Targeted sequencing to identify novel genetic risk factors for deep vein thrombosis: a study of 734 genes.

Essentials Deep vein thrombosis (DVT) has a large unknown genetic component. We sequenced coding areas of 734 hemostasis-related genes in 899 DVT patients and 599 controls. Variants in F5, FGA-FGG, CYP4V2-KLKB1-F11, and ABO were associated with DVT risk. Associations in KLKB1 and F5 suggest a more complex genetic architecture than previously thought. SUMMARY: Background Although several genetic risk factors for deep vein thrombosis (DVT) are known, almost all related to hemostasis, a large genetic component remains unexplained. Objectives To identify novel genetic determinants by using targeted DNA sequencing. Patients/Methods We included 899 DVT patients and 599 controls from three case-control studies (DVT-Milan, Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis [MEGA], and the Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism [THE-VTE] study) for sequencing of the coding regions of 734 genes involved in hemostasis or related pathways. We performed single-variant association tests for common variants (minor allele frequency [MAF] ≥ 1%) and gene-based tests for rare variants (MAF ≤ 1%), accounting for multiple testing by use of the false discovery rate (FDR). Results Sixty-two of 3617 common variants were associated with DVT risk (FDR < 0.10). Most of these mapped to F5,ABO,FGA-FGG, and CYP4V2-KLKB1-F11. The lead variant at F5 was rs6672595 (odds ratio [OR] 1.58, 95% confidence interval [CI] 1.29-1.92), in moderate linkage with the known variant rs4524. Reciprocal conditional analyses suggested that intronic variation might drive this association. We also observed a secondary association at the F11 region: missense KLKB1 variant rs3733402 remained associated conditional on known variants rs2039614 and rs2289252 (OR 1.36, 95% CI 1.10-1.69). Two novel variant associations were observed, in CBS and MASP1, but these were not replicated in the meta-analysis data from the International Network against Thrombosis (INVENT) consortium. There was no support for a burden of rare variants contributing to DVT risk (FDR > 0.2). Conclusions We confirmed associations between DVT and common variants in F5,ABO,FGA-FGG, and CYP4V2-KLKB1-F11, and observed secondary signals in F5 and CYP4V2-KLKB1-F11 that warrant replication and fine-mapping in larger studies.

High risk of recurrent venous thrombosis in patients with lower-leg cast immobilization.

Essentials The risk of recurrent venous thrombosis (VT) after leg-cast in patients with prior VT is unknown. In a nested case-control study within the MEGA follow-up study we aimed to estimate this risk. Patients with a history of VT who require lower-leg cast have a 4.5-fold risk for recurrence. This relative risk translates to an absolute risk for recurrent VT of about 3.2% within 3 months. SUMMARY: Background Patients with lower-leg cast immobilization have a substantially increased risk of developing a first venous thrombosis (VT), whereas the risk in patients with a history of VT is as yet unknown. Aims To estimate the risk of recurrent VT after lower-leg cast immobilization in patients with a history of VT. Methods A case-control study nested within a cohort of 4597 patients with a first VT who were followed over time for recurrence from 1999 to 2010 (MEGA follow-up study). Participants completed a questionnaire on risk factors for recurrent thrombosis, including having a cast in the first 3 months before a recurrence (cases) or a random 3-month period during follow-up for participants without recurrence (controls). In total, 2723/4597 (59%) participants returned the questionnaire. Odds ratios (ORs), adjusted for age and sex, were calculated to compare risks of recurrence between subjects with and without a cast. Results A total of 2525/2723 participants (93%) filled out information on cast immobilization and were included in the analysis (451 cases; 2074 controls). Twenty (1.0%) controls and 10 (2.2%) cases reported having had a lower-leg cast in the 3 months before the control or recurrence date (adjusted OR, 2.4; 95% confidence Interval [CI], 1.1-5.3). We cross-checked the data with these patients' medical records. Cast application within 3 months was verified in seven (0.3%) controls vs. six (1.3%) cases, leading to an adjusted OR of 4.5 (95% CI, 1.5-14.0) and corresponding cumulative incidence of 3.2%. Conclusions Lower-leg cast immobilization increases the risk of recurrent VT in the 3 months after its application in patients with a history of VT.

