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Background Genotypes generated in next generation sequencing studies contain errors which can significantly impact the power to detect signals in common and rare variant association tests. These genotyping errors are not explicitly filtered by the standard GATK Variant Quality Score Recalibration (VQSR) tool and thus remain a source of errors in whole exome sequencing (WES) projects that follow GATK's recommended best practices. Therefore, additional data filtering methods are required to effectively remove these errors before performing association analyses with complex phenotypes. Here we empirically derive thresholds for genotype and variant filters that, when used in conjunction with the VQSR tool, achieve higher data quality than when using VQSR alone. Results The detailed filtering strategies improve the concordance of sequenced genotypes with array genotypes from 99.33% to 99.77%; improve the percent of discordant genotypes removed from 10.5% to 69.5%; and improve the Ti/Tv ratio from 2.63 to 2.75. We also demonstrate that managing batch effects by separating samples based on different target capture and sequencing chemistry protocols results in a final data set containing 40.9% more high-quality variants. In addition, imputation is an important component of WES studies and is used to estimate common variant genotypes to generate additional markers for association analyses. As such, we demonstrate filtering methods for imputed data that improve genotype concordance from 79.3% to 99.8% while removing 99.5% of discordant genotypes. Conclusions The described filtering methods are advantageous for large population-based WES studies designed to identify common and rare variation associated with complex diseases. Compared to data processed through standard practices, these strategies result in substantially higher quality data for common and rare association analyses. [ABSTRACT FROM AUTHOR]

Background: Much controversy surrounds the association of traditional cardiovascular disease risk factors with venous thromboembolism (VTE).Methods: We performed an individual level random-effect meta-analysis including 9 prospective studies with measured baseline cardiovascular disease risk factors and validated VTE events. Definitions were harmonized across studies. Traditional cardiovascular disease risk factors were modeled categorically and continuously using restricted cubic splines. Estimates were obtained for overall VTE, provoked VTE (ie, VTE occurring in the presence of 1 or more established VTE risk factors), and unprovoked VTE, pulmonary embolism, and deep-vein thrombosis.Results: The studies included 244 865 participants with 4910 VTE events occurring during a mean follow-up of 4.7 to 19.7 years per study. Age, sex, and body mass index-adjusted hazard ratios for overall VTE were 0.98 (95% confidence interval [CI]: 0.89-1.07) for hypertension, 0.97 (95% CI: 0.88-1.08) for hyperlipidemia, 1.01 (95% CI: 0.89-1.15) for diabetes mellitus, and 1.19 (95% CI: 1.08-1.32) for current smoking. After full adjustment, these estimates were numerically similar. When modeled continuously, an inverse association was observed for systolic blood pressure (hazard ratio=0.79 [95% CI: 0.68-0.92] at systolic blood pressure 160 vs 110 mm Hg) but not for diastolic blood pressure or lipid measures with VTE. An important finding from VTE subtype analyses was that cigarette smoking was associated with provoked but not unprovoked VTE. Fully adjusted hazard ratios for the associations of current smoking with provoked and unprovoked VTE were 1.36 (95% CI: 1.22-1.52) and 1.08 (95% CI: 0.90-1.29), respectively.Conclusions: Except for the association between cigarette smoking and provoked VTE, which is potentially mediated through comorbid conditions such as cancer, the modifiable traditional cardiovascular disease risk factors are not associated with increased VTE risk. Higher systolic blood pressure showed an inverse association with VTE. [ABSTRACT FROM AUTHOR]

Background: For the relationship between obesity and venous thromboembolism (VTE), nonalcoholic fatty liver disease (recently termed metabolic dysfunction-associated steatotic liver disease) is of interest given the hepatic role in hemostasis., Objectives: We aimed to assess the association between the fatty liver index (FLI), as a proxy for nonalcoholic fatty liver disease, and VTE risk in a population-based cohort., Methods: Data from the Tromsø 4 (1994-1995) and 6 (2007-2008) surveys were used to calculate the FLI in 9870 participants. All VTEs were recorded up to December 31, 2020. We used Cox regression to estimate hazard ratios for VTE with 95% CIs by FLI groups defined according to clinical cut-offs (<30, 30-59, and ≥60). Because waist circumference and body mass index (BMI) are main determinants for FLI calculation, we assessed the potential contribution of FLI to VTE risk beyond these body fat measures., Results: During a median follow-up of 13.1 years, 507 incident VTEs occurred. Compared with the reference group (FLI < 30), the hazard ratios for VTE were 1.5 (95% CI, 1.1-1.9) and 1.8 (95% CI, 1.4-2.3) for the FLI 30-59 and ≥60 groups, respectively, in models adjusted for age, sex, alcohol intake, educational level, and physical activity. The association of FLI with VTE was no longer observed, with risk estimates close to unity, when participants were stratified by clinical categories of waist circumference and BMI., Conclusion: Higher values of the FLI were associated with a higher VTE risk. This association was explained by waist circumference and BMI, which reflect excessive body fat deposition and are determinants of the FLI., (© 2024 The Author(s).)

