INR control calculation: comparison of Dutch and international methods.

Results of trials with new oral anticoagulant drugs and vitamin K antagonists (VKA) might not be directly applicable to Dutch clinical practice due to the high level of control of anticoagulation in the Netherlands. In addition, the Dutch method for assessing anticoagulation control uses cross-sectional international normalised ratio (INR) test results while the method used in the trials is based on person-time. To enable comparisons, the two calculation methods were applied to INR data of a cohort of 5422 atrial fibrillation patients treated with VKA. Overall, 74% of test results and 77% of person-time were in the therapeutic range [2.0-3.5]. For the narrower target INR interval [2.5-3.5], 59% of test results and 61% of person-time were in range. It was only between two and six months after the start of treatment that the percentage of person-time in range was lower than the percentage of test results in range. Control of anticoagulation, expressed as a percentage of person-time spent in range, in this Dutch dataset was similar to recent trials with new oral anticoagulants, although it should be noted that the Dutch INR target is higher than the target in these trials. INR control as estimated by the two calculation methods (cross-sectional and longitudinal) was similar.

New gene variants associated with venous thrombosis: a replication study in White and Black Americans.

BACKGROUND: We evaluated 10 single-nucleotide polymorphisms (SNPs) identified in three European case-control studies as risk factors for venous thrombosis. OBJECTIVES: We sought to replicate the positive findings from this report among Whites and to evaluate the association of these SNPs with venous thrombosis for the first time among Blacks. PATIENT/METHODS: These SNPs were evaluated in a case-control study of deep vein thrombosis and pulmonary embolism that included 1076 cases and 1239 controls. About 50% of subjects were African Americans. We measured plasma factor (F) XI on a subset of subjects. RESULTS: Among Whites, positive findings for rs13146272 in the CYP4V2 gene, for rs3087505 in the KLKB1 gene and for rs3756008 and rs2036914 in the F11 gene were found. We did not find significant associations for rs2227589 in the SERPINC1 gene and for rs1613662 in the GP6 gene. Among Blacks, rs2036914 in F11 and rs670659 in RGS7 were related to venous thrombosis, but the study had limited statistical power for many SNPs. Among Blacks, plasma FXI was related to two SNPs and the OR relating to the 90th percentile of the control distribution of plasma FXI was 2.6 (95% CI, 1.4, 5.0). CONCLUSIONS: Our study supports the finding that genetic variants in the F11 gene are risk factors for venous thrombosis among both Whites and Blacks, although the findings in Blacks require confirmation. A meta-analysis of five case-control studies indicates that rs2227589 in the SERPINC1 gene, rs13146272 in the CYP4V2 gene and rs1613662 in the GP6 gene are risk factors for venous thrombosis among Whites.

Genetic variants associated with deep vein thrombosis: the F11 locus.

BACKGROUND: Recent studies have found associations between deep vein thrombosis (DVT) and single nucleotide polymorphisms (SNPs) in a 4q35.2 locus that contains genes encoding factor XI (F11), a cytochrome P450 family member (CYP4V2), and prekallikrein (KLKB1). OBJECTIVE: We investigated which of the common SNPs in this locus are independently associated with DVT. METHODS: The study populations were the Leiden Thrombophilia Study (LETS) (443 DVT cases and 453 controls) and the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study) (2712 DVT cases and 4634 controls). We assessed the association between DVT and 103 SNPs in a 200 kb region using logistic regression. RESULTS: We found that two SNPs (rs2289252 and rs2036914 in F11) were independently associated with DVT. After adjusting for age, sex, and the other SNP, the odds ratios (risk vs. non-risk homozygotes) of these two SNPs were 1.49 for rs2289252 (95% CI, 1.25-1.76) and 1.33 for rs2036914 (95% CI, 1.11-1.59). We found that rs2289252 was also associated with FXI levels, as has been previously reported for rs2036914; these two SNPs remained associated with DVT with somewhat attenuated risk estimates after adjustment for FXI levels. CONCLUSION: Two SNPs, rs2289252 and rs2036914 in F11, appear to independently contribute to the risk of DVT, a contribution that is explained at least in part by an association with FXI levels.

Mechanisms of the factor V Leiden paradox.

OBJECTIVE: Carriers of the factor V Leiden mutation (FVL-carriers) have a substantially increased risk of deep venous thrombosis (DVT), whereas the risk of pulmonary embolism (PE) is only mildly increased compared with noncarriers. So far few studies have investigated possible mechanisms for this so-called FVL paradox. METHODS AND RESULTS: Consecutive patients with a first DVT or PE were included in a large population-based case-control study (MEGA study). Patients, aged 18 to 70 years, provided a questionnaire, DNA (n=3313), or plasma (n=1474). Surgery, injury, and travel were considered thrombosis-provocative. Of 2063 patients with isolated DVT, 20% were FVL-carrier, as were 8% of the 885 patients with isolated PE. Among DVT patients, FVL-carriers had their thrombi more often proximal and a higher number of affected veins than noncarriers. No differences were observed between FVL-carriers and noncarriers in time between provocation and diagnosis, in vitro coagulation time, and thrombus density. Compared with patients with both DVT and PE, isolated DVT patients more often had thrombi located distally and had a similar number of affected veins. Compared with isolated PE patients, isolated DVT patients had a similar time between provocation and diagnosis, and similar in vitro coagulation time and thrombus density. CONCLUSIONS: Although some effects were differential for FVL-carriers and noncarriers, and some were differential for PE and DVT patients, none of the potential mechanisms offered a clear explanation.

Relationship of alcohol intake and sex steroid concentrations in blood in pre- and post-menopausal women: the European Prospective Investigation into Cancer and Nutrition.

OBJECTIVE: Women with a moderate intake of alcohol have higher concentrations of sex steroids in serum, and higher risk of developing breast cancer, compared to non-drinkers. In the present study, we investigate the relationships between alcohol consumption and serum levels of sex steroids and sex-hormone binding globulin (SHBG) in 790 pre- and 1,291 post-menopausal women, who were part of the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: Serum levels of testosterone (T), androstenedione (Delta4), dehydroepiandrosterone sulphate (DHEAS), estrone (E1), estradiol (E2) and SHBG were measured by direct immunoassays. Free T (fT) and free E2 (fE2) were calculated according to mass action laws. Current alcohol intake exposure to alcohol was assessed from dietary questionnaires. RESULTS: Pre-menopausal women who consumed more than 25 g/day of alcohol had about 30% higher DHEAS, T and fT, 20% higher Delta4 and about 40% higher E1, concentrations compared to women who were non-consumers. E2, fE2 and SHBG concentrations showed no association with current alcohol intake. In post-menopausal women, DHEAS, fT, T, Delta4, and E1 concentrations were between 10% and 20% higher in women who consumed more than 25 g/day of alcohol compared to non-consumers. E2 or fE2 were not associated with alcohol intake at all. SHBG levels were about 15% lower in alcohol consumers compared to non-consumers. CONCLUSION: This study supports the hypothesis of an influence of alcohol intake on sex hormone concentrations in blood.