Mild antithrombin deficiency and risk of recurrent venous thromboembolism: results from the MEGA follow-up study.

Essentials Mild antithrombin deficiency may increase the risk of recurrent venous thromboembolism (VTE). In a cohort study, we stratified patients with VTE to various cut-off antithrombin levels. A 1.6-3.7-fold increased risk of recurrent VTE was observed in the lowest antithrombin categories. Mild antithrombin deficiency (activity < 5th percentile of normal) increases recurrent VTE risk. SUMMARY: Background Mild antithrombin deficiency (previously defined as antithrombin activity below 70% or 80%) has been associated with a 2.4-3.5-fold increased risk of recurrent venous thromboembolism (VTE). This finding may have implications for duration of antithrombotic therapy in VTE patients with mild antithrombin deficiency. Objectives To externally validate whether mild antithrombin deficiency is a risk factor for recurrent VTE. Methods In a population-based cohort study, patients with a first VTE (n = 2357) were stratified according to percentile cut-off antithrombin levels (< 5th [< 87%], 5-10th [87-92%], > 10th percentile [> 92%]) and functional antithrombin levels (< 70%, 70-80%, > 80%). Results During a median follow-up of 7.4 years, 361 recurrent events occurred (incidence rate, 2.5/100 patient-years). We observed an increased risk of recurrent VTE in the lowest antithrombin activity category (< 5th percentile; < 87%) as compared with antithrombin activity that was > 10th percentile (> 92%), with an adjusted hazard ratio (HR) of 1.5 (95%CI, 1.0-2.3). When analyses were stratified to antithrombin cut-off criteria of< 70% vs. patients with antithrombin activity > 80%, the adjusted HR for venous recurrence was 3.7 (95% CI, 1.4-9.9). Mild antithrombin deficiency was able to predict recurrent VTE over at least 8 years of follow-up and the association remained present when the population was stratified to the presence or absence of thrombosis risk factors. Restriction analyses, where patients who used anticoagulation at time of blood draw and those who reported drinking ≥ 5 glasses alcohol daily were excluded, did not materially affect these outcomes. Conclusion This study confirms that mild antithrombin deficiency is a risk factor for recurrent VTE.

Metabolomic analysis of 92 pulmonary embolism patients from a nested case-control study identifies metabolites associated with adverse clinical outcomes.

Essentials Risk-stratification often fails to predict clinical deterioration in pulmonary embolism (PE). First-ever high-throughput metabolomics analysis of risk-stratified PE patients. Changes in circulating metabolites reflect a compromised energy metabolism in PE. Metabolites play a key role in the pathophysiology and risk stratification of PE. SUMMARY: Background Patients with acute pulmonary embolism (PE) exhibit wide variation in clinical presentation and outcomes. Our understanding of the pathophysiologic mechanisms differentiating low-risk and high-risk PE is limited, so current risk-stratification efforts often fail to predict clinical deterioration and are insufficient to guide management. Objectives To improve our understanding of the physiology differentiating low-risk from high-risk PE, we conducted the first-ever high-throughput metabolomics analysis (843 named metabolites) comparing PE patients across risk strata within a nested case-control study. Patients/methods We enrolled 92 patients diagnosed with acute PE and collected plasma within 24 h of PE diagnosis. We used linear regression and pathway analysis to identify metabolites and pathways associated with PE risk-strata. Results When we compared 46 low-risk with 46 intermediate/high-risk PEs, 50 metabolites were significantly different after multiple testing correction. These metabolites were enriched in the following pathways: tricarboxylic acid (TCA) cycle, fatty acid metabolism (acyl carnitine) and purine metabolism, (hypo)xanthine/inosine containing. Additionally, energy, nucleotide and amino acid pathways were downregulated in intermediate/high-risk PE patients. When we compared 28 intermediate-risk with 18 high-risk PE patients, 41 metabolites differed at a nominal P-value level. These metabolites were enriched in fatty acid metabolism (acyl cholines), and hemoglobin and porphyrin metabolism. Conclusion Our results suggest that high-throughput metabolomics can provide insight into the pathophysiology of PE. Specifically, changes in circulating metabolites reflect compromised energy metabolism in intermediate/high-risk PE patients. These findings demonstrate the important role metabolites play in the pathophysiology of PE and highlight metabolomics as a potential tool for risk stratification of PE.