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., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Patients with ischemic stroke have increased risk of venous thromboembolism (VTE). Obesity is prevalent in stroke patients and a well-established risk factor for VTE. Whether obesity further increases the VTE risk in patients with stroke remains unclear., Objectives: We investigated the joint effect of ischemic stroke and obesity on the risk of incident VTE in a population-based cohort., Methods: Participants ( n  = 29,920) were recruited from the fourth to sixth surveys of the Tromsø Study (1994-1995, 2001, and 2007-2008) and followed through 2014. Incident events of ischemic stroke and VTE during follow-up were recorded. Hazard ratios (HRs) of VTE with 95% CIs were estimated according to combined categories of ischemic stroke and obesity (body mass index ≥ 30 kg/m 2 ), with exposure to neither risk factors as reference., Results: During a median follow-up of 19.6 years, 1388 participants experienced ischemic stroke and 807 participants developed VTE. Among those with stroke, 51 developed VTE, yielding an incidence rate of VTE after stroke of 7.2 per 1000 person-years (95% CI, 5.5-9.5). In subjects without stroke, obesity was associated with a 1.8-fold higher VTE risk (HR, 1.76; 95% CI, 1.47-2.11). In nonobese subjects, stroke was associated with a 1.8-fold higher VTE risk (HR, 1.77; 95% CI, 1.27-2.46). Obese subjects with stroke had a 2-fold increased VTE risk (HR, 2.44; 95% CI, 1.37-4.36)., Conclusion: The combination of obesity and ischemic stroke did not yield an excess risk of VTE. Our findings suggest that obese subjects with ischemic stroke do not have a more than additive risk of VTE., (© 2024 The Authors.)

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/m 2 , 25-30 kg/m 2 (overweight), and ≥30 kg/m 2 (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/m 2 . 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., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Data on the proportion of venous thromboembolism (VTE) risk attributed to prothrombotic genotypes in men and women are limited., Objectives: We aimed to estimate the population attributable fraction (PAF) of VTE for recognized, common prothrombotic genotypes in men and women using a population-based case cohort., Methods: Cases with incident VTE ( n  = 1493) and a randomly sampled subcohort ( n  = 13,069) were derived from the Tromsø study (1994-2012) and the Trøndelag Health Study (1995-2008) cohorts. DNA samples were genotyped for 17 single-nucleotide polymorphisms (SNPs) previously associated with VTE. PAFs with 95% bias-corrected CIs (based on 10,000 bootstrap samples) were estimated for SNPs significantly associated with VTE, and a 6-SNP cumulative model was constructed for both sexes., Results: In women, the individual PAFs for SNPs included in the cumulative model were 16.9% for ABO (rs8176719), 17.6% for F11 (rs2036914), 15.1% for F11 (rs2289252), 8.7% for FVL (rs6025), 6.0% for FGG (rs2066865), and 0.2% for F2 (rs1799963). The cumulative PAF for this 6-SNP model was 37.8%. In men, the individual PAFs for SNPs included in the cumulative model were 21.3% for ABO , 12.2% for F11 (rs2036914), 10.4% for F11 (rs2289252), 7.5% for FVL , 7.8% for FGG , and 1.1% for F2 . This resulted in a cumulative PAF in men of 51.9%., Conclusion: Our findings in a Norwegian population suggest that 52% and 38% of the VTEs can be attributed to known prothrombotic genotypes in men and women, respectively., (© 2024 The Author(s).)

