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

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

Surgery As a Trigger for Incident Venous Thromboembolism: Results from a Population-Based Case-Crossover Study.

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.

Plasma levels of P-selectin and future risk of incident venous thromboembolism.

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.

Survival after cancer-related venous thrombosis: the Scandinavian Thrombosis and Cancer Study.

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.

Low D-dimer levels at diagnosis of venous thromboembolism are associated with reduced risk of recurrence: data from the TROLL registry.

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.

Hand grip strength and risk of incident venous thromboembolism: The Tromsø study.

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.

Risk factors and predictors for venous thromboembolism in people with ischemic stroke: A systematic review.

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.

Plasma levels of platelet-derived microvesicles are associated with risk of future venous thromboembolism.

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.

Association of smoking and cancer with the risk of venous thromboembolism: the Scandinavian Thrombosis and Cancer cohort.

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.

Prothrombotic genotypes and risk of venous thromboembolism in occult cancer.

BACKGROUND: Studies have reported that the combination of some prothrombotic genotypes and overt cancer yields a synergistic effect on VTE risk. Whether individual prothrombotic genotypes or number of risk alleles in a genetic risk score (GRS) affect VTE risk in occult cancer have not been addressed. The aim of this study was to investigate the joint effect of five prothrombotic genotypes and occult cancer on VTE risk. METHODS: Cases with incident VTE (n = 1566) and a subcohort (n = 14,537) were sampled from the Scandinavian Thrombosis and Cancer Cohort (1993-2012). Five single nucleotide polymorphisms previously reported in a GRS were genotyped: ABO (rs8176719), F5 (rs6025), F2 (rs1799963), FGG (rs2066865) and F11 (rs2036914). Hazard ratios (HRs) for VTE by individual SNPs and GRS were estimated according to non-cancer and occult cancer (one year preceding a cancer diagnosis) exposure. RESULTS: Occult cancer occurred in 1817 subjects, and of these, 93 experienced a VTE. The VTE risk was 4-fold higher (HR 4.05, 95% CI 3.28-5.00) in subjects with occult cancer compared with those without cancer. Among subjects with occult cancer, those with VTE had a higher proportion of prothrombotic and advanced cancers than those without VTE. The VTE risk increased according to individual prothrombotic genotypes and GRS in cancer-free subjects, while no such effect was observed in subjects with occult cancer (HR for ≥4 versus ≤1 risk alleles in GRS: 1.14, 95% CI 0.61-2.11). CONCLUSIONS: Five well-established prothrombotic genotypes, individually or combined, were not associated with increased risk of VTE in individuals with occult cancer.

Plasma levels of von Willebrand factor and future risk of incident venous thromboembolism.

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.

Platelet count and risk of major bleeding in venous thromboembolism.

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

Combined effects of five prothrombotic genotypes and cancer on the risk of a first venous thromboembolic event.

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.

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

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

Prothrombotic genotypes and risk of major bleeding in patients with incident venous thromboembolism.

BACKGROUND: Genotypes associated with venous thromboembolism (VTE) may protect against bleeding due to a hypercoagulable state. Whether the risk of major bleeding is reduced in parallel with an increasing number of prothrombotic genotypes during anticoagulant treatment in VTE remains unknown. OBJECTIVES: To investigate the association between multiple prothrombotic genotypes and risk of major bleeding in patients with VTE. METHODS: Patients with incident VTE (n = 676) derived from the Tromsø Study were genotyped for rs6025 (F5), rs1799963 (F2), rs8176719 (ABO), rs2066865 (FGG) and rs2036914 (F11) single nucleotide polymorphisms (SNPs). Major bleeding events were recorded during the first year after VTE according to the International Society on Thrombosis and Haemostasis criteria. Cox-regression was used to calculate hazard ratios with 95% confidence intervals (CIs) for major bleeding adjusted for age, sex and duration of anticoagulation according to individual prothrombotic SNPs and categories of risk alleles (5-SNP score; 0-1, 2, 3 and ≥4). RESULTS: In total, 50 patients experienced major bleeding (incidence rate: 9.5/100 person-years, 95% CI 7.2-12.5). The individual SNPs and number of risk alleles were not associated with major bleeding risk. The hazard ratios for major bleeding per category increase of genetic risk score were 1.0 (95% CI 0.8-1.3) for the total study population and 1.1 (95% CI 0.8-1.5) when patients with active cancer were excluded. Analyses restricted to the first 3 months after VTE yielded similar results. CONCLUSION: Our findings suggest that an increasing number of prothrombotic risk alleles is not protective against major bleeding in VTE patients during anticoagulation.