Aging of the venous valves as a new risk factor for venous thrombosis in the elderly: the BATAVIA study.

Essentials Risk of venous thrombosis (VT) related to valve thickness and valvular reflux in unknown. Venous valves and reflux were measured by ultrasonography in cases and controls aged 70+. Risk of VT was associated with increased valve thickness and valvular reflux >1second. Thickening of valves is a generic process: there was no difference between right and left legs. SUMMARY: Background Increasing age is the strongest risk factor for venous thrombosis (VT). Increasing age has been related to a thickening of the venous valves and a decreased valvular function. The association between valve thickness and the risk of VT is not known. Objectives To assess the association between increased valve thickness and valve closure time (VCT) and the risk of VT. Methods Analyses were performed in the BATAVIA study, including 70 cases aged 70 + with a first VT and 96 controls. We performed an ultrasound examination of the valves in the popliteal veins. The valves were imaged with a 9 MHz linear probe using B-mode ultrasonography. VCT was measured as an indicator for valve function using an automatic inflatable cuff. To estimate the risk of VT, valve thickness was dichotomized at the 90th percentile as measured in controls and VCT was dichotomized at 1 s. Results Mean valve thickness of controls was similar in the left (0.36 mm, 95% CI 0.34-0.37) and right (0.36 mm, 95% CI 0.35-0.38) leg. In 45 cases a valve was observed in the contralateral leg with a mean valve thickness of 0.39 mm (95% CI 0.36-0.42). Cases had an increased valve thickness compared with controls: mean difference 0.028 mm (95%CI 0.001-0.055). Valve thickness > 90th percentile increased the risk of VT 2.9-fold. Mean VCT in controls was 0.38 s, in contralateral leg of cases 0.58 s. VCT > 1 s increased the risk of VT 2.8-fold (95% CI 0.8-10.4). Conclusions Risk of VT was associated with increased valve thickness and valvular reflux of > 1 s.

Recurrent venous thrombosis related to overweight and obesity: results from the MEGA follow-up study.

Essentials Whether excess body weight influences recurrent venous thrombosis (VT) risk is uncertain. We included 3889 VT patients, classified into body mass index (BMI) strata to estimate recurrent VT risk. No evidence of an increased risk for excess body weight was found. Measuring BMI is not a good tool to identify patients at high risk of VT recurrence. SUMMARY: Background Studies on the risk of recurrent venous thrombosis in patients with excess body weight have yielded conflicting results. Objective To estimate whether excess body weight increases the risk of recurrent venous thrombosis. Patients/Methods We included 3889 patients, followed after a first venous thrombosis for a median of 5.6 years. Body mass index (BMI) was calculated as weight in kilograms/height in meters squared, and classified according to three a priori-defined categories (normal weight, overweight, and obesity), as well as by percentiles. Crude incidence rates with 95% confidence intervals (CIs) of recurrent venous thrombosis were estimated as the number of events over the accumulated follow-up time in each BMI category. Cox regression models were used to compare groups, adjusted for age and sex. Results The incidence rate of recurrent venous thrombosis was 3.3 per 100 patient-years. Adjusted hazard ratios of recurrent venous thrombosis in overweight or obese patients in comparison with patients with normal weight were 1.05 (95% CI 0.88-1.27) and 0.94 (95% CI 0.74-1.19), respectively. Stratification by BMI percentile categories yielded similar results. The association between BMI and recurrent venous thrombosis was also absent after stratification by sex, (although a small effect for overweight, but not for obese women, was found), or into those with a first provoked or unprovoked event, or deep vein thrombosis and pulmonary embolism. Conclusions We found no evidence of an association between excess body weight and recurrent venous thrombosis. Measuring BMI is not a useful tool to identify patients at high risk of recurrence.

