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Helle Jørgensen,1– 3 Erzsébet Horváth-Puhó,2 Kristina Laugesen,2 Sigrid K Braekkan,1,3 John-Bjarne Hansen,1,3 Henrik Toft Sørensen2 1Thrombosis Research Center (TREC), Department of Clinical Medicine, UiT, The Arctic University of Norway, Tromsø, Norway; 2Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University Hospital and Aarhus University, Aarhus, Denmark; 3Division of Internal Medicine, University Hospital of North Norway, Tromsø, NorwayCorrespondence: Helle Jørgensen, Email helle.jorgensen@uit.noBackground: Venous thromboembolism (VTE) is associated with increased risk of disability pension. How socioeconomic status (SES) impacts the risk of disability pension after a VTE is unknown. The aim of this nationwide population based cohort study to investigate the interaction between SES and incident VTE on the risk of subsequent disability pension.Methods: Using Danish national medical and administrative databases, we established a nationwide cohort of 41,781 individuals aged 25– 65 years with incident VTE during 1995– 2016 and a comparison cohort (n=208,905) from the general population matched on year of birth, sex, and calendar year of VTE. We computed incidence rates (IRs) as the number of disability pension events per 1000 person-years at risk and measured the interaction between VTE and levels of SES (high, medium, low) on an additive scale by calculating interaction contrasts (difference in IR difference).Results: Among individuals with high SES, the disability pension IR per 1000 person-years was 5.4 (95% CI: 4.8– 6.1) in the VTE cohort and 1.6 (95% CI: 1.5– 1.7) in the comparison cohort (IR difference 3.8). The corresponding disability pension IR in individuals with low SES was 55.1 (95% CI: 52.1– 58.1) in the VTE cohort and 26.1 (95% CI: 25.1– 27.1) in the comparison cohort (IR difference 24.0). An interaction contrast of 25.1 indicated that interaction accounted for 45.6% (25.1/55.1) of the disability pension IR in individuals with VTE and low SES.Conclusion: SES and VTE interact to increase the risk of disability pension after VTE beyond their independent effects.Keywords: education, employment, income, deep-vein thrombosis, pulmonary embolism, burden of illness

Essentials Discovery of predictive biomarkers of venous thromboembolism (VTE) may aid risk stratification. A case-control study where plasma was sampled before the occurrence of VTE was established. We generated untargeted plasma proteomic profiles of 200 individuals by use of mass spectrometry. Assessment of the biomarker potential of 501 proteins yielded 46 biomarker candidates.AbstractBackground Prophylactic anticoagulant treatment may substantially reduce the incidence of venous thromboembolism (VTE) but entails considerable risk of severe bleeding. Identification of individuals at high risk of VTE through the use of predictive biomarkers is desirable in order to achieve a favorable benefit-to-harm ratio. Objective We aimed to identify predictive protein biomarker candidates of VTE. Methods We performed a case-control study of 200 individuals that participated in the Tromsø Study, a population-based cohort, where blood samples were collected before the VTE events occurred. Untargeted tandem mass tag-synchronous precursor selection-mass spectrometry (TMT-SPS-MS3)-based proteomic profiling was used to study the plasma proteomes of each individual. Results Of the 501 proteins detected in a sufficient number of samples to allow multivariate analysis, 46 proteins were associated with VTE case-control status with P-values below the 0.05 significance threshold. The strongest predictive biomarker candidates, assessed by statistical significance, were transthyretin, vitamin K-dependent protein Z and protein/nucleic acid deglycase DJ-1. Conclusions Our untargeted approach of plasma proteome profiling revealed novel predictive biomarker candidates of VTE and confirmed previously reported candidates, thereby providing conceptual support for the validity of the study. A larger nested case-control study will be conducted to validate our findings.

