High microRNA-145 plasma levels are associated with decreased risk of future incident venous thromboembolism: the HUNT study.

ABSTRACT: MicroRNA-145 (miR-145) has been reported to downregulate the expression of tissue factor and factor XI in vitro and decrease venous thrombus formation in animal models. However, the association between miR-145 and risk of future venous thromboembolism (VTE) in the general population remains unknown. We investigated the association between plasma levels of miR-145 and risk of future VTE in a case-cohort study. Incident VTE cases (n = 510) and a subcohort (n = 1890) were derived from the third survey of the Trøndelag Health Study (HUNT3), a population-based cohort. The expression levels of miR-145 were measured in plasma samples obtained at baseline. The study population was divided into quartiles based on miR-145 levels in participants in the subcohort, and weighted Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Plasma levels of miR-145 were inversely associated with VTE risk. Participants with miR-145 levels in the highest quartile had a 49% lower risk of VTE (HR, 0.51; 95% CI, 0.38-0.68) than those with miR-145 in the lowest quartile in age- and sex-adjusted analysis, and the inverse association was most pronounced for unprovoked VTE (HR, 0.39; 95% CI, 0.25-0.61). Risk estimates remained virtually the same after further adjustment for body mass index, and cancer and arterial cardiovascular disease at baseline. In conclusion, elevated expression levels of miR-145 in plasma were associated with decreased risk of future incident VTE. The protective role of miR-145 against VTE is consistent with previous experimental data and suggests that miR-145 has the potential to be a target for VTE prevention.

Combined effects of plasma von Willebrand factor and platelet measures on the risk of incident venous thromboembolism.

Plasma von Willebrand factor (VWF) and platelet reactivity are risk factors for venous thromboembolism (VTE), and VWF can promote hemostasis by interaction with platelets. In this study, we explored the combined effects of plasma VWF and platelet measures on the risk of incident VTE. A population-based nested case-control study with 403 cases and 816 controls was derived from the Tromsø Study. VWF, platelet count and mean platelet volume (MPV) were measured in blood samples drawn at baseline. Odds ratios (ORs) with 95% confidence intervals (CIs) for VTE were estimated across VWF tertiles, within predefined MPV (<8.5, 8.5-9.5, and ≥9.5 fL) and platelet count (<230, 230-299, and ≥300 ×109/L) strata. Here, participants with VWF levels in the highest tertile and with MPV ≥9.5 fL had an OR of 1.98 (95% CI, 1.17-3.36) for VTE compared with those in the lowest VWF tertile and with MPV <8.5 fL in the age- and sex-adjusted model. In the joint exposure group, 48% (95% CI, 15-96) of VTEs were attributable to the biological interaction between VWF and MPV. Similarly, individuals with VWF in the highest tertile and platelet count ≥300 × 109/L had an OR of 2.91 (95% CI, 1.49-5.67) compared with those with VWF in the lowest tertile and platelet count <230 × 109/L, and 39% (95% CI, -2 to 97) of VTEs in the joint exposure group were explained by the interaction. Our results suggest that platelet reactivity and platelet count interact biologically with high plasma VWF, resulting in an increased risk for incident VTE.

High Levels of Complement Activating Enzyme MASP-2 Are Associated With the Risk of Future Incident Venous Thromboembolism.

BACKGROUND: Experimental studies have shown that the complement activating enzyme MASP-2 (mannose-binding lectin associated serine protease 2) exhibits a thrombin-like activity and that inhibition of MASP-2 protects against thrombosis. In this study, we investigated whether plasma MASP-2 levels were associated with risk of future venous thromboembolism (VTE) and whether genetic variants linked to MASP-2 levels were associated with VTE risk. METHODS: We conducted a population-based nested case-control study involving 410 VTE patients and 842 age- and sex-matched controls derived from the Norwegian Tromsø Study. Logistic regression was used to estimate odds ratios (ORs) of VTE across MASP-2 quartiles. Whole-exome sequencing and protein quantitative trait loci analyses were performed to assess genetic variants associated with MASP-2 levels. A 2-sample Mendelian randomization study, also including data from the INVENT consortium (International Network of Venous Thrombosis), was performed to assess causality. RESULTS: Subjects with plasma MASP-2 in the highest quartile had a 48% higher OR of VTE (OR, 1.48 [95% CI, 1.06-2.06]) and 83% higher OR of deep vein thrombosis (OR, 1.83 [95% CI, 1.23-2.73]) compared with those with MASP-2 levels in the lowest quartile. The protein quantitative trait loci analysis revealed that 3 previously described gene variants, rs12711521 (minor allele frequency, 0.153), rs72550870 (minor allele frequency, 0.045; missense variants in the MASP2 gene), and rs2275527 (minor allele frequency, 0.220; exon variant in the adjacent MTOR gene) explained 39% of the variation of MASP-2 plasma concentration. The OR of VTE per 1 SD increase in genetically predicted MASP-2 was 1.03 ([95% CI, 1.01-1.05] P=0.0011). CONCLUSIONS: Our findings suggest that high plasma MASP-2 levels are causally associated with risk of future VTE.

Plasma levels of growth differentiation factor 15 are associated with future risk of venous thromboembolism.

Growth differentiation factor 15 (GDF-15), a marker of inflammation and oxidative stress, has emerged as a biomarker for arterial cardiovascular disease. However, the association between GDF-15 and venous thromboembolism (VTE) remains uncertain. We therefore investigated the association between plasma GDF-15 levels and future risk of incident VTE and explored the potential of a causal association using Mendelian randomization (MR). We conducted a population-based nested case-control study comprising 416 VTE patients and 848 age- and sex-matched controls derived from the Tromsø Study. Logistic regression was used to calculate odds ratios (ORs) for VTE across GDF-15 quartiles. For the MR, we used data from the International Network on Venous Thrombosis (INVENT) consortium to examine whether single nucleotide polymorphisms (SNPs) associated with GDF-15 levels with genome-wide significance were related to VTE. We found that the ORs for VTE increased across GDF-15 quartiles (Ptrend = .002). Participants with GDF-15 values in the highest quartile (≥358 pg/mL) had an OR for VTE of 2.05 (95% confidence interval, 1.37-3.08) compared with those with GDF-15 in the lowest quartile (<200 pg/mL) in the age- and sex-adjusted model. ORs remained essentially the same after further adjustment for body mass index, smoking, hormone therapy, physical activity, and C-reactive protein. Similar results were obtained for provoked/unprovoked events, deep vein thrombosis, and pulmonary embolism. GDF-15 levels, as predicted by the SNPs, were not associated with VTE in MR. Our results indicate that high GDF-15 levels are associated with increased risk of VTE, but MR suggests that this association is not causal.

Association Between Hepatic Triglyceride Content and Coagulation Factors: The Netherlands Epidemiology of Obesity Study.

OBJECTIVE: Whether hepatic triglyceride content (HTGC) contributes to hypercoagulability beyond total body fat (TBF) and visceral adipose tissue (VAT) is unclear. We, therefore, aimed to investigate the association between HTGC and coagulation factors (F)I (fibrinogen), VIII, IX, and XI while adjusting for TBF and VAT. Approach and Results: In this cross-sectional analysis of the NEO study (Netherlands Epidemiology of Obesity; n=6671), a random subset of participants underwent magnetic resonance imaging and magnetic resonance spectroscopy to assess VAT and HTGC (n=2580). We excluded participants without complete imaging and coagulation assessment, and with history of liver disease, venous thrombosis, or on anticoagulation. Mean differences in coagulation factor levels across HTGC quartiles were estimated by linear regression adjusted for age, sex, ethnicity, education, alcohol intake, physical activity, smoking, estrogen, and menopause, in addition to TBF and VAT. Among the 1946 participants included, median HTGC was 2.66% (interquartile range: 1.34%-6.27%). Coagulation factor levels increased dose-dependently across HTGC quartiles. Mean differences between the fourth and first quartiles were 14.7 mg/dL (95% CI, 2.1-27.2) for fibrinogen, 6.7 IU/dL (95% CI, 0.5-12.9) for FVIII, 26.1 IU/dL (95% CI, 22.4-29.8) for FIX, and 8.6 IU/dL (95% CI, 4.6-12.6) for FXI. With further adjustment for TBF and VAT, the dose-response association of HTGC with FIX persisted, whereas associations with other factors disappeared. CONCLUSIONS: HTGC was associated with various coagulation factors, of which FIX remained associated with HTGC after adjustment for TBF and VAT. HTGC might contribute to venous thrombosis risk beyond total body and visceral fat through FIX levels.

Platelet count and risk of major bleeding in venous thromboembolism.

The relationship between platelet count and risk of major bleeding in patients with venous thromboembolism (VTE) during anticoagulation remains unclear. We therefore investigated the association between platelet count, measured at VTE diagnosis and before the thrombotic event, and risk of major bleeding. Participants comprised 744 patients with incident VTE derived from the Tromsø Study. Major bleedings were recorded during the first year after VTE. Cox-regression was used to calculate hazard ratios (HRs) for major bleeding across platelet count quartiles.There were 55 major bleedings (incidence rate 9.1/100 person-years, 95% confidence interval [CI] 7.0-11.8). The major bleeding risk increased across quartiles of platelet count measured at VTE diagnosis (P for trend<0.02). In the age- and sex-adjusted model, subjects with platelet count in the highest quartile (≥300x109/L) had a 4.3-fold (95% CI 1.7-10.9) higher risk of major bleeding compared to those with platelet count in the lowest quartile (≤192x109/L), and exclusion of patients with cancer yielded similar results. When platelet count was measured on average 7 years before a VTE, the corresponding HR was 2.5 (95% CI 0.9-6.7). Our results suggest that increasing platelet count, assessed several years before and at VTE diagnosis, is associated with a higher risk of major bleeding, and could be a stable individual marker of major bleeding risk in VTE-patients.

Role of microRNAs in Venous Thromboembolism.

MicroRNAs (miRNAs) are non-coding RNAs that execute their function by targeted downregulation of gene expressions. There is growing evidence from epidemiological studies and animal models suggesting that the expression level of miRNAs is dysregulated in venous thromboembolism (VTE). In this review, we summarize the current knowledge on the role of miRNAs as biomarkers for VTE and provide general insight into research exploring the modulation of miRNA activity in animal models of venous thrombosis. Up to now, published studies have yielded inconsistent results on the role of miRNAs as biomarkers for VTE with most of the reports focused on diagnostic research. The limited statistical power of the individual studies, due to the small sample sizes, may substantially contribute to the poor reproducibility among studies. In animal models, over-expression or inhibition of some miRNAs appear to influence venous thrombus formation and resolution. However, there is an important gap in knowledge on the potential role of miRNAs as therapeutic targets in VTE. Future research involving large cohorts should be designed to clarify the clinical usefulness of miRNAs as biomarkers for VTE, and animal model studies should be pursued to unravel the role of miRNAs in the pathogenesis of VTE and their potential as therapeutic targets.

Glucose levels and diabetes are not associated with the risk of venous thrombosis: results from the MEGA case-control study.

It is unclear whether hyperglycaemia or diabetes mellitus are risk factors for a first venous thrombosis (VT). Self-reported diabetes status and fasting glucose (FG) measures were collected from the Multiple Environmental and Genetic Assessment (MEGA) study to confirm these associations. FG levels were categorized based on the World Health Organization criteria [<6·1 (reference), 6·1-7·0 (2nd), ≥7·0 (3rd) mmol/l]. Logistic regression was performed to quantify the associations. Neither increased FG levels [Odds ratio (95% confidence interval): 0·98 (0·69-1·37) 2nd vs. reference, 0·97 (0·58-1·63) 3rd vs. reference] nor self-reported diabetes [1·12 (0·80-1·58)] were associated with an increased risk of a first VT.

Lipid levels and risk of venous thrombosis: results from the MEGA-study.

The relationship between lipid levels and risk of venous thrombosis is not well established. We aimed to assess the association between several lipids and risk of venous thrombosis using data from a population-based case-control study, and to evaluate the underlying mechanism, considering confounding by common risk factors and mediation via hemostatic factors and C-reactive protein. From the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study, 2234 patients with a first venous thrombosis and 2873 controls were included. Percentile categories of total/low-density lipoprotein/high-density lipoprotein cholesterol, triglycerides, and apolipoproteins B and A1 were established in controls (<10th, 10th-25th, 25th-75th [reference], 75th-90th, >90th percentile). In age- and sex-adjusted models, decreasing levels of apolipoproteins B and A1 were dose-dependently associated with increased thrombosis risk, with odds ratios of 1.35 (95% confidence interval 1.12-1.62) and 1.50 (95% confidence interval 1.25-1.79) for the lowest category versus the reference category, respectively. The dose-response relation remained with further adjustment for body mass index, estrogen use, statin use, and diabetes. Although apolipoproteins B and A1 were associated with several hemostatic factors and C-reactive protein, none explained the increased risk in mediation analyses. The other lipids were not associated with venous thrombosis risk. In conclusion, decreasing levels of apolipoproteins B and A1 were associated with increased risk of venous thrombosis. Our findings are consistent with experimental data on the anticoagulant properties of apolipoproteins B and A1. These findings need to be confirmed and the underlying mechanism further investigated.

The Risk of Incident Venous Thromboembolism Attributed to Overweight and Obesity: The Tromsø Study.

BACKGROUND: Obesity is a well-established risk factor for venous thromboembolism (VTE). However, data on the proportion of incident VTEs attributed to overweight and obesity in the general population are limited. OBJECTIVE: To investigate the population attributable fraction (PAF) of VTE due to overweight and obesity in a population-based cohort with repeated measurements of body mass index (BMI). METHODS: Participants from the fourth to seventh surveys of the Tromsø Study (enrolment: 1994-2016) were followed through 2020, and all incident VTEs were recorded. In total, 36,341 unique participants were included, and BMI measurements were updated for those attending more than one survey. BMI was categorized as <25 kg/m2, 25-30 kg/m2 (overweight), and ≥30 kg/m2 (obesity). Time-varying Cox regression models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). The PAF was estimated based on age- and sex-adjusted HRs and the prevalence of BMI categories in VTE cases. RESULTS: At baseline, the prevalence of overweight and obesity was 37.9 and 13.8%, respectively. During a median follow-up of 13.9 years, 1,051 VTEs occurred. The age- and sex-adjusted HRs of VTE were 1.40 (95% CI: 1.21-1.61) for overweight and 1.86 (95% CI: 1.58-2.20) for obesity compared with subjects with BMI <25 kg/m2. The PAF of VTE due to overweight and obesity was 24.6% (95% CI: 16.6-32.9), with 12.9% (95% CI: 6.6-19.0) being attributed to overweight and 11.7% (95% CI: 8.5-14.9) to obesity. Similar PAFs were obtained in analyses stratified by sex and VTE subtypes (provoked/unprovoked events, deep vein thrombosis, pulmonary embolism). CONCLUSION: Our findings indicate that almost 25% of all VTE events can be attributed to overweight and obesity in a general population from Norway.