Background: High factor VIII (FVIII) levels and large platelets, as reflected by a high mean platelet volume (MPV), are separately associated with increased risk of venous thromboembolism (VTE). Whether the combination of high FVIII levels and large platelets has a supra-additive effect on VTE risk is unknown., Objectives: We aimed to investigate the joint effect of high FVIII levels and large platelets, as reflected by high MPV, on the risk of future incident VTE., Methods: A population-based nested case-control study with 365 incident VTE cases and 710 controls was derived from the Tromsø study. FVIII antigen levels and MPV were measured in blood samples drawn at baseline. Odds ratios with 95% CIs were estimated across FVIII tertiles (<85%, 85%-108%, and ≥108%) and within predefined MPV strata (<8.5, 8.5-9.5, and ≥9.5 fL)., Results: VTE risk increased linearly across FVIII tertiles (P trend  < .001) in models adjusted for age, sex, body mass index, and C-reactive protein. In the combined analysis, participants with FVIII levels in the highest tertile and an MPV of ≥9.5 fL (ie, joint exposure) had an odds ratio for VTE of 2.71 (95% CI, 1.44-5.11) compared with those with FVIII levels in the lowest tertile and an MPV of <8.5 fL (reference). In the joint exposure group, 52% (95% CI, 17%-88%) of VTEs were attributable to the biological interaction between FVIII and MPV., Conclusion: Our results suggest that large platelets, as reflected by high MPV, might play a role in the mechanism by which high FVIII level increases the risk of incident VTE., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background  Surgery is a major transient risk factor for venous thromboembolism (VTE). However, the impact of major surgery as a VTE trigger has been scarcely investigated using a case-crossover design. Aim  To investigate the role of major surgery as a trigger for incident VTE in a population-based case-crossover study while adjusting for other concomitant VTE triggers. Methods  We conducted a case-crossover study with 531 cancer-free VTE cases derived from the Tromsø Study cohort. Triggers were registered during the 90 days before a VTE event (hazard period) and in four preceding 90-day control periods. Conditional logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for VTE according to major surgery and after adjustment for other VTE triggers. Results  Surgery was registered in 85 of the 531 (16.0%) hazard periods and in 38 of the 2,124 (1.8%) control periods, yielding an OR for VTE of 11.40 (95% CI: 7.42-17.51). The OR decreased to 4.10 (95% CI: 2.40-6.94) after adjustment for immobilization and infection and was further attenuated to 3.31 (95% CI: 1.83-5.96) when additionally adjusted for trauma, blood transfusion, and central venous catheter. In a mediation analysis, 51.4% (95% CI: 35.5-79.7%) of the effect of surgery on VTE risk could be mediated through immobilization and infection. Conclusions  Major surgery was a trigger for VTE, but the association between surgery and VTE risk was in part explained by other VTE triggers often coexisting with surgery, particularly immobilization and infection., Competing Interests: Conflict of Interest There are no conflicts of interest reported by any of the authors., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Background: P-selectin levels are elevated following acute deep vein thrombosis and reported to predict recurrent venous thromboembolism (VTE) and cancer-associated VTE. Yet, it is unknown whether plasma P-selectin levels are associated with incident VTE., Objectives: We aimed to investigate the association between plasma P-selectin levels and risk of future incident VTE., Methods: We performed a nested case-control study in 415 patients with VTE and 843 age- and sex-matched controls derived from the general population (Tromsø IV Study). Plasma P-selectin levels were measured using enzyme-linked immunosorbent assay. Logistic regression models were used to estimate odds ratios (ORs) for VTE across quartiles of plasma P-selectin level. Sex-stratified analysis was also performed., Results: Plasma P-selectin levels were higher in men (41.4 ng/mL) than in women (38.7 ng/mL, p = .0046). We found no association between plasma P-selectin levels and risk of VTE in the overall analyses. However, sex-stratified analyses revealed that women with P-selectin levels in the highest quartile (>44.3 ng/mL) had higher risk of VTE (OR, 1.63; 95% CI, 1.01-2.64) than women with P-selectin levels in the lowest quartile (≤29.9 ng/mL). In contrast, higher levels of P-selectin were apparently associated with lower risk of VTE in men (OR for highest vs lowest quartile of P-selectin, 0.69; 95% CI, 0.42-1.15). The observed associations were stronger when the time between blood sampling and VTE was shorter., Conclusion: Elevated levels of plasma P-selectin were associated with increased risk of VTE in women but not in men, suggesting a differential impact of sex on the association between P-selectin and VTE risk., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Patients with cancer have an increased risk of developing venous thromboembolism (VTE), and this combination is reported to result in poorer survival compared with cancer alone. This study aimed to investigate the impact of VTE on the survival of patients with cancer in a general population. The Scandinavian Thrombosis and Cancer (STAC) cohort, a population-based cohort including 144 952 participants without previous VTE or cancer, was used. During follow-up, cancer and VTE incidences were registered. "Cancer-related VTE" was defined as VTE diagnosed in patients with overt or occult cancer. The survival of participants without cancer and/or VTE ("disease-free") was compared with the survival of participants with cancer and cancer-related VTE. Cox regression models with cancer and VTE as time-varying exposures were performed to calculate hazard ratios for death. Subanalyses were performed across cancer types and stages and VTE type (deep vein thrombosis or pulmonary embolism). During follow-up (mean, 11.7 years), 14 621 participants developed cancer, and 2444 developed VTE, of which 1241 were cancer-related. The mortality rates (per 100 person years) for disease-free participants, VTE only, cancer only, and cancer-related VTE were 0.63, 5.0, 9.2, and 45.3, respectively. Compared with patients with cancer only, the risk of death for patients with cancer-related VTE was increased 3.4-fold. Within all cancer types, the occurrence of VTE increased the mortality risk 2.8- to 14.7-fold. In a general population, patients with cancer with VTE had a 3.4-fold higher mortality risk than patients with cancer without VTE, independent of cancer type., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Venous thromboembolism (VTE) is a frequent disease with a high risk of recurrence. It has been suggested that the D-dimer level at the time of VTE diagnosis can be used to identify patients at a low risk of recurrence., Objectives: We aimed to investigate the impact of D-dimer levels measured at the time of VTE diagnosis on the risk of recurrence in a large cohort of patients with a first-time VTE., Methods: The study included 2585 patients with first symptomatic non-cancer-associated VTE from the Venous Thrombosis Registry in Østfold Hospital (TROLL) (2005-2020). All recurrent events during the follow-up were recorded, and cumulative incidences of recurrence were estimated according to D-dimer levels of ≤1900 ng/mL (≤25th percentile) and >1900 ng/mL., Results: During a median follow-up of 3.3 years, 395 patients experienced a recurrent VTE. The 1- and 5-year cumulative incidences of recurrence were 2.9% (95% CI: 1.8-4.6) and 11.4% (95% CI: 8.7-14.8), respectively, in those with a D-dimer concentration of ≤1900 ng/mL and 5.0% (95% CI, 4.0-6.1) and 18.3% (95% CI: 16.2-20.6), respectively, in those with a D-dimer concentration of >1900 ng/mL, respectively. In patients with unprovoked VTE, the 5-year cumulative incidence was 14.3% (95% CI: 10.3-19.7) in the ≤1900-ng/mL category, and 20.2% (95% CI: 17.3-23.5) in the >1900-ng/mL category., Conclusions: D-dimer levels within the lowest quartile, measured at the time of VTE diagnosis, were associated with lower recurrence risk. Our findings imply that D-dimer levels measured at the time of diagnosis may be used to identify patients with VTE at a low risk of recurrent VTE., Competing Interests: Declaration of competing interests C.T.J. reports lecture honoraria from Bayer. H.H.P. reports receiving fees from Sanofi and Novartis. W.G. reports receiving fees for participation in an advisory board from Amgen, Novartis, Pfizer, Principia Biopharma Inc—a Sanofi Company, Sanofi, SOBI, Grifols, UCB, Argenx, Cellphire; lecture honoraria from Amgen, Novartis, Pfizer, Bristol Myers Squibb, SOBI, Grifols, Sanofi, and Bayer; and research grants from Bayer, BMS/Pfizer, and UCB. The remaining authors F.B.R, S.K.B, and J.-B.H have no competing interests to disclose., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: There is limited information on the relationship between muscle strength and recurrence and mortality after incident venous thromboembolism (VTE)., Objectives: To investigate whether weak hand grip strength (HGS) was associated with risk of recurrence and mortality in patients with VTE recruited from the general population., Methods: Participants from the Tromsø Study with a first-time VTE ( n  = 545) were included, and all VTE recurrences and deaths among the participants were recorded in the period 1994 to 2020. Weak HGS was defined as lowest 25th percentile of the general population, and incidence rates for VTE recurrence and mortality according to weak vs normal (>25th percentile) HGS, with 95% CIs, were estimated., Results: There were 90 recurrences and 350 deaths during a median of 3.7 years of follow-up. The fully adjusted hazard ratio (HR) for overall VTE recurrence for those with weak HGS vs those with normal HGS was 2.02 (95% CI, 1.23-3.30). The corresponding HRs for recurrence were 2.22 (95% CI, 1.18-4.17) in patients with a first deep vein thrombosis and 1.60 (95% CI, 0.72-3.57) in patients with a first pulmonary embolism. The cumulative 1-year survival was 74.9% and 77.8% in those with weak and normal HGS, respectively. For overall mortality after incident VTE, the fully adjusted HR for those with weak HGS was 1.34 (95% CI, 1.04-1.72)., Conclusion: Weak HGS was associated with an increased risk of recurrent VTE, and the association appeared to be particularly pronounced after incident deep vein thrombosis. There was a slightly lower survival probability among those with weak HGS than among those with normal HGS., (© 2023 The Author(s).)