Hilde Jensvoll,1,2 Marianne T Severinsen,3,4 Jens Hammerstrøm,5 Sigrid K Brækkan,1,2 Søren R Kristensen,4,6 Suzanne C Cannegieter,7 Kristine Blix,1,2 Anne Tjønneland,8 Frits R Rosendaal,1,7,9 Olga Dziewiecka,1 Kim Overvad,10,11 Inger Anne Næss,12 John-Bjarne Hansen1,21Department of Clinical Medicine, KG Jebsen – Thrombosis Research and Expertise Center (TREC), UiT – The Arctic University of Norway, 2Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway; 3Department of Hematology, Aalborg University Hospital, 4Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 5Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; 6Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark; 7Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; 8Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark; 9Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands; 10Department of Cardiology, Aalborg University Hospital, Aalborg, 11Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark; 12Department of Hematology, Trondheim University Hospital, Trondheim, NorwayBackground: Although venous thromboembolism (VTE) is a known common complication in cancer patients, there is limited knowledge on patient-related and cancer-specific risk factors in the general population. The Scandinavian Thrombosis and Cancer (STAC) Cohort was established by merging individual data from three large Scandinavian cohorts (The Tromsø Study, the second Nord-Trøndelag Health Study, and the Danish Diet, Cancer and Health Study). Here, we present the profile of the STAC cohort and provide age-specific incidence rates of VTE and cancerMethods: The STAC cohort includes 144,952 subjects aged 19–101 years without previous VTE or cancer. Baseline information collected in 1993–1997 included physical examination, self-administered questionnaires, and blood samples. Validated VTE events and cancer diagnoses were registered up to 2007–2012.Results: There were 2,444 VTE events (1.4 per 1,000 person-years [PY]) during follow-up, and the incidence increased exponentially from 0.3 per 1,000 PY in subjects aged 20–29 years to 6.4 per 1,000 PY in subjects aged 80+. Overall, 51% of the VTE events were provoked, and cancer was the most common provoking factor (19%), followed by immobilization and surgery (both 15%). In total, 19,757 subjects developed cancer during follow-up (9.8 per 1,000 PY), and the 5-year age-specific incidence rates of cancer were coherent with corresponding rates from the Norwegian Cancer Registry.Conclusion: The STAC cohort will provide a unique opportunity to explore the epidemiology and impact of genetic and environmental patient-related and cancer-specific risk factors for VTE in the general population.Keywords: venous thromboembolism, incidence rates, person-years, pulmonary embolism, population-based cohort, prospective, cancer

An association between body height and venous thromboembolism (VTE) has been suggested by previous studies including males only. The aim of this prospective cohort study was to investigate the sex-specific impact of body height on risk of VTE in a general population. Risk factors, including body height and weight, were registered for 26,727 subjects aged 25-96 years who participated in the Tromsø Study (Norway) in 1994-1995. Incident VTE events were registered through September 1, 2007. There were 462 VTE events during a median 12.5 years of follow-up. Body height was a risk factor for VTE in men, but not in women. Multivariable hazard ratios per 10 cm, adjusted for age, body mass index, diabetes, smoking, and hormone therapy (women), were 1.34 (95% confidence interval: 1.09, 1.64) for men and 1.13 (95% confidence interval: 0.91, 1.40) for women. Hazard ratios by quartiles of body height revealed that men in the upper quartile (>181 cm) had a 1.99-fold (95% confidence interval: 1.35, 2.92) increased risk of VTE compared with men in the lowest quartile (<173 cm) (P for trend across quartiles = 0.002). There was no significant trend (P = 0.2) across quartiles of body height for women. Study findings revealed that body height is a sex-specific risk factor for VTE in men. [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  International guidelines are increasingly recommending direct oral anticoagulants (DOACs) as the first-line treatment for cancer-associated thrombosis (CAT). However, data regarding treatment patterns and adherence to guidelines in patients with CAT are scarce. Objectives  This study aimed to explore anticoagulant treatment patterns in patients with CAT and to calculate the incidence rates of bleeding events. Methods  Patients ≥18 years with active cancer and a first-time venous thromboembolism between 2005 and 2020 were identified through the Venous T hrombosis R egistry in Østf OL d Hospita L . Outcome measures were patterns of anticoagulant treatment during the study period and bleeding events. We calculated overall incidence rates per 100 person-years and 6- and 12-month cumulative incidence of major and clinically relevant nonmajor bleeding (CRNMB) during anticoagulant treatment. Results  Median age of 842 CAT patients at the time of thrombosis was 69 years (interquartile range 61-77), and 443 (52.6%) were men. In total, 526 patients (62.5%) had pulmonary embolism and 255 (30.3%) had deep vein thrombosis. Low molecular weight heparin (LMWH) was prescribed to 713 (85.8%) patients, whereas 64 (7.7%) received DOACs and 54 (6.5%) received vitamin K antagonists as the initial anticoagulant treatment. Prescription of DOACs as initial treatment increased from 3.0% in 2013/2014 to 18.0% in 2019/2020. The incidence rate of major bleeding was 6.9 (95% confidence interval [CI] 5.2-9.2) and 10.1 (95% CI 8.0-12.9) in CRNMB. Conclusion  Most patients were treated with LMWH. However, a gradual shift in treatment toward DOACs was observed. Overall, bleeding complications were rare and comparable to those reported in randomized trials., Competing Interests: Conflict of Interest C.T.J. reports lecture honoraria from Bayer. W.G. reports fees for participation in Advisory board from Amgen, Novartis, Pfizer, Principia Biopharma Inc—a Sanofi Company, Sanofi, SOBI, Grifols, UCB, Argenx, Cellphire, Alpine, Kedrion, HiBio, Hutchmed; lecture honoraria from Amgen, Novartis, Pfizer, Bristol Myers Squibb, SOBI, Grifols, Sanofi and Bayer; research grants from Bayer, BMS/Pfizer and UCB. H.H.P. received honoraria from Sanofi and Novartis. A.S. received honoraria from Janssen; participation in Advisory board in Astra Zeneca; leader of the Norwegian Prostate Pathway Group and leadership participation in Norwegian guidelines for prostate cancer. All other authors disclose no conflict of interest., (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:  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: There are limited data on the long-term risk of venous thromboembolism (VTE) after high-risk isolated superficial vein thrombosis (iSVT) treated with anticoagulants., Objectives: To determine the short- and long-term risk of VTE and iSVT recurrence after cessation of anticoagulant treatment and to calculate 45-day cumulative bleeding incidence in patients with iSVT., Methods: Between January 2014 and December 2021, 229 patients with high-risk iSVT (ie, thrombus length ≥5cm), without active cancer, with no history of VTE or iSVT, and who had received anticoagulant treatment for the iSVT were identified through the Venous Thrombosis Registry in Østfold Hospital (TROLL registry), Norway. Cumulative incidences of VTE and iSVT recurrence, as well as cumulative incidences of major and clinically relevant nonmajor bleeding events, were assessed., Results: Median age was 60 years (IQR, 48-71), and 125 (55%) were women. Most patients were treated with direct oral anticoagulants (74%), and of these, 79% received a dose of rivaroxaban 10 mg daily. Low-molecular-weight heparin was given to 26% of the patients. The 1- and 5-year cumulative incidences of VTE after iSVT were 4.6% (95% CI, 2.5-8.3) and 15.9% (95% CI, 10.8-22.9), respectively. Further, the 1- and 5-year cumulative incidences of iSVT recurrence were 6.5% (95% CI, 3.9-10.7) and 15.9% (95% CI, 10.8-23.1), respectively. The overall 45-day cumulative incidence of major and clinically relevant nonmajor bleeding events was 0.4% (95% CI, 0.06-3.06) and 1.8% (95% CI, 0.7-4.6), respectively. No major bleeding events were observed in patients treated with direct oral anticoagulants., Conclusion: Despite anticoagulant treatment, the risk of VTE after high-risk iSVT was substantial, while bleeding complications were low., Competing Interests: Declaration of competing interests C.T.J. reports lecture honoraria from Bayer. W.G. reports fees for participation on advisory boards from Amgen, Novartis, Pfizer, Principia Biopharma Inc (a Sanofi Company), Sanofi, SOBI, Griffols, UCB, and Argenx; lecture honoraria from Bayer, Amgen, Novartis, Pfizer, Bristol Myers Squibb, SOBI, Griffols, and Sanofi; and research grants from Bayer and BMS/Pfizer. E.T. reports fees from Novartis, SOBI, Alexion, Janssen, BiGene, AbbVie, Grifols, Jazz, Takeda, and Incyte. H.H.P. reports fees from Novartis and Sanofi. M.T., E.F., and S.K.B. have no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

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: Isolated distal deep vein thrombosis (IDDVT) is a common presentation of deep vein thrombosis. There are limited data on the long-term risk of recurrence after IDDVT., Objectives: We aimed to determine the short- and long-term incidence of venous thrombosis (VTE) recurrence after cessation of anticoagulation and the 3-month incidence of bleeding during anticoagulant treatment in patients with IDDVT., Methods: Between January 2005 and May 2020, 475 patients with IDDVT and without active cancer were identified from the Venous Thrombosis Registry in Østfold Hospital, which is an ongoing registry of consecutive patients with VTE at Østfold Hospital, Norway. Major and clinically relevant, nonmajor bleeding as well as recurrent VTE were registered, and the cumulative incidences of these events were assessed., Results: The median age of the patients was 59 years (IQR, 48-72 years), 243 (51%) patients were women, and 175 events (36.8%) were classified as unprovoked. The 1-, 5-, and 10-year cumulative incidences of recurrent VTE were 5.6% (95% CI, 3.7-8.4), 14.7% (95% CI, 11.1-19.4), and 27.2% (95% CI, 21.1-34.5), respectively. The recurrence rates were higher for unprovoked IDDVT than for provoked IDDVT. Among the recurrent events, 18 (29%) were pulmonary embolisms and 21 (33%) were proximal deep vein thromboses. The 3-month cumulative incidence of major bleeding was 1.5% (95% CI, 0.7-3.1) overall and 0.8% (95% CI, 0.2-3.1) when restricted to patients treated with direct oral anticoagulants., Conclusion: Despite initial treatment, the long-term risk of VTE recurrence after first-time IDDVT is high. The bleeding rates during anticoagulation, particularly with direct oral anticoagulants, were acceptably low., Competing Interests: Declaration Of Competing Interests C.T.J. reports lecture honoraria from Bayer. W.G. reports fees for participation in the advisory board of Amgen, Novartis, Pfizer, Principia Biopharma Inc (a Sanofi company), Sanofi, SOBI, Griffols, UCB, Argenx, and Cellphire and lecture honoraria from Bayer, Amgen, Novartis, Pfizer, Bristol Myers Squibb, SOBI, Griffols, and Sanofi. E.T. reports lecture honoraria from BMS, Pfizer, Bayer, Alexion, Novartis, AOP, Incyte, Grifols, SOBI, Takeda, and Janssen. H.H.P. reports fees from Novartis and Sanofi. M.T., E.F., and S.K.B. disclose no conflict of interest., (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.)

(1) Background: The current diagnostic algorithm for acute pulmonary embolism (PE) is associated with the overuse of CT pulmonary angiography (CTPA). An additional highly specific blood test could potentially lower the proportion of patients with suspected PE that require CTPA. The aim was to summarize the literature on the diagnostic performance of biomarkers of patients admitted to an emergency department with suspected acute PE. (2) Methods: Medline and Embase databases were searched from 1995 to the present. The study selection process, data extraction, and risk of bias assessment were conducted by two reviewers. Eligibility criteria accepted all blood biomarkers except D-dimer, and CTPA was used as the reference standard. Qualitative data synthesis was performed. (3) Results: Of the 8448 identified records, only 6 were included. Eight blood biomarkers were identified, of which, three were investigated in two separate studies. Red distribution width and mean platelet volume were reported to have a specificity of ≥ 90% in one study, although these findings were not confirmed by other studies. The majority of the studies contained a high risk of selection bias. (4) Conclusions: The modest findings and the uncertain validity of the included studies suggest that none of the biomarkers identified in this systematic review have the potential to improve the current diagnostic algorithm for acute PE by reducing the overuse of CTPA.

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.)

The complement system appears to be involved in the pathogenesis of venous thromboembolism (VTE). We investigated the association of complement factors (CF) B, D, and the alternative pathway convertase, C3bBbP, measured at inclusion, with the risk of future VTE in a nested case-control study; 380 VTE patients and 804 age- and sex-matched controls derived from the Tromsø study. Odds ratios (ORs) with 95% confidence intervals (95% CI) for VTE across tertiles of CF concentrations were estimated using logistic regression. There was no association between CFB or CFD and risk of future VTE. Higher levels of C3bBbP gave an increased risk of provoked VTE; subjects in Q4 had a 1.68-fold higher OR compared with Q1 in the age-, sex- and BMI-adjusted model (OR 1.68; 95% CI 1.08-2.64). There was no increased risk of future VTE in individuals with higher levels of complement factors B or D of the alternative pathway. Increased levels of the alternative pathway activation product, C3bBbP, showed an association with future risk of provoked VTE., (Copyright © 2023 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.)

Background: Hand grip strength (HGS), a common proxy of whole-body muscular strength, is associated with a wide range of adverse health outcomes and mortality. However, there are limited data on the association between HGS and risk of venous thromboembolism (VTE)., Objectives: We aimed to investigate the association between HGS and risk of incident VTE in a population-based cohort., Methods: Participants ( n  = 13,704) from the fourth to seventh surveys of the Tromsø study (Tromsø4-Tromsø7, enrollment: 1994-2016) were followed throughout 2020, and all incident VTEs were recorded. HGS of the nondominant hand was measured using a Martin Vigorimeter (Tromsø4-Tromsø6) and a Jamar Digital Dynamometer (Tromsø7). Hazard ratios (HRs) for VTE with 95% confidence intervals (CIs) according to weak HGS (less than 25th percentile) versus normal HGS (25th percentile or greater) were estimated using Cox regression models and adjusted for age, sex, body height, body mass index, physical activity, cardiovascular disease, and cancer., Results: During a median of 6.5 years of follow-up, 545 incident VTEs occurred. Participants with weak HGS had a 27% higher risk of VTE (HR, 1.27; 95% CI, 1.03-1.57) compared to those with normal HGS. Subgroup analyses revealed that the point estimates were higher for unprovoked VTE (HR, 1.35; 95% CI, 0.96-1.91) and deep vein thrombosis (DVT; HR, 1.52; 95% CI, 1.14-2.01). Similar results were found in analyses restricted to men, women, and elderly (aged greater than 75 years)., Conclusion: A weak HGS was associated with increased risk of VTE, and particularly unprovoked VTE and isolated DVT. Our findings suggest that weak muscle strength may be a risk factor for VTE., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background:  A high mean platelet volume (MPV), a marker of increased platelet reactivity, is a risk factor for venous thromboembolism (VTE). Whether established prothrombotic single nucleotide polymorphisms (SNPs) further increase the VTE risk in subjects with high MPV because of biological interaction remains unknown., Aim:  To investigate the joint effect of high MPV and prothrombotic genotypes, comprising a 5-SNP genetic risk score (GRS), on the risk of VTE in a population-based case-cohort., Methods:  Incident VTE cases ( n  = 653) and a subcohort ( n  = 1,774) were derived from the Tromsø Study (1994-2012). DNA was genotyped for rs8176719 ( ABO ), rs6025 ( F5 ), rs1799963 ( F2 ), rs2036914 ( F11 ), and rs2066865 ( FGG ). Hazard ratios (HRs) for VTE with 95% confidence intervals (CIs) were estimated according to predefined MPV-strata (<8.5, 8.5-9.5, ≥9.5 fL) and number of risk alleles for each individual SNP and the GRS (0-1, 2-3, ≥4 risk alleles) in models adjusted for age, sex, body mass index, and platelet count., Results:  The combination of high MPV and risk alleles, either as individual SNPs or the GRS, had an additive effect on VTE risk. Compared with subjects with MPV <8.5 fL and 0-1 risk allele, those with high MPV (≥9.5 fL) and ≥4 risk alleles had HRs of 2.80 (95% CI: 1.77-4.43) for overall VTE and 4.60 (95% CI: 2.20-9.60) for unprovoked events, respectively, but there was no supra-additive effect on risk estimates., Conclusion:  The combination of high MPV and prothrombotic genotypes had an additive effect on VTE risk, suggesting there is no biological interaction between these risk factors in the pathogenesis of VTE., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources., Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations., Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis., Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

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.

Purpose: The incidence of venous thromboembolism (VTE) is expected to increase over the next decades, further increasing its substantial impact on patients and health care resources. Registries have the benefit of reporting real-world data without excluding clinically important subgroups. Our aim was to describe a Norwegian VTE registry and to provide descriptive data on the population and management., Registry Population: The Venous Thrombosis Registry in Østfold Hospital (TROLL) is an ongoing registry of consecutive patients diagnosed with, treated, and/or followed up for VTE at Østfold Hospital, Norway, since 2005. Baseline and follow-up data, including demographics, clinical features, risk factors, diagnostic procedures, classification of VTE, and treatment were collected during hospitalization, and at scheduled outpatient visits., Findings to Date: From January 2005 to June 2021, 5037 patients were eligible for research in TROLL. Median age was 67 years (interquartile range, 55-77), and 2622 (52.1%) were male. Of these, 2736 (54.3%) had pulmonary embolism (PE), 2034 (40.4%) had deep vein thrombosis (DVT), and 265 (5.3%) had upper-extremity DVT or splanchnic or cerebral sinus vein thrombosis. In total, 2330 (46.3%) were classified as unprovoked VTE, and 1131 (22.5%) had cancer. Direct oral anticoagulants were the most frequent therapeutic agents (39.3%) followed by low-molecular-weight heparins (30.4%) and vitamin K antagonists (30.3%). Outpatient treatment for PE increased from 4% in 2005 to 23% in 2019., Future Plans: TROLL is a population-based ongoing registry that represents a valuable source of real-world data that will be used for future research on the management and outcomes of VTE., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background:  The proportion of venous thromboembolism (VTE) events that can be attributed to established prothrombotic genotypes has been scarcely investigated in the general population. We aimed to estimate the proportion of VTEs in the population that could be attributed to established prothrombotic genotypes using a population-based case-cohort., Methods:  Cases with incident VTE ( n  = 1,493) and a randomly sampled subcohort ( n  = 13,069) were derived from the Tromsø Study (1994-2012) and the Nord-Trøndelag Health (HUNT) study (1995-2008). DNA samples were genotyped for 17 single-nucleotide polymorphisms (SNPs) associated with VTE. Hazard ratios with 95% confidence intervals (CIs) were estimated in Cox regression models. Population-attributable fractions (PAFs) with 95% bias-corrected CIs (based on 10,000 bootstrap samples) were estimated using a cumulative model where SNPs significantly associated with VTE were added one by one in ranked order of the individual PAFs., Results:  Six SNPs were significantly associated with VTE (rs1799963 [Prothrombin], rs2066865 [FGG], rs6025 [FV Leiden], rs2289252 [F11], rs2036914 [F11], and rs8176719 [ABO]). The cumulative PAF for the six-SNP model was 45.3% (95% CI: 19.7-71.6) for total VTE and 61.7% (95% CI: 19.6-89.3) for unprovoked VTE. The PAF for prothrombotic genotypes was higher for deep vein thrombosis (DVT; 52.9%) than for PE (33.8%), and higher for those aged <70 years (66.1%) than for those aged ≥70 years (24.9%)., Conclusion:  Our findings suggest that 45 to 62% of all VTE events in the population can be attributed to known prothrombotic genotypes. The PAF of established prothrombotic genotypes was higher in DVT than in PE, and higher in the young than in the elderly., Competing Interests: None declared., (Thieme. All rights reserved.)

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.)

Background:  Inflammation is present in several conditions associated with risk of venous thromboembolism. The gut microbiome might be a source of systemic inflammation and activation of coagulation, by translocation of lipopolysaccharides from gram-negative bacteria to the systemic circulation., Objective:  To investigate whether a vancomycin-induced shift of the gut microbiome in a gram-negative direction influences systemic inflammation and plasma factor (F) VIII procoagulant activity (FVIII:C)., Methods and Results:  We performed a randomized controlled trial including 43 healthy volunteers aged 19 to 37 years. Twenty-one were randomized to 7 days of oral vancomycin intake and 22 served as controls. Feces and blood were sampled at baseline, the day after the end of intervention, and 3 weeks after intervention. Gut microbiome composition was assessed by amplicon sequencing., Fviii: C was measured using an activated partial thromboplastin time-based assay, cytokines were measured using multiplex technology, complement activation was measured using the enzyme-linked immunosorbent assay, and high-sensitivity C-reactive protein (CRP) was measured by an immunoturbidimetric assay. Vancomycin intake reduced gut microbiome diversity and increased the abundance of gram-negative bacteria. Change in FVIII:C in the intervention group was +4 IU/dL versus -6 IU/dL ( p  = 0.01) in the control group. A similar change was observed for log-transformed CRP (+0.21 mg/dL vs. -0.25 mg/dL, p  = 0.04). The cytokines and complement activation markers remained similar in the two groups., Conclusion:  The found slight increases in FVIII:C and CRP levels might support the hypothesis that a vancomycin-induced gram-negative shift in the gut microbiome could induce increased systemic inflammation and thereby a procoagulant state., Competing Interests: None declared., (Thieme. All rights reserved.)

