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Background:Testicular cancer patients have an increased risk for cardiovascular disease (CVD), which might be related to the increased prevalence of the metabolic syndrome (MetS) in this group of patients.Methods:We assessed the prevalence of MetS and calculated the 10-year CVD risk in a cohort of 255 testicular germ cell tumour survivors (median age, 38.7 years; interquartile range, 31–48) at a mean of 7.8 years after anti-cancer treatment, and compared these with data obtained from 360 healthy men.Results:Survivors had an age-adjusted increased risk for MetS of 1.9 compared with that of healthy controls. The risk for MetS was highest in survivors treated with combination chemotherapy (CT) 2.3 (Adult Treatment Panel of the National Cholesterol Education Program classification) and 2.2 (International Diabetes Federation classification). The risk of MetS was especially increased in survivors with testosterone levels in the lowest quartile (OR, 2.5). Ten-year cardiovascular risk as assessed by the Framingham Risk Score (3.0%) and Systemic Coronary Risk Evaluation (1.7%) algorithms was low, independent of treatment, and was comparable to controls.Conclusion:Testicular germ cell tumour survivors have an increased prevalence of MetS, with hypogonadism and CT treatment being clear risk factors for the development of the syndrome. The increased prevalence of MetS was not associated with an increased 10-year cardiovascular risk.

To cite this article: Debeij J, van Zaane B, Dekkers OM, Doggen CJM, Smit JWA, van Zanten AP, Brandjes DPM, B€ uller HR, Gerdes VEA, Rosendaal FR, Cannegieter SC. High levels of procoagulant factors mediate the association between free thyroxine and the risk of venous thrombosis: the MEGA study. J Thromb Haemost 2014; 12: 839-46.Summary. Background: Thyroid hormone affects the coagulation system, but its effect on clinical disease is not clear. We determined the associations of levels of free thyroxine (FT4), thyroid-stimulating hormone (TSH) and anti-thyroid peroxidase antibodies (antiTPO) with levels of coagulation factors and the risk of venous thrombosis. Methods: In a large population based case-control study (Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis study) on the etiology of venous thrombosis, we determined the levels of FT4, TSH, antiTPO, factor FII, FVII, FVIII, FIX, FX, von Willebrand factor (VWF), antithrombin, protein C, protein S and fibrinogen in 2177 cases and 2826 controls. Results: High levels of FT4 were associated with increased concentrations of procoagulant factors, and not with levels of anticoagulant factors. High levels of FT4 were also associated with the risk of venous thrombosis, up to an odds ratio (OR) of 2.2 (95% confidence interval [CI] 1.0-4.6) for levels above 24.4 pM relative to FT4 levels between 15.5 and 18.9 pM. In 11 cases and one control, clinical hyperthyroidism had been diagnosed within a year of the thrombotic event, leading to an OR of 17.0 (95% CI 2.2-133.0) for thrombosis. The ORs approached unity after adjustment for FVIII and VWF, which suggests that the effect was mediated by these factors. Low TSH levels were also, but less evidently, associated with thrombosis, whereas there was no association between antiTPO and venous thrombosis risk. Conclusions: High levels of FT4 increase the concentrations of the procoagulant proteins FVIII, FIX, fibrinogen, and VWF, and by this mechanism increase the risk of venous thrombosis.

SummaryRecently, it has been described that elevated plasma levels of factor VIII are a strong risk factor for venous thrombosis. We analysed the data of the Leiden Thrombophilia Study, a population based case-control study on the causes of venous thrombosis, to verify whether the risk due to oral contraceptive use was higher in women with higher factor VIII levels. Furthermore we investigated the joint risk of high factor VIII levels and oral contraceptive use.We selected 155 premenopausal women with deep-vein thrombosis and 169 control subjects, aged 15-49, who were at the time of their thrombosis (or similar date in control) not pregnant, nor in the puerperium, did not have a recent miscarriage, and were not using injectable progestogens. Of the patients, 109 (70%) women had used oral contraceptives during the month preceding their deep-vein thrombosis, in contrast to 65 (38%) of the control subjects (index date), yielding an odds ratio for oral contraceptive use of 3.8 (95% CI 2.4-6.0). Of the women who suffered a deep-vein thrombosis 56 (36%) had high factor VIII levels (≥150 IU/dl) as compared with 29 (17%) of the control subjects, yielding an odds ratio for high factor VIII of 4.0 (95% CI 2.0-8.0), relative to factor VIII levels <100 IU/dl. The joint effect of oral contraceptive use and high factor VIII resulted in an odds ratio of 10.3 (95% CI 3.7-28.9), comparing women who had both with women who had neither. We conclude that there is an increase in risk due to oral contraceptive use in women with higher factor VIII levels and that both factors have additive effects.

Background The risk of venous thrombosis (VT) associated with oral hormone therapy (HT) may differ by type of estrogen compound. Objective To compare the thrombotic profile of women using oral conjugated equine estrogens (CEE) with that of women using oral estradiol (E2). Methods In postmenopausal female health maintenance organization (HMO) members with no history of VT, we measured thrombin generation, levels of factor VII activity, antithrombin activity, and total protein S antigen. Mean levels of hemostasis biomarkers were cross-sectionally compared by use and type of estrogen using multiple linear regressions. The type of estrogen used was determined primarily by the HMO formulary, which changed its preferred estrogen from CEE to E2 during the study period. Results The sample included 92 E2 users and 48 CEE users, with a mean age of 64.1y and mean BMI of 29.1kg/m2. Twenty-seven percent of HT contained medroxyprogesterone acetate. Compared with E2 users, CEE users had greater thrombin generation peak values, endogenous thrombin potential, and lower total protein S (multivariate adjusted differences of 49.8 nM (95%CI: 21.0, 78.6); 175.0 nMxMin (95%CI: 54.4, 295.7); and -13.4% (95%CI: −9.8, −6.9), respectively). Factor VII and antithrombin levels were not different between E2 and CEE users. Results were similar in subgroups of users of unopposed HT, opposed HT, low-dose estrogen and standard dose estrogen. Conclusion The hemostatic profile of women using CEE is more prothrombotic than that of women using E2. These findings provide further evidence for a different thrombotic risk for oral CEE and oral E2.