Background: von Willebrand factor (VWF) and its cleaving protease, ADAMTS-13, form a pivotal axis that regulates hemostasis. However, the role of the VWF-ADAMTS-13 axis in the risk of future venous thromboembolism (VTE) is unknown., Objectives: To investigate whether plasma ADAMTS-13 levels and an imbalance with VWF levels, assessed as the VWF/ADAMTS-13 ratio, are associated with the risk of future VTE., Patients/methods: A population-based nested case-control study, comprising 383 incident VTE cases and 780 age- and sex-matched controls, was derived from the Tromsø study cohort (1994-2007). Antigen levels of ADAMTS-13 and VWF were measured in plasma samples obtained at cohort baseline. Odds ratios (ORs) with 95% CIs were estimated according to quartile cutoffs of ADAMTS-13 and VWF/ADAMTS-13 ratio determined in controls., Results: In age- and sex-adjusted analysis, ADAMTS-13 levels were inversely associated with the VTE risk, with an OR of 1.40 (95% CI, 0.99-1.99) for the lowest vs highest quartiles. The VWF/ADAMTS-13 ratio was linearly associated with the VTE risk (P for trend = .001), with an OR of 1.70 (95% CI, 1.19-2.43) for the highest vs lowest quartiles, and the association was particularly pronounced for unprovoked VTE (OR, 2.81; 95% CI, 1.65-4.81). The ORs were only slightly attenuated after additional adjustments for body mass index and C-reactive protein., Conclusions: Lowered ADAMTS-13 levels and an imbalance between ADAMTS-13 and VWF levels, reflected by an increased VWF/ADAMTS-13 ratio, were associated with an increased risk of future VTE. Our findings suggest that the VWF-ADAMTS-13 axis is involved in the pathogenesis of VTE., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: The psychologic consequences of acute venous thromboembolism (VTE) have not been investigated in depth., Objectives: We aimed to examine the association between VTE and the risk of subsequent depression., Methods: Using Danish nationwide registries, we established a population-based cohort of 64 596 individuals with incident VTE during 1996 to 2016 and a comparison cohort (n = 322 999) selected randomly from the general population and individually matched by birth year, sex, and calendar year of VTE. The participants were followed up for 3 years, and depression was defined as any hospital diagnosis of depression or ≥1 prescription for antidepressants. Incidence rates were computed as the number of events per 1000 person-years, and hazard ratios with 95% CIs were computed as estimates of the risk conferred by VTE using the comparison cohort as reference. We estimated absolute risks using cumulative incidence functions, treating death as a competing event., Results: Depression was observed in 6225 individuals after VTE and 16 363 members of the comparison cohort (incidence rates of 44.4 and 19.4 per 1000 person-years, respectively). The absolute risk of depression was 10.3% (95% CI, 10.1%-10.6%) in the VTE cohort and 5.6% (95% CI, 5.5%-5.6%) in the comparison cohort, corresponding to 4.7 excess cases of depression per 100 individuals with VTE. VTE was associated with a 2.35-fold (95% CI, 2.28-2.43) increased risk of depression compared with that in the comparison cohort. The association was attenuated after adjustments for socioeconomic status and comorbidities (hazard ratio, 1.91; 95% CI, 1.85-1.97)., Conclusion: VTE was associated with an increased risk of depression after adjustment for comorbidities., (Copyright © 2022 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary embolism is a leading cause of maternal morbidity and mortality in Western countries. In the United States, pulmonary embolism-related mortality rates have plateaued in the general population after an initial decrease in the past 20 years., Objective: This study aimed to describe the changes in pulmonary embolism-related maternal mortality rates in the United States over the past 2 decades., Study Design: In this epidemiologic study of public vital registration data (death certificates encompassing underlying and contributing causes of death) from the Centers for Disease Control and Prevention Multiple Cause of Death database (2003-2020), we identified all maternal deaths with a pulmonary embolism code listed in any position of the death certificates. We investigated the changes in annual crude pulmonary embolism-related maternal mortality rates for the years 2003 to 2020, considering the effect of the introduction of the pregnancy checkbox in death certificates on the pulmonary embolism-related maternal mortality rates., Results: Overall, 735 pulmonary embolism-related maternal deaths out of 12,871 total maternal deaths (5.7%) were recorded between 2003 and 2020; the overall pulmonary embolism-related maternal mortality rate was 1.02 (95% confidence interval, 0.95-1.10) per 100,000 live births. The pulmonary embolism-related maternal mortality rate increased from 0.93 in 2003 to 1.96 in 2020; however, when accounting for the implementation of the pregnancy checkbox in the death certificates, the trends in pulmonary embolism-related maternal mortality were largely unchanged from 2003 to 2020. The crude pulmonary embolism-related maternal mortality rates differed across maternal age groups (overall 0.61, 1.09, and 3.83 maternal deaths per 100,000 live births for those aged ≤24, 25-39, and ≥40 years, respectively) and racial/ethnicity groups (2.89, 0.47, 0.77, and 0.63 maternal deaths per 100,000 live births for Black non-Hispanics, other non-Hispanics, White non-Hispanics, and Hispanics, respectively)., Conclusion: Maternal mortality rates related to pulmonary embolism did not decrease during the period from 2003 to 2020, as opposed to mortality rates related to pulmonary embolism in the general population. More research is required to assess whether improvement in venous thromboembolism prevention and pulmonary embolism diagnosis and management strategies might reduce death owing to pulmonary embolism in this vulnerable population., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Identification of individuals with ischemic stroke at particularly high risk of venous thromboembolism (VTE) is crucial for targeted thromboprophylaxis. To guide clinical decision-making and development of risk prediction models, increased knowledge on risk factors and biomarkers is needed. Therefore, we set out to identify risk factors and predictors for VTE in people with ischemic stroke by conducting a systematic review of the literature. Medline and Embase were searched from January 1990 and onwards. Studies investigating demographic, clinical, and/or laboratory factors for stroke-related VTE were considered. Two reviewers screened all retrieved records, independently and in duplicate. Risk of bias assessments were guided by a structured framework (PROSPERO-ID: CRD42020176361). Of 4674 identified records, 26 studies were included. Twenty-six demographic, clinical, and laboratory factors associated with increased risk of stroke-related VTE after multivariable adjustments were identified. The following factors were reported by ≥2 studies: prior VTE, cancer, prestroke disability, leg weakness, increasing lesion volume of the brain infarct, infection, low Barthel Index, increasing length of hospital stay, biochemical indices of dehydration, as well as elevated levels of D-dimer, C-reactive protein, and homocysteine. The majority of the studies were of poor quality with moderate or high risk of bias. In conclusion, this systematic review informs on several potential risk factors and predictors for VTE in people with ischemic stroke. To improve risk stratification and guide development of risk prediction models, further confirmation is needed because there were few high-quality studies on each factor., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: Myocardial infarction (MI) is associated with an increased risk of venous thromboembolism (VTE). Obesity is a recognized risk factor for both MI and VTE. Whether obesity further increases the risk of VTE in MI patients is scarcely investigated., Aim: To study the joint effect of MI and obesity on the risk of VTE., Methods: Study participants (n = 29 410) were recruited from three surveys of the Tromsø Study (conducted in 1994-1995, 2001, and 2007-2008) and followed up through 2014. All incident MI and VTE cases during follow-up were recorded. Cox regression models with MI as a time-dependent variable were used to estimate hazard ratios (HRs) of VTE (adjusted for age and sex) by combinations of MI exposure and obesity status. Joint effects were assessed by calculating relative excess risk and attributable proportion (AP) due to interaction., Results: During a median of 19.6 years of follow-up, 2090 study participants experienced an MI and 784 experienced a VTE. Among those with MI, 55 developed a subsequent VTE, yielding an overall incidence rate (IR) of VTE of 5.3 per 1000 person-years (95% confidence interval [CI]: 4.1-6.9). In the combined exposure group (MI+/Obesity+), the IR was 11.3 per 1000 person-years, and the adjusted HR indicated a 3-fold increased risk of VTE (HR 3.16, 95% CI: 1.99-4.99) compared to the reference group (MI-/Obesity-). The corresponding AP was 0.46 (95% CI: 0.17-0.74)., Conclusions: The combination of MI and obesity yielded a supra-additive effect on VTE risk of which 46% of the VTE events were attributed to the interaction., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

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.

Background: Plasminogen activator inhibitor-1 (PAI-1), the main inhibitor of fibrinolysis, is frequently elevated in obesity and could potentially mediate the risk of venous thromboembolism (VTE) in obese subjects. However, whether PAI-1 is associated with VTE remains uncertain., Objective: To investigate the association between plasma PAI-1 levels and risk of future incident VTE and whether PAI-1 could mediate the VTE risk in obesity., Methods: A population-based nested case-control study, comprising 383 VTE cases and 782 age- and sex-matched controls, was derived from the Tromsø Study cohort. PAI-1 antigen levels were measured in samples collected at cohort inclusion. Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for VTE across PAI-1 tertiles., Results: The VTE risk increased dose-dependently across PAI-1 tertiles (P for trend <.001) in the age- and sex-adjusted model. The OR of VTE for the highest versus lowest tertile was 1.73 (95% CI 1.27-2.35), and risk estimates were only slightly attenuated with additional stepwise adjustment for body mass index (BMI; OR 1.59, 95% CI 1.16-2.17) and C-reactive protein (CRP; OR 1.54, 95% CI 1.13-2.11). Similar results were obtained for provoked/unprovoked events, deep vein thrombosis, and pulmonary embolism. In obese subjects (BMI of ≥30 kg/m 2 vs. <25 kg/m 2 ), PAI-1 mediated 14.9% (95% CI 4.1%-49.4%) of the VTE risk in analysis adjusted for age, sex, and CRP., Conclusion: Our findings indicate that plasma PAI-1 is associated with increased risk of future incident VTE and has the potential to partially mediate the VTE risk in obesity., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: Microvesicles (MVs) are small double-membrane encapsulated particles shed from cells. Case-control studies have reported elevated plasma levels of platelet-derived MVs (PDMVs) in patients with venous thromboembolism (VTE). However, it is not known whether high PDMV levels is a risk factor or a consequence of the acute VTE event., Objectives: To investigate the association between PDMVs in plasma and risk of future incident VTE., Methods: We performed a population-based nested case-control study with 314 VTE cases and 705 age- and sex-matched controls (from The Tromsø Study) to investigate the association between the proportion of PDMVs (PDMVs%) in plasma and risk of future incident VTE. MVs isolated from plasma sampled at baseline (i.e., before VTE) were stained for platelet markers and analyzed by flow cytometry. PDMVs% were defined as the number of PDMVs divided by the total number of MVs. Odds ratios (ORs) with 95% confidence intervals (CI) for VTE risk were estimated across quartiles of PDMVs%., Results: Subjects with PDMVs% in the highest quartile had an OR for VTE of 1.78 (95% CI: 1.21-2.64) and 1.99 (95% CI: 1.24-3.26) for provoked VTE, compared to those in the lowest quartile. The association was moderately affected by multivariable adjustment for age, sex, body mass index, C-reactive protein, platelet count, and cancer. The OR for VTE was higher when the time between blood sampling and event was shorter., Conclusions: Our results show that high proportions of PDMVs are associated with future risk of incident VTE and imply a role of platelet activation in the pathogenesis of VTE., (© 2022 International Society on Thrombosis and Haemostasis.)