Background:  Circulating levels of leptin, an adipocyte-derived hormone, are frequently elevated in obesity. Leptin has been reported to upregulate prothrombotic hemostatic factors in vitro and could potentially mediate venous thromboembolism (VTE) risk in obesity. However, whether leptin is associated with VTE remains uncertain., Objective:  This article investigates the association between plasma leptin and risk of incident VTE, and the potential of leptin to mediate VTE risk in obesity., Methods:  A population-based nested case-control study with 416 VTE cases and 848 age- and sex-matched controls was derived from the Tromsø Study. Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for VTE across leptin quartiles. Analyses were performed separately in men and women using sex-specific quartile cut-offs determined in controls., Results:  In the age-adjusted model, the VTE risk increased across leptin quartiles, particularly in men. Compared with the lowest quartile, the ORs for VTE in the highest quartile were 1.70 (95% CI 1.04-2.79) in men and 1.36 (95% CI 0.85-2.17) in women. However, with additional adjustment for body mass index (BMI), risk estimates were markedly attenuated in men (OR 1.03, 95% CI 0.55-1.93) and women (OR 0.82, 95% CI 0.45-1.48). The ORs for VTE were increased in obese men and women (BMI ≥ 30 kg/m 2 ) and were only marginally affected after adjustment for leptin., Conclusion:  Our results indicate that the apparent association between plasma leptin levels and VTE risk is confounded by BMI and that leptin is not a relevant mediator for VTE risk in obesity., Competing Interests: None declared., (Thieme. All rights reserved.)

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: The impact of the combination of obesity and multiple prothrombotic genotypes on venous thromboembolism (VTE) risk remains unclear., Objective: To investigate the joint effect of obesity and a genetic risk score (GRS) composed of established prothrombotic single nucleotide polymorphisms (SNPs) on VTE risk using a population-based case-cohort., Methods: Cases with incident VTE ( n  = 1,470) and a subcohort ( n  = 12,826) were derived from the Tromsø Study (1994-2012) and the Trøndelag Health Study (HUNT) (1995-2008). Participants were genotyped for ABO (rs8176719), F5 (rs6025), F2 (rs1799963), FGG (rs2066865), and F11 (rs2036914) SNPs. Age- and sex-adjusted hazard ratios (HRs) were estimated according to body mass index (BMI) categories and number of risk alleles for individual SNPs and the GRS (0-1, 2, 3, ≥4 alleles)., Results: The combination of obesity (BMI ≥ 30kg/m 2 ) and risk alleles, either as individual SNPs or as a GRS, had an additive effect on VTE risk (i.e., no biological interaction). Obese subjects who were carriers of ≥4 risk alleles had a 2.85-fold (95% confidence interval [CI]: 2.05-3.96) increased risk of overall VTE compared with those with BMI <25 kg/m 2 and 0 to 1 risk allele. However, in subgroups, the combination of obesity and ≥4 risk alleles was more pronounced for deep vein thrombosis (DVT) (HR: 3.20; 95% CI: 2.09-4.90) and unprovoked VTE (HR: 3.82; 95% CI: 2.25-6.47), suggesting a supra-additive effect., Conclusion: Our findings indicate that the combination of obesity and GRS has an additive effect on the risk of overall VTE. However, it may have a supra-additive effect on the risk of DVT and unprovoked VTE., Competing Interests: None declared., (Thieme. All rights reserved.)

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).)

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., (© 2021 by The American Society of Hematology.)

Background: D-dimer, a global biomarker for activation of the coagulation and fibrinolysis systems, is useful in assessing individual risk of venous thromboembolism (VTE) recurrence. However, there is limited information on the association between D-dimer and risk of a first lifetime VTE event., Objectives: To investigate the association between plasma D-dimer levels and risk of future incident VTE., Methods: A population-based nested case-control study, comprising 414 VTE patients and 843 randomly selected age- and sex-matched controls, was derived from the Tromsø Study (1994-2007). D-dimer was measured in plasma samples collected at cohort baseline (1994-95). Odds ratios (ORs) for VTE with 95% confidence intervals (CIs) were estimated according to quartile cut-offs of D-dimer levels determined in controls., Results: The risk of VTE increased across quartiles of D-dimer levels (P trend  = 0.014) in the age- and sex-adjusted model. Participants with plasma D-dimer levels in the highest quartile (≥152 ng/mL) had an OR for VTE of 1.65 (95% CI 1.14-2.40) compared with those in the lowest quartile (<94 ng/mL). The ORs were marginally attenuated after additional adjustment for body mass index (BMI) (OR 1.51, 95% CI 1.04-2.20) and C-reactive protein (CRP) (OR 1.34, 95% CI 0.90-1.98). Similar results were obtained for VTE subgroups, i.e. deep vein thrombosis, pulmonary embolism, and provoked/unprovoked events., Conclusion: Our results indicate that elevated plasma D-dimer levels are associated with increased risk of incident VTE. However, the attenuation of risk estimates upon additional adjustment for BMI and CRP suggests that D-dimer partly reflects underlying conditions associated with obesity and an inflammatory state., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The role of complement in the pathogenesis of venous thromboembolism (VTE) is unclear. We wanted to investigate (1) whether plasma complement component C5 (C5) levels are influenced by genetic variants or chronic inflammation and (2) the association between plasma C5 and risk of future VTE in a nested case-control study of 415 patients with VTE and 848 age- and sex-matched controls derived from the Tromsø Study. Plasma C5 levels were measured at inclusion. Odds ratios (ORs) with 95% confidence intervals (95% CIs) for provoked and unprovoked VTE across tertiles of C5 concentrations were estimated by logistic regression. Adjustment for C-reactive protein (CRP) served as a proxy for general inflammation. Whole-exome sequencing and protein quantitative trait loci analyses were performed to assess genetic influence on C5 concentrations. There was no association between genome-wide or C5-related gene variants and C5 levels. The association between plasma C5 levels and VTE risk displayed a threshold effect, where subjects with C5 levels above the lowest tertile had increased risk of VTE. Subjects in tertile 3 (highest C5 levels) had an age- and sex-adjusted OR of 1.45 (95% CI, 1.07-1.96) compared with tertile 1 (lowest). These statistics were more pronounced for unprovoked VTE (OR, 1.70; 95% CI, 1.11-2.60). Adjustments for body mass index and CRP had minor impact on risk estimates. The OR increased substantially with shorter time between blood sampling and VTE event. In conclusion, plasma C5 was associated with risk of future VTE. C5 levels were not genetically regulated and were only slightly influenced by chronic inflammation., (© 2021 by The American Society of Hematology.)

Smoking is a well-established risk factor for cancer, and cancer patients have a high risk of venous thromboembolism (VTE). Conflicting results have been reported on the association between smoking and risk of VTE, and the effect of smoking on VTE-risk in subjects with cancer is scarcely studied. We aimed to investigate the association between smoking and VTE in subjects with and without cancer in a large population-based cohort. The Scandinavian Thrombosis and Cancer (STAC) cohort included 144,952 participants followed from 1993-1997 to 2008-2012. Information on smoking habits was derived from self-administered questionnaires. Active cancer was defined as the first two years following the date of cancer diagnosis. Former smokers (n = 35,890) and those with missing information on smoking status (n = 3680) at baseline were excluded. During a mean follow up of 11 years, 10,181 participants were diagnosed with cancer, and 1611 developed incident VTE, of which 214 were cancer-related. Smoking was associated with a 50% increased risk of VTE (HR 1.49, 95% CI 1.12-1.98) in cancer patients, whereas no association was found in cancer-free subjects (HR 1.07, 95% CI 0.96-1.20). In cancer patients, the risk of VTE among smokers remained unchanged after adjustment for cancer site and metastasis. Stratified analyses showed that smoking was a risk factor for VTE among those with smoking-related and advanced cancers. In conclusion, smoking was associated with increased VTE risk in subjects with active cancer, but not in those without cancer. Our findings imply a biological interaction between cancer and smoking on the risk of VTE., (© 2021. The Author(s).)