Comparison of assays measuring extracellular vesicle tissue factor in plasma samples: communication from the ISTH SSC Subcommittee on Vascular Biology.

BACKGROUND: Scientific and clinical interest in extracellular vesicles (EVs) is growing. EVs that expose tissue factor (TF) bind factor VII/VIIa and can trigger coagulation. Highly procoagulant TF-exposing EVs are detectable in the circulation in various diseases, such as sepsis, COVID-19, or cancer. Many in-house and commercially available assays have been developed to measure EV-TF activity and antigen, but only a few studies have compared some of these assays. OBJECTIVES: The International Society on Thrombosis and Haemostasis Scientific and Standardization Committee Subcommittee on Vascular Biology initiated a multicenter study to compare the sensitivity, specificity, and reproducibility of these assays. METHODS: Platelet-depleted plasma samples were prepared from blood of healthy donors. The plasma samples were spiked either with EVs from human milk or EVs from TF-positive and TF-negative cell lines. Plasma was also prepared from whole human blood with or without lipopolysaccharide stimulation. Twenty-one laboratories measured EV-TF activity and antigen in the prepared samples using their own assays representing 18 functional and 9 antigenic assays. RESULTS: There was a large variability in the absolute values for the different EV-TF activity and antigen assays. Activity assays had higher specificity and sensitivity compared with antigen assays. In addition, there was a large intra-assay and interassay variability. Functional assays that used a blocking anti-TF antibody or immunocapture were the most specific and sensitive. Activity assays that used immunocapture had a lower coefficient of variation compared with assays that isolated EVs by high-speed centrifugation. CONCLUSION: Based on this multicenter study, we recommend measuring EV-TF using a functional assay in the presence of an anti-TF antibody.

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.

Recurrent venous thromboembolism and bleeding with extended anticoagulation: the VTE-PREDICT risk score.

AIMS: Deciding to stop or continue anticoagulation for venous thromboembolism (VTE) after initial treatment is challenging, as individual risks of recurrence and bleeding are heterogeneous. The present study aimed to develop and externally validate models for predicting 5-year risks of recurrence and bleeding in patients with VTE without cancer who completed at least 3 months of initial treatment, which can be used to estimate individual absolute benefits and harms of extended anticoagulation. METHODS AND RESULTS: Competing risk-adjusted models were derived to predict recurrent VTE and clinically relevant bleeding (non-major and major) using 14 readily available patient characteristics. The models were derived from combined individual patient data from the Bleeding Risk Study, Hokusai-VTE, PREFER-VTE, RE-MEDY, and RE-SONATE (n = 15,141, 220 recurrences, 189 bleeding events). External validity was assessed in the Danish VTE cohort, EINSTEIN-CHOICE, GARFIELD-VTE, MEGA, and Tromsø studies (n = 59 257, 2283 recurrences, 3335 bleeding events). Absolute treatment effects were estimated by combining the models with hazard ratios from trials and meta-analyses. External validation in different settings showed agreement between predicted and observed risks up to 5 years, with C-statistics ranging from 0.48-0.71 (recurrence) and 0.61-0.68 (bleeding). In the Danish VTE cohort, 5-year risks ranged from 4% to 19% for recurrent VTE and 1% -19% for bleeding. CONCLUSION: The VTE-PREDICT risk score can be applied to estimate the effect of extended anticoagulant treatment for individual patients with VTE and to support shared decision-making.

Redefining clinical venous thromboembolism phenotypes: a novel approach using latent class analysis.

BACKGROUND: Patients with venous thromboembolism (VTE) are commonly classified by the presence or absence of provoking factors at the time of VTE to guide treatment decisions. This approach may not capture the heterogeneity of the disease and its prognosis. OBJECTIVES: To evaluate clinically important novel phenotypic clusters among patients with VTE without cancer and to explore their association with anticoagulant treatment and clinical outcomes. METHODS: Latent class analysis was performed with 18 baseline clinical variables in 3062 adult patients with VTE without active cancer participating in PREFER in VTE, a noninterventional disease registry. The derived latent classes were externally validated in a post hoc analysis of Hokusai-VTE (n = 6593), a randomized trial comparing edoxaban with warfarin. The associations between cluster membership and anticoagulant treatment, recurrent VTE, bleeding, and mortality after initial treatment were studied. RESULTS: The following 5 clusters were identified: young men cluster (n = 1126, 37%), young women cluster (n = 215, 7%), older people cluster (n = 1106, 36%), comorbidity cluster (n = 447, 15%), and history of venous thromboembolism cluster (n = 168, 5%). Patient characteristics varied by age, sex, medical history, and treatment patterns. Consistent clusters were evident on external validation. In Cox proportional hazard models, recurrence risk was lower in the young women cluster (hazard ratio [HR], 0.27; 95% CI, 0.12-0.61) compared with the comorbidity cluster, after adjusting for extended anticoagulation. The risk of bleeding was lower in young men, young women, and older people clusters (HR, 0.50; 95% CI, 0.38-0.66; HR, 0.23; 95% CI, 0.11-0.46; and HR, 0.55; 95% CI 0.41-0.73, respectively). CONCLUSION: The heterogeneity of VTE cases extends beyond the distinction between provoked and unprovoked 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.

Risk of a permanent work-related disability pension after incident venous thromboembolism in Denmark: A population-based cohort study.

BACKGROUND: Long-term complications of venous thromboembolism (VTE) hamper physical function and impair quality of life; still, it remains unclear whether VTE is associated with risk of permanent work-related disability. We aimed to assess the association between VTE and the risk of receiving a permanent work-related disability pension and to assess whether this association was explained by comorbidities such as cancer and arterial cardiovascular disease. METHODS AND FINDINGS: A Danish nationwide population-based cohort study consisting of 43,769 individuals aged 25 to 66 years with incident VTE during 1995 to 2016 and 218,845 birth year-, sex-, and calendar year-matched individuals from the general population, among whom 45.9% (N = 120,540) were women, was established using Danish national registries. The cohorts were followed throughout 2016, with permanent work-related disability pension as the outcome. Hazard ratios (HRs) with 95% confidence intervals (CIs) for disability pension were computed and stratified by sex and age groups (25 to 34, 35 to 44, 45 to 54, and 55 to 66 years of age) and adjusted for comorbidities and socioeconomic variables. Permanent work-related disability pensions were granted to 4,415 individuals with VTE and 9,237 comparison cohort members (incidence rates = 17.8 and 6.2 per 1,000 person-years, respectively). VTE was associated with a 3-fold (HR 3.0, 95% CI: 2.8 to 3.1) higher risk of receiving a disability pension. Adjustments for socioeconomic status and comorbidities such as cancer and cardiovascular diseases reduced the estimate (HR 2.3, 95% CI: 2.2 to 2.4). The risk of disability pension receipt was slightly higher in men than in women (HR 2.5, 95% CI: 2.3 to 2.6 versus HR 2.1, 95% CI: 2.0 to 2.3). As this study is based on medical and administrative registers, information on post-VTE care, individual health behavior, and workplace factors linked to disability pension in the general population are lacking. Furthermore, as disability pension schemes vary, our results might not be directly generalizable to other countries or time periods. CONCLUSIONS: In this study, incident VTE was associated with increased risk of subsequent permanent work-related disability, and this association was still observed after accounting for comorbidities such as cancer and cardiovascular diseases. Our results emphasize the social consequences of VTE and may help occupational and healthcare professionals to identify vulnerable individuals at risk of permanent exclusion from the labor market after a VTE event.

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.

Development and implementation of common data elements for venous thromboembolism research: on behalf of SSC Subcommittee on official Communication from the SSC of the ISTH.

Clinical research in venous thromboembolism (VTE) is hindered by variability in the collection and reporting of data and outcomes. A consistent data language facilitates efficiencies, leads to higher quality data, and permits between-study comparisons and evidence synthesis. The International Society on Thrombosis and Haemostasis (ISTH) launched an international task force of more than 50 researchers to develop common data elements for clinical research in venous thromboembolism. The project was organized in seven working groups, each focusing on a topic area: General Core Data Elements; Anticoagulation and Other Therapies; Chronic VTE and Functional Outcomes; Diagnosis of VTE; Malignancy; Perioperative; and Predictors of VTE. The groups met via teleconference to collaboratively identify key data elements and develop definitions and data standards that were structured in a project-specific taxonomy. A Steering Committee met by teleconference and in-person to determine the overall scope of the project and resolve questions arising from the working groups. ISTH held an open public comment period to enable broader stakeholder involvement and feedback. The common data elements were then refined by the working groups to create a set of 512 unique data elements that are publicly available at http://isth.breakthrough.healthcare. The ISTH VTE Common Data Elements are intended to be a living project with ongoing curation, future expansion, and adaptation to meet the needs of the thrombosis and hemostasis research community.

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.

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.

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.

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.