Male-specific risk of first and recurrent venous thrombosis: a phylogenetic analysis of the Y chromosome.

Essentials Men have an unexplained higher risk of a first and recurrent venous thrombosis (VT) than women. We studied the role of the major European Y chromosome haplogroups in first and recurrent VT. In contrast to a study on coronary artery disease, haplogroup I was not linked to VT risk. Haplogroup E-carriers may have an increased risk of recurrent VT, but a larger study is needed. SUMMARY: Background The risk of venous thrombosis (VT) recurrence is higher in men than in women. When reproductive risk factors are excluded, this sex difference is also apparent for a first VT. The current explanations for this difference are insufficient. Objectives To study the association between chromosome Y haplogroups and the risks of a first and recurrent VT. Methods Y chromosomes of 3742 men (1729 patients; 2013 controls) from the MEGA case-control study were tracked into haplogroups according to the phylogenetic tree. We calculated the risk of a first VT by comparing the major haplogroups with the most frequent haplogroup. For recurrence risk, 1645 patients were followed for a mean of 5 years, during which 350 developed a recurrence (21%; MEGA follow-up study). We calculated recurrence rates for the major haplogroups, and compared groups by calculating hazard ratios. Results We observed 13 haplogroups, of which R1b was the most frequent (59%). The major haplogroups were not associated with a first VT, with odds ratios ranging from 1.01 to 1.15. Haplogroup E carriers had the highest recurrence rate (53.5 per 1000 person-years, 95% confidence interval [CI] 33.3-86.1), whereas haplogroup R1a carriers had the lowest recurrence rate (24.3 per 1000 person-years, 95% CI 12.6-46.6). As compared with haplogroup R1b carriers, both haplogroups were not significantly associated with recurrence risk. Conclusions In contrast to a study on coronary artery disease, our results do not show a clear predisposing effect of Y haplogroups on first and recurrent VT risk in men. It is therefore unlikely that Y variation can explain the sex difference in VT risk.

Genetic risk factors for venous thrombosis in the elderly in a case-control study.

UNLABELLED: Essentials Risk of venous thrombosis (VT) related to common genetic variants in those aged 70+ is unknown. We studied Factor V Leiden, prothrombin mutation, non-O blood group and family history (FH) of VT. Risk of VT was increased 2.2-, 1.4-, 1.3- and 2.1-fold respectively. FH is easy to obtain and can be implemented in clinical decision rules of VT risk in the elderly. Click to hear Prof. Reitsma discuss genetic risk factors of arterial and venous thrombosis SUMMARY: Background As the incidence of venous thrombosis (VT) increases steeply with age and the number of elderly people is on the rise, studies of VT in this age group are important. Objectives We aimed to study the associations of common genetic risk factors (i.e. the factor V Leiden and prothrombin G20210A mutations, non-O blood group and family history of VT) with risk of a first VT in older age (> 70 years). Methods Four hundred and one consecutive cases with a first-time thrombosis and 431 controls (all ≥ 70 years) were included in the AT-AGE case-control study. Information on risk factors for VT, including family history of VT in first-degree relatives, was obtained by interview. Unprovoked VT was defined as thrombosis not related to surgery, fracture, plaster cast or immobility within 3 months prior to VT. Results The risk of VT was 2.2-fold increased in factor V Leiden carriers (95% confidence interval [CI], 1.2-3.9), 1.4-fold increased in prothrombin mutation carriers (95% CI, 0.5-3.9), and 1.3-fold increased in those with non-O blood group (95% CI, 1.0-1.8). Positive family history of VT was associated with a 2.1-fold increased risk of VT (95% CI, 1.5-3.1). The highest risk of VT was found in individuals who had both a positive family history and were carriers of one of the two prothrombotic mutations. Conclusions Genetic factors clearly related to VT in younger populations were also risk factors in older age and a positive family history was also important in this age group.

Is there still room for additional common susceptibility alleles for venous thromboembolism?

UNLABELLED: Essentials Genetic architecture of venous thromboembolism (VTE) remains to be fully disentangled. 11 newly discovered candidate polymorphisms were genotyped in 3019 VTE cases and 2605 controls. None of the 11 polymorphisms were significantly associated with VTE risk. Additional major efforts are needed to identify VTE-associated genetic variants. SUMMARY: Background Through a meta-analysis of 12 genome-wide association studies, the International Network against VENous Thrombosis (INVENT) consortium identified two novel susceptibility loci for venous thromboembolism (VTE). This project has also generated other candidates that need to be confirmed. Objectives To assess the association with VTE of common single-nucleotide polymorphisms (SNPs) that demonstrated strong statistical, but not genome-wide, significance in the INVENT cohorts. Patients/methods Eleven SNPs were genotyped and tested for association with VTE in three case-control studies totaling 3019 patients and 2605 healthy individuals. Results and conclusions None of the tested SNPs showed evidence for association with VTE. Different strategies are needed to decipher the whole spectrum of common and rare genetic variations associated with VTE risk.

Predictive value of factor VIII levels for recurrent venous thrombosis: results from the MEGA follow-up study.

BACKGROUND: Prediction of recurrent venous thrombosis remains a challenge in the clinic. OBJECTIVE: To investigate the predictive value of coagulation factor VIII (FVIII) levels for recurrent venous thrombosis. PATIENTS/METHODS: Patients, aged 18-70 years with a first venous thrombosis, were followed from discontinuation of anticoagulant treatment (1999-2010 MEGA follow-up study). The levels of FVIII activity, FVIII antigen and von Willebrand factor (VWF) antigen were measured at least 3 months after cessation of anticoagulant treatment. RESULTS: Of 2242 patients followed for a median of 6.9 years, 343 developed recurrent thrombosis (incidence rate 2.7/100 patient-years; 95% confidence interval [CI] 2.5-3.1). Recurrence rates steadily increased with higher FVIII activity levels, from 1.4 (95% CI 1.0-1.9), 2.3 (95% CI 1.8-2.9), 3.0 (95% CI 2.4-3.7), 3.2 (95% CI 2.5-4.1), 3.9 (95% CI 2.8-5.3) to 5.1 (95% CI 3.8-6.8) per 100 patient-years, for levels ranging from < 100 IU dL(-1) to > 200 IU dL(-1) . Patients in the highest category of FVIII (> 200 IU dL(-1) ) had a three-fold higher recurrence rate than patients in the lowest category (≤ 100 IU dL(-1) ) (hazard ratio 3.4; 95% CI 2.2-5.3). Results were similar for FVIII antigen and VWF antigen levels, in several sensitivity analyses, and FVIII predicted recurrence rates over a long time period. Within subgroups of patients currently assumed to have low recurrence risks, a high level of FVIII was still predictive for recurrences. Adding FVIII to an existing prediction model (DASH score) improved its predictive value, and, after replacement of D-dimer with FVIII, the model performed equally well, if not better. CONCLUSIONS: FVIII predicted recurrence in a dose-response fashion, overall and in several subgroups, and is a strong candidate component of recurrence prediction tools.

Elevated levels of factor VIII and subsequent risk of all-cause mortality: results from the MEGA follow-up study.