Fibrinogen gamma gene rs2066865 and risk of cancer-related venous thromboembolism.

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.

Dietary Intake of Marine Polyunsaturated n-3 Fatty Acids and Risk of Recurrent Venous Thromboembolism.

BACKGROUND: Limited knowledge exists on the association between intake of long-chained n-3 polyunsaturated fatty acids (n-3 PUFAs) and risk of recurrence and all-cause mortality in patients with venous thromboembolism (VTE). OBJECTIVES: This article investigates whether intake of marine n-3 PUFAs was associated with risk of recurrence and mortality in patients with incident VTE. METHODS: A total of 595 patients with incident VTE and available data on n-3 PUFA intake were derived from the Tromsø Study surveys 4 (1994-1995) and 6 (2007-2008). Weekly intake of n-3 PUFAs was categorized as low, medium, and high based on tertiles. Recurrent VTEs and all-cause mortality were registered up to December 31, 2016. Hazard ratios (HRs) were calculated using Cox regression models with the low intake category as reference. RESULTS: There were 98 recurrent VTEs and 227 deaths during follow-up. Overall, we found no association between intake of n-3 PUFAs and risk of recurrent VTE. However, inverse associations were found for high intakes in patients with unprovoked VTE (HR 0.45, 95% confidence interval [CI]: 0.20-1.01), cancer-free patients (HR 0.51, 95% CI: 0.27-0.95), and deep vein thrombosis (DVT) patients (HR 0.49, 95% CI: 0.24-0.97). The inverse associations were more evident when follow-up was restricted to the time after discontinuation of anticoagulant therapy. No association was observed between intake of n-3 PUFAs and mortality after incident VTE. CONCLUSION: A high dietary intake of marine n-3 PUFAs was associated with lower risk of recurrent VTE after unprovoked index events, DVT, and in cancer-free patients.

Prediction of recurrent venous thrombosis in all patients with a first venous thrombotic event: The Leiden Thrombosis Recurrence Risk Prediction model (L-TRRiP).

BACKGROUND: Recurrent venous thromboembolism (VTE) is common. Current guidelines suggest that patients with unprovoked VTE should continue anticoagulants unless they have a high bleeding risk, whereas all others can stop. Prediction models may refine this dichotomous distinction, but existing models apply only to patients with unprovoked first thrombosis. We aimed to develop a prediction model for all patients with first VTE, either provoked or unprovoked. METHODS AND FINDINGS: Data were used from two population-based cohorts of patients with first VTE from the Netherlands (Multiple Environment and Genetic Assessment of Risk Factors for Venous Thrombosis [MEGA] follow-up study, performed from 1994 to 2009; model derivation; n = 3,750) and from Norway (Tromsø study, performed from 1999 to 2016; model validation; n = 663). Four versions of a VTE prediction model were developed: model A (clinical, laboratory, and genetic variables), model B (clinical variables and fewer laboratory markers), model C (clinical and genetic factors), and model D (clinical variables only). The outcome measure was recurrent VTE. To determine the discriminatory power, Harrell's C-statistic was calculated. A prognostic score was assessed for each patient. Kaplan-Meier plots for the observed recurrence risks were created in quintiles of the prognostic scores. For each patient, the 2-year predicted recurrence risk was calculated. Models C and D were validated in the Tromsø study. During 19,201 person-years of follow-up (median duration 5.7 years) in the MEGA study, 507 recurrences occurred. Model A had the highest predictive capability, with a C-statistic of 0.73 (95% CI 0.71-0.76). The discriminative performance was somewhat lower in the other models, with C-statistics of 0.72 for model B, 0.70 for model C, and 0.69 for model D. Internal validation showed a minimal degree of optimism bias. Models C and D were externally validated, with C-statistics of 0.64 (95% CI 0.62-0.66) and 0.65 (95% CI 0.63-0.66), respectively. According to model C, in 2,592 patients with provoked first events, 367 (15%) patients had a predicted 2-year risk of >10%, whereas in 1,082 patients whose first event was unprovoked, 484 (45%) had a predicted 2-year risk of <10%. A limitation of both cohorts is that laboratory measurements were missing in a substantial proportion of patients, which therefore were imputed. CONCLUSIONS: The prediction model we propose applies to patients with provoked or unprovoked first VTE-except for patients with (a history of) cancer-allows refined risk stratification, and is easily usable. For optimal individualized treatment, a management study in which bleeding risks are also taken into account is necessary.

