. Apart from adiposity, these risk factors were less strongly associated with VTE than CHD. There were inconsistent associations of VTEs with diabetes and blood pressure across ERFC and UK Biobank, and there was limited ability to study lipid and inflammation markers. Conclusions and Relevance Older age, smoking, and adiposity were consistently associated with higher VTE risk.

Atherothrombosis is a leading cause of cardiovascular mortality and long-term morbidity. Platelets and coagulation proteases, interacting with circulating cells and in different vascular beds, modify several complex pathologies including atherosclerosis. In the second Maastricht Consensus Conference on Thrombosis, this theme was addressed by diverse scientists from bench to bedside. All presentations were discussed with audience members and the results of these discussions were incorporated in the final document that presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following five topics: 1. Risk factors, biomarkers and plaque instability: In atherothrombosis research, more focus on the contribution of specific risk factors like ectopic fat needs to be considered; definitions of atherothrombosis are important distinguishing different phases of disease, including plaque (in) stability; proteomic and metabolomics data are to be added to genetic information. 2. Circulating cells including platelets and atherothrombosis: Mechanisms of leukocyte and macrophage plasticity, migration, and transformation in murine atherosclerosis need to be considered; diseasemechanism-based biomarkers need to be identified; experimental systems are needed that incorporatewhole-blood flow to understand how red blood cells influence thrombus formation and stability; knowledge on platelet heterogeneity and priming conditions needs to be translated toward the in vivo situation. 3. Coagulation proteases, fibrin(ogen) and thrombus formation: The role of factor (F) XI in thrombosis including the lower margins of this factor related to safe and effective antithrombotic therapy needs to be established; FXI is a key regulator in linking platelets, thrombin generation, and inflammatory mechanisms in a renin-angiotensin dependent manner; however, the impact on thrombin-dependent PAR signaling needs further study; the fundamental mechanisms in FXIII biology and biochemistry and its impact on thrombus biophysical characteristics need to be explored; the interactions of red cells and fibrin formation and its consequences for thrombus formation and lysis need to be addressed. Platelet-fibrin interactions are pivotal determinants of clot formation and stability with potential therapeutic consequences. 4. Preventive and acute treatment of atherothrombosis and arterial embolism; novel ways and tailoring? The role of protease-activated receptor (PAR)-4 vis a vis PAR-1 as target for antithrombotic therapy merits study; ongoing trials on platelet function test-based antiplatelet therapy adjustment support development of practically feasible tests; risk scores for patients with atrial fibrillation need refinement, taking new biomarkers including coagulation into account; risk scores that consider organ system differences in bleeding may have added value; all forms of oral anticoagulant treatment require better organization, including education and emergency access; laboratory testing still needs rapidly available sensitive tests with short turnaround time. 5. Pleiotropy of coagulation proteases, thrombus resolution and ischaemia-reperfusion: Biobanks specifically for thrombus storage and analysis are needed; further studies on novelmodified activated protein C-based agents are required including its cytoprotective properties; new avenues for optimizing treatment of patients with ischaemic stroke are needed, also including novel agents that modify fibrinolytic activity (aimed at plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor.