Causality assessment of circulating Vitamin D level on venous thromboembolism: A Mendelian randomization study.

BACKGROUND AND AIMS: The associations of vitamin D level with venous thromboembolism (VTE) reported in observational studies, whereas these causal associations were uncertain in European population. Therefore, we used Mendelian randomization (MR) method to explore the causal associations between 25-hydroxyvitamin D (25(OH)D) concentrations and the risk of VTE and its subtypes [including deep vein thrombosis (DVT) and pulmonary embolism (PE)]. METHODS AND RESULTS: We used three kinds of genetic instruments to proxy the exposure of 25(OH)D, including genetic variants significantly associated with 25(OH)D, expression quantitative trait loci of 25(OH)D target genes, and genetic variants within or nearby 25(OH)D target genes. MR analyses did not provide any evidence for the associations of 25(OH)D levels with VTE and its subtypes (p > 0.05). The summary-data-based MR (SMR) analyses indicated that elevated expression of VDR was associated with decreased risk of VTE (OR = 0.81; 95% CI, 0.65-0.998; p = 0.047) and PE (OR = 0.67; 95% CI, 0.50-0.91; p = 0.011), and expression of AMDHD1 was associated with PE (OR = 0.93; 95% CI, 0.88-0.99; p = 0.027). MR analysis provided a significant causal effect of 25(OH)D level mediated by gene AMDHD1 on PE risk (OR = 0.09; 95% CI, 0.01-0.60; p = 0.012). CONCLUSION: Our MR analysis did not support causal association of 25(OH)D level with the risk of VTE and its subtypes. In addition, the expression of VDR and AMDHD1 involved in vitamin D metabolism showed a strong association with VTE or PE and might represent targets for these conditions.

Assessment of heat shock proteins and endothelial dysfunction in acute pulmonary embolism.

We determined the levels of some heat shock proteins (HSP27, HSP70, and HSP90), L-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) levels in patients with acute pulmonary embolism. The present case-control study comprised a healthy control group (n = 57) and patients with acute pulmonary embolism (n = 84). HSPs, L-arginine, ADMA, and SDMA levels were measured in all of the cases. The mean age of the control group was 56.72 ±â€Š8.44 years, and the mean age of the patients with acute pulmonary embolism was 60.20 ±â€Š16.56 years (P = 0.104). Compared with controls, patients with acute pulmonary embolism had significantly higher mean serum HSP27, HSP90, and ADMA levels, whereas the mean serum L-arginine and SDMA levels were lower (P < 0.001, for all parameters). In patients with acute pulmonary embolism serum HSP27, HSP70, and ADMA levels were negatively correlated with partial pressures of arterial oxygen levels (r = -0.281, P = 0.01; r = -0.263, P = 0.016; and r = -0.275, P = 0.011, respectively) and arterial oxygen saturation (r = -0.225, P = 0.039; r = -0.400, P < 0.001; r = -0.299, P = 0.006, respectively). The findings of the present study demonstrated that oxidative stress and endothelial damage increase in acute pulmonary embolism.

Testing for factor V Leiden in patients with pulmonary or venous thromboembolism: a cost-effectiveness analysis.

BACKGROUND: Survivors of venous thromboembolism who have the factor V Leiden mutation have an increased risk of recurrent venous thromboembolism (VTE), but the cost-effectiveness of testing for factor VLeiden has not been assessed. METHODS: We used a Markov state transition decision model to evaluate the cost-effectiveness of factor V Leiden testing and treatment strategies in survivors of VTE using a societal perspective for costs, effectiveness-measured in quality-adjusted life years, and incremental cost-effectiveness. Data sources included the English language literature using MEDLINE searches and bibliographies from selected articles. Cost estimates were derived from Medicare reimbursement and other sources. The analysis examined 3 hypothetical cohorts of 35-year-old women having suffered their 1st episode of VTE. Interventions included oral anticoagulant therapy for 6 months versus testing. Patients found to have the factor V Leiden mutation were then treated with either 3 years or lifelong oral anticoagulant therapy. RESULTS: Total costs for testing followed by 3 years of treatment were $9,676, whereas those for no testing were $10,392 and those for testing followed by lifelong therapy were $13,179. Testing followed by 3 years of treatment increased quality-adjusted life expectancy by roughly 0.15 years. In sensitivity analyses using a more plausible constant risk model of recurrent VTE, testing followed by lifelong anticoagulation was the favored strategy. However, the marginal cost-effectiveness ratio was highly dependent on the rate of recurrent VTE, the risk of major hemorrhage, prevalence of factor V Leiden, patient age, and the efficacy of anticoagulation therapy. CONCLUSIONS: Testing followed by lifelong anticoagulation is unlikely to be a cost-effective strategy in patient populations with a very low prevalence of factor V Leiden; for those with a lower risk for recurrent VTE, such as patients with a clear precipitant; or for patients with risk factors for bleeding while receiving anticoagulant therapy. The only patients for whom testing followed by lifelong anticoagulant therapy may be a reasonable strategy are those with no obvious precipitant for VTE (i.e., idiopathic VTE) who are at low risk for bleeding complications from oral anticoagulant therapy. These results highlight the need for further clinical investigation and the development of multivariable models predicting the risk of recurrent VTE based on factor V Leiden status, idiopathic versus precipitated VTE, treatment, and the coinheritance of other common thrombophilias, such as the prothrombin gene mutation.