Incidence of venous thromboembolism (VTE) risk varies by age and sex. Some studies have reported overall higher risk in men, especially when VTEs triggered by female reproductive factors are excluded. However, higher mortality rates in men may have led to overestimation of lifetime VTE risk in men compared with women. Therefore, we estimated the lifetime risk of VTE in men and women in a Danish, nationwide cohort, taking into account the competing risk of death. Within the population of Denmark (> 5 million persons), all first-time VTEs occurring in 1995-2016 were identified from the Danish National Patient Registry covering all Danish hospitals. The cumulative incidences of VTE were estimated in men and women with age as timescale, taking into account the competing risk of death. Estimated lifetime risk was defined as cumulative incidence at age 100. In a simulation study, we excluded the proportion of female cases that could be attributed to reproductive risk factors and re-estimated the cumulative incidence. We identified 123,543 incident VTEs. The cumulative incidence of VTE was 1.9% in women and 1.3% in men at age 50, 4.3% in women and 4.4% in men at age 70, and 9.3% in women and 8.1% in men at age 100. After accounting for VTEs attributed to reproductive factors, the corresponding incidences in women were 1.2% at age 50, 3.2% at age 70, and 8.2% at age 100. In conclusion, the estimated lifetime risk of VTE was slightly higher in women than in men when accounting for competing risk of death. Our simulation study suggested that reproductive risk factors contribute modestly to the estimated lifetime VTE risk in women., (© 2021. The Author(s).)

Background: Negatively charged procoagulant phospholipids, phosphatidylserine (PS) in particular, are vital to coagulation and expressed on the surface membrane of extracellular vesicles. No previous study has investigated the association between plasma procoagulant phospholipid clotting time (PPL CT ) and future risk of venous thromboembolism (VTE)., Objectives: To investigate the association between plasma PPL CT and the risk of incident VTE in a nested case-control study., Methods: We conducted a nested case-control study in 296 VTE patients and 674 age- and sex-matched controls derived from a general population cohort (The Tromsø Study 1994-2007). PPL CT was measured in platelet-free plasma using a modified factor Xa-dependent clotting assay. Logistic regression was used to estimate odds ratio (OR) with 95% confidence intervals (CI) for VTE with PPL CT modelled as a continuous variable across quartiles and in dichotomized analyses., Results: There was a weak inverse association between plasma PPL CT and risk of VTE per 1 standard deviation increase of PPL CT (OR 0.93, 95% CI 0.80-1.07) and when comparing those with PPL CT in the highest quartile (OR 0.89, 95% CI 0.60-1.30) with those in the lowest quartile. Subjects with PPL CT >95th percentile had substantially lowered OR for VTE (OR 0.35, 95% CI 0.13-0.81). The inverse association was stronger when the analyses were restricted to samples taken shortly before the event. The risk estimates by categories of plasma PPL CT were similar for deep vein thrombosis and pulmonary embolism., Conclusion: Our findings suggest that high plasma PPL CT is associated with reduced risk of VTE., (© 2021 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Several case-control studies have reported elevated plasma von Willebrand factor (VWF) levels in patients with venous thromboembolism (VTE) compared with controls. However, because few studies have investigated the association in a prospective design, it is unclear whether elevated plasma VWF is a risk factor or a consequence of the VTE event. Therefore, we aimed to investigate the prospective association between plasma VWF levels and risk of VTE, as well as to perform subgroup analyses of deep vein thrombosis (DVT) and pulmonary embolism. We established a population-based nested case-control study of 414 VTE cases and 843 age- and sex-matched controls based on the Tromsø study cohort (1994-2007). Blood samples were collected at cohort baseline (1994-1995). Odds ratios (ORs) with 95% confidence intervals (CIs) for VTE were estimated across quartiles of VWF levels. We found that the risk of VTE increased linearly across quartiles of VWF levels (P for trend = .023). Participants with VWF in the highest quartile had an OR of 1.45 (95% CI, 1.03-2.03) for VTE compared with those in the lowest quartile. The association was strongest for unprovoked VTE (OR, 2.74; 95% CI, 1.66-4.54) and unprovoked DVT in particular (OR, 6.73; 95% CI, 3.07-14.76). Further adjustment for body mass index, C-reactive protein, hypertension, estrogen use, and smoking had a modest effect on the risk estimates. To conclude, we found a dose-dependent relationship between plasma VWF levels and future risk of incident VTE, and unprovoked events in particular. Our findings suggest that VWF may represent a promising biomarker for future risk of incident VTE., (© 2021 by The American Society of Hematology.)

Background: The role of combined prothrombotic genotypes in cancer-related venous thromboembolism (VTE) is scarcely studied. We aimed to investigate the impact of a 5-single nucleotide polymorphism (SNP) score on the risk of VTE in patients with and without cancer using a population-based case-cohort., Methods: Cases with a first VTE (n = 1493) and a subcohort (n = 13 072) were derived from the Tromsø Study (1994-2012) and the Nord-Trøndelag Health Study (1995-2008). Five SNPs previously reported as a risk score were genotyped: ABO (rs8176719), F5 (rs6025), F2 (rs1799963), FGG (rs2066865), and F11 (rs2036914). Hazard ratios (HRs) for VTE were estimated according to cancer status and the number of risk alleles in the 5-SNP score (0-1, 2-3, and ≥4 alleles)., Results: During a median follow-up of 12.3 years, 1496 individuals were diagnosed with cancer, of whom 232 experienced VTE. The VTE risk increased with the number of risk alleles in the 5-SNP score among subjects without and with cancer. In cancer-free subjects, the HR was 2.17 (95% confidence interval [CI] 1.79-2.62) for ≥4 versus 0-1 risk alleles. In cancer patients, the corresponding HR was 1.93 (95% CI 1.28-2.91). The combination of cancer and ≥4 risk alleles yielded a 17-fold (HR 17.1, 95% CI 12.5-23.4) higher risk of VTE compared with cancer-free subjects with 0-1 risk alleles., Conclusion: The risk of VTE increases with the number of prothrombotic risk alleles in subjects with and without cancer, and the combination of prothrombotic risk alleles and cancer leads to a highly elevated risk of VTE., (© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: Atrial fibrillation (AF) is associated with increased risk of ischemic stroke and all-cause mortality. Patients with AF are also at increased risk of venous thromboembolism (VTE), but information on how AF impacts VTE-related mortality is scarce., Objectives: To investigate the impact of AF on all-cause mortality in subjects with and without a thromboembolic event (VTE or ischemic stroke)., Methods: We followed 29 833 participants from the Tromsø study (1994-2008) through 2013 and recorded all deaths during follow-up. Incident AF, VTE, and ischemic stroke were registered as time-dependent exposures. We calculated mortality rates (MRs) by exposure during follow-up and obtained hazard ratios (HRs) for death with 95% confidence intervals (CIs)., Results: A total of 2087 AF cases, 756 VTEs, and 1279 ischemic strokes were registered during a median follow-up of 18.7 years, and 4797 people (16.1%) died. The age-adjusted MR for participants without any event was 1.19 per 100 person-years (PY; 95% CI, 1.15-1.23). Compared to these participants, subjects with the joint AF + VTE exposure had a 3.7-fold increased risk of death (HR, 3.67; 95% CI, 2.77-4.66) in age- and sex-adjusted analyses, similar to the risk observed for VTE alone (HR, 3.76; 95% CI, 3.28-4.30). Participants with stroke had a 2.9-fold increased risk of death (HR, 2.85; 95% CI, 2.56-3.18), and the risk was further increased in participants with both AF and stroke (HR, 4.38; 95% CI, 3.85-4.98)., Conclusions: AF was significantly associated with increased risk of death in participants with incident stroke. In contrast, concomitant AF was not associated with excess mortality risk in VTE patients., (© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Venous thromboembolism (VTE) is a frequent complication in patients with cancer. Homozygous carriers of the fibrinogen gamma gene (FGG) rs2066865 have a moderately increased risk of VTE, but the effect of the FGG variant in cancer is unknown. We aimed to investigate the effect of the FGG variant and active cancer on the risk of VTE. Cases with incident VTE (n=640) and a randomly selected age-weighted sub-cohort (n=3,734) were derived from a population-based cohort (the Tromsø study). Cox-regression was used to estimate hazard ratios (HR) with 95% confidence intervals (CI) for VTE according to categories of cancer and FGG In those without cancer, homozygosity at the FGG variant was associated with a 70% (HR 1.7, 95% CI: 1.2-2.3) increased risk of VTE compared to non-carriers. Cancer patients homozygous for the FGG variant had a two-fold (HR 2.0, 95% CI: 1.1-3.6) higher risk of VTE than cancer patients without the variant. Moreover, the six-months cumulative incidence of VTE among cancer patients was 6.4% (95% CI: 3.5-11.6) in homozygous carriers of FGG and 3.1% (95% CI: 2.3-4.7) in those without risk alleles. A synergistic effect was observed between rs2066865 and active cancer on the risk of VTE (synergy index: 1.81, 95% CI: 1.02-3.21, attributable proportion: 0.43, 95% CI: 0.11-0.74). In conclusion, homozygosity at the FGG variant and active cancer yielded a synergistic effect on the risk of VTE., (Copyright© 2020 Ferrata Storti Foundation.)

Background: The risk of venous thromboembolism (VTE) is increased after a myocardial infarction (MI). Some prothrombotic genotypes associated with VTE have also been associated with risk of MI. Whether prothrombotic single-nucleotide polymorphisms (SNPs) further increase the risk of VTE in MI patients is scarcely investigated., Aim: To study the combined effect of MI and prothrombotic SNPs on the risk of VTE., Methods: Cases with incident VTE (n = 641) and a randomly sampled subcohort weighted for age (n = 1761) were identified from the 4 to 6 surveys of the Tromsø Study (1994-2012). DNA was genotyped for rs8176719 ( ABO ), rs6025 ( F5 ), rs1799963 ( F2 ), rs2066865 ( FGG ), and rs2036914 ( F11 ). Hazard ratios (HRs) for VTE with 95% confidence intervals (CIs) were estimated by categories of risk alleles and MI status., Results: Patients with MI had a 1.4-fold increased risk of VTE, and adjustments for the 5 SNPs, either alone or in combination, did not affect this relationship (adjusted HR, 1.52; 95% CI, 1.12-2.07). In subjects without MI, an increased risk of VTE was observed for each of the individual SNPs (≥1 vs. 0 risk alleles), and the risk increased linearly with increasing number of risk alleles in the 5-SNP score. The combination of MI and prothrombotic genotypes, either as individual SNPs or in the 5-SNP score, did not result in an excess risk of VTE., Conclusion: The relationship between MI and VTE was not explained by these 5 prothrombotic genotypes. Prothrombotic genotypes did not yield an excess risk of VTE in patients with MI., (© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis.)

Background: Chronic obstructive pulmonary disease (COPD) is associated with risk of venous thromboembolism (VTE). It remains unknown whether individual respiratory symptoms and lowered oxygen saturation (SpO 2 ), individually and in combination with COPD, affect the risk of VTE., Objectives: To investigate whether measures of respiratory impairments including respiratory symptoms and SpO 2 , individually and combined with COPD, were associated with an increased risk of VTE., Methods: Spirometry, SpO 2 , and self-reported respiratory symptoms were collected in 8686 participants from the fifth (2001-2002) and sixth (2007-2008) surveys of the Tromsø Study. Incident VTE events were registered from the date of inclusion to December 31, 2016. Cox regression models with exposures and confounders as time-varying covariates (for repeated measurements) were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for VTE., Results: During a median follow-up of 9.1 years, 330 participants developed incident VTE. Subjects with SpO 2  ≤ 96% (lowest 20th percentile) had a 1.5-fold higher risk of VTE (adjusted HR, 1.48; 95% CI, 1.13-1.93) compared with those with SpO 2  ≥ 98%. Severe respiratory symptoms (dyspnea, cough, and phlegm) were associated with a 1.4- to 2.0-fold higher risk of VTE compared with no such symptoms. COPD, combined with respiratory symptoms or lowered SpO 2 , had an additive effect on the VTE risk., Conclusions: Lowered SpO 2 and severe respiratory symptoms were associated with increased VTE risk. COPD combined with respiratory impairments had an additive effect on VTE risk, and may suggest particular attention on VTE preventive strategies in COPD patients with respiratory impairments., (© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis.)

Background: Cardiorespiratory fitness (CRF) is a strong predictor of future arterial cardiovascular disease and premature mortality. However, there are limited data on the association between CRF and the risk of incident venous thromboembolism (VTE)., Objectives: To investigate whether estimated CRF (eCRF) was associated with the risk of incident VTE in a cohort recruited from the general population., Methods: Participants (n = 10 393) from the sixth survey of the Tromsø Study (2007-08) were included, and incident VTEs were recorded up to 31 December 2016. CRF was estimated in sex-specific algorithms based on age, waist circumference, resting heart rate, and self-reported physical activity. Hazard ratios (HRs) with 95% confidence intervals (CIs) of VTE according to categories of eCRF were estimated in Cox regression models adjusted for sex with age as timescale. The impact of weight status was evaluated in analyses stratified by weight category., Results: There were 176 incident VTEs during follow-up. Compared with individuals with eCRF < 85% of age-predicted, those with eCRF of 85% to 100% and >100% of age-predicted had 46% (HR 0.54; 95% CI 0.39-0.77) and 67% (HR 0.33; 95% CI 0.20-0.54) lower VTE risk, respectively. Compared with overweight/obese individuals with eCRF < 85% of age-predicted, overweight/obese individuals with eCRF ≥ 85% had 50% (HR 0.50, 95% CI 0.35-0.74) lower risk, and normal weight individuals with eCRF ≥ 85% had 55% (HR 0.45, 95% CI 0.30-0.68) lower risk., Conclusions: Higher eCRF was associated with lower risk of incident VTE. The association was independent of weight categories, suggesting that higher eCRF may modify the association between obesity and VTE., (© 2019 International Society on Thrombosis and Haemostasis.)

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

Background: Animal and observational studies have suggested a pathophysiological role for complement in venous thromboembolism (VTE), but the initiating mechanisms are unknown. Mannose-binding lectin (MBL) bound to altered host cells leads to activation of the lectin complement pathway, and both high and low MBL levels have been implicated in the pathophysiology of cardiovascular disease., Objectives: To investigate the association between plasma MBL levels and future risk of incident VTE., Methods: We conducted a nested case-control study in 417 VTE patients and 849 age-matched and sex-matched controls derived from the general population (Tromsø Study). Plasma MBL levels were measured using enzyme-linked immunosorbent assay. Logistic regression models were used to estimate odds ratio (OR) for VTE across quartiles of plasma MBL levels., Results: Subjects with plasma MBL levels in the lowest quartile (<435 ng/mL) had a reduced OR for overall VTE (OR 0.79, 95% confidence interval [CI]: 0.56-1.10) and for DVT (OR 0.70, 95% CI: 0.47-1.04) compared to those with MBL in the highest quartile (≥2423 ng/mL) after multivariable adjustments. For VTE, DVT, and pulmonary embolism (PE) the ORs decreased substantially with decreasing time between blood sampling and VTE event., Conclusions: Our findings suggest that low plasma MBL levels are associated with reduced risk of VTE, and DVT in particular., (© 2019 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)