Myocardial Infarction as a Transient Risk Factor for Incident Venous Thromboembolism: Results from a Population-Based Case-Crossover Study.

Patients with myocardial infarction (MI) are at increased short-term risk of venous thromboembolism (VTE). The mechanisms behind this association are unclear. We aimed to investigate the impact of acute MI as a transient risk factor for incident VTE while taking other concomitant VTE risk factors into account. We conducted a case-crossover study of VTE patients (n = 707) recruited from the fourth survey of the Tromsø Study. VTE risk factors and hospitalizations were registered during the 90-day period preceding the VTE diagnosis (hazard period) and in four 90-day control periods. Conditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for VTE according to acute MI and after adjustment for other risk factors. Additionally, we applied a mediation analysis to quantify how much the known transient risk factors account for the observed effect of MI on VTE risk. MI was recorded in 13 (1.8%) of the hazard periods and in 6 (0.2%) of the control periods, which yielded a crude OR of 11.9 (95% CI: 3.9-36.7). Adjustment for immobilization and infection yielded an OR of 2.7 (95% CI: 0.6-11.2). The OR was attenuated to 2.6 (95% CI: 0.6-11.9) after further adjustment for major surgery, trauma, red blood cell transfusion, and central venous catheterization. Approximately 60% of the association between MI and VTE was mediated through infection and immobilization. In conclusion, our findings suggest that the increased VTE risk after MI may to a large extent be explained by concomitant conditions related to MI, particularly infections and immobilization.

The Role of Stroke as a Trigger for Incident Venous Thromboembolism: Results from a Population-based Case-Crossover Study.

Stroke is associated with a short-term increased risk of subsequent venous thromboembolism (VTE). It is unclear to what extent this association is mediated by stroke-related complications that are potential triggers for VTE, such as immobilization and infection. We aimed to investigate the role of acute stroke as a trigger for incident VTE while taking other concomitant VTE triggers into account. We conducted a population-based case-crossover study with 707 VTE patients. 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 with 95% confidence intervals (CIs) for VTE according to triggers. Stroke was registered in 30 of the 707 (4.2%) hazard periods and in 6 of the 2,828 (0.2%) control periods, resulting in a high risk of VTE, with odds ratios of 20.0 (95% CI: 8.3-48.1). After adjustments for immobilization and infection, odds ratios for VTE conferred by stroke were attenuated to 6.0 (95% CI: 1.6-22.1), and further to 4.0 (95% CI: 1.1-14.2) when other triggers (major surgery, red blood cell transfusion, trauma, and central venous catheter) were added to the regression model. A mediation analysis revealed that 67.8% of the total effect of stroke on VTE risk could be mediated through immobilization and infection. Analyses restricted to ischemic stroke yielded similar results. In conclusion, acute stroke was a trigger for VTE, and the association between stroke and VTE risk appeared to be largely mediated by immobilization and infection.