BACKGROUND: Factor VIII (FVIII) levels are increased in individuals with a non-O blood group and play a role in the etiology of thrombosis. High FVIII levels have also been associated with increased all-cause mortality. OBJECTIVE: We explored whether elevated FVIII levels are associated with an increased risk of death in patients who had venous thrombosis and in individuals from the general population, and to what extent this association is causal. METHODS: We followed 2178 patients with previous venous thrombosis and 2827 age and sex-matched community controls for on average 5.5 years and measured their FVIII levels and ABO blood group. RESULTS: All-cause mortality increased in a dose-response fashion with increasing percentiles of FVIII levels. In the thrombosis patients the risk was highest above the 97.5th percentile (FVIII > 199 IU dL(-1) ) with an adjusted hazard ratio (HR) of 3.1 (95% confidence interval [CI], 0.9-10.8) as compared with patients in the 25th percentile category (FVIII ≤ 85 IU dL(-1) ). The adjusted HR was 4.5 (95% CI, 1.4-14.3) in controls. Using non-O blood group as a measure of genetically elevated FVIII levels to determine a causal relationship between FVIII and death showed observed HRs of 0.99 (95% CI, 0.72-1.36) in patients and 1.25 (95% CI, 0.82-1.90) in controls. CONCLUSIONS: We showed a dose-response relationship between high FVIII levels and risk of death in venous thrombosis patients and in individuals from the general population. However, environmental factors, such as chronic comorbidities and chronic inflammation, are at least in part responsible for the association between factor VIII and mortality.

The risk of a first and a recurrent venous thrombosis associated with an elevated D-dimer level and an elevated thrombin potential: results of the THE-VTE study.

BACKGROUND: D-dimer and thrombin generation have been associated with the risk of recurrent venous thrombosis. However, for both measurements, different assays are available, and in vitro thrombin generation may be affected by the problem of contact activation during blood sampling. OBJECTIVES: To determine the association between hypercoagulability and first and recurrent thrombosis by the use of different D-dimer and thrombin generation assays, to assess whether the addition of corn trypsin inhibitor (CTI) prior to blood sampling to inhibit contact activation improved the association between thrombin generation and thrombosis risk, and to calculate the DASH score with two different D-dimer assays. METHODS: A case-control study (626 patients and 361 controls) with subsequent follow-up of the cases was performed (2987 patient-years after stopping of anticoagulant therapy). Blood was drawn 2-3 months after discontinuation of anticoagulation for the first event in citrate tubes with and without CTI. RESULTS/CONCLUSIONS: An elevated D-dimer level and elevated thrombin generation were associated with an increased risk of a first event regardless of the assay used (odds ratios: 1.8-3.4). An elevated D-dimer level but not elevated thrombin generation was associated with the risk of recurrence. Patients with elevated D-dimer levels had a more than two-fold increased recurrence rate (Vidas - hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.4-3.8; HemosIL - HR 2.4, 95% CI 1.5-3.9; Thrombinoscope and Technoclone assay - HR 1.3). Elimination of contact factor activation did not improve the predictive value of thrombin generation. In patients with unprovoked first events, the DASH score had a similar predictive value for deep vein thrombosis and pulmonary embolism, both when calculated with Vidas D-dimer and when calculated with HemosIL D-dimer.

Body height, mobility, and risk of first and recurrent venous thrombosis.

BACKGROUND: Tall people have an increased risk of a first venous thrombosis. Sedentary lifestyle has been shown to act synergistically with body height, especially during long-haul flights. OBJECTIVE: To estimate the relation between height and risk of a first and recurrent venous thrombosis and a possible additional association with a mobile or an immobile lifestyle. METHODS: Patients with a first venous thrombosis and control subjects were included between 1999 and 2004 (MEGA case-control study). Patients were followed for recurrence for an average time of 5.1 years (MEGA follow-up study). Odds ratios and hazard ratios (HRs) per increase of 5 cm were calculated compared with a height of 165-170 cm, separately and in combination with (im)mobility. RESULTS: In 4464 patients who reported their height, we found an increasing risk of a first and recurrent event with height. For men, a 2.9-fold (95% confidence interval [CI] 1.9-4.4) increased risk for first venous thrombosis was found for those between 195 and 200 cm and a 3.8-fold (95% CI 1.5-9.8) higher risk for those > 200 cm compared with the reference category. For recurrence risk, the HRs were 1.7 (95% CI 0.8-3.3) and 3.7 (95% CI 1.4-10.0), respectively. For women, a 1.5-fold (95% CI 0.7-3.4) and 3-fold (95% CI 0.9-9.4) increased risk was found for those > 185 cm for first and recurrent venous thrombosis, respectively. For the tallest men and women, a slight additionally increased risk was observed for sedentary lifestyle. CONCLUSIONS: Tall men and women have an increased risk of first and recurrent venous thrombosis, possibly higher in combination with a sedentary lifestyle.

Differential associations of oral estradiol and conjugated equine estrogen with hemostatic biomarkers.

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 64.1 years and mean BMI of 29.1 kg m(-2) . Twenty-seven per cent of HT contained medroxyprogesterone acetate. Compared with E2 users, CEE users had greater thrombin generation peak values and endogenous thrombin potential, and lower total protein S (multivariate adjusted differences of 49.8 nm (95% CI, 21.0, 78.6), 175.0 nm × Min (95% CI, 54.4, 295.7) and -13.4% (95% CI, -19.8, -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.

The contribution of immobility risk factors to the incidence of venous thrombosis in an older population.

BACKGROUND: Venous thrombosis is common in the older population. Assessment of risk factors is necessary to implement preventive measures. OBJECTIVES: We studied the associations between immobility-related risk factors and thrombosis, specifically, hospitalization, surgery, fractures, plaster cast use, minor injuries, and transient immobility at home, in an older population. PATIENTS AND METHODS: Analyses were performed in the Age and Thrombosis, Acquired and Genetic risk factors in the Elderly (AT-AGE) study, a two-center population-based case-control study. Consecutive cases aged > 70 years with a first-time thrombosis (n = 401) and control subjects > 70 years old without a history of thrombosis (n = 431) were included. Exclusion criteria were active malignancy and severe cognitive disorders. We calculated odds ratios (OR) with 95% confidence intervals (95% CI) after adjustment for age, sex, body mass index, study center, and population-attributable risks. RESULTS: There was a 15-fold (OR 14.8, 95% CI 4.4-50.4) increased risk of thrombosis within 2 weeks after hospital discharge. Surgery (OR 6.6, 95% CI 3.7-11.6), fractures (OR 12.7, 95% CI 3.7-43.7), plaster cast (OR 6.2, 95% CI 2.0-18.9), minor leg injuries (OR 1.9, 95% CI 1.1-3.3), and transient immobility at home (OR 5.0, 95% CI 2.3-11.2) were all associated with thrombosis risk over 3 months. The population-attributable risks for in-hospital immobility was 27%, and for out-of-hospital immobility, 15%. CONCLUSIONS: In those > 70 years of age, in-hospital and out-of hospital immobility are strong risk factors for thrombosis. Additional studies on preventive measures during immobilization in this age group should not focus solely on hospital settings.

Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis.

OBJECTIVE: To provide a comprehensive overview of the risk of venous thrombosis in women using different combined oral contraceptives. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: PubMed, Embase, Web of Science, Cochrane, Cumulative Index to Nursing and Allied Health Literature, Academic Search Premier, and ScienceDirect up to 22 April 2013. REVIEW METHODS: Observational studies that assessed the effect of combined oral contraceptives on venous thrombosis in healthy women. The primary outcome of interest was a fatal or non-fatal first event of venous thrombosis with the main focus on deep venous thrombosis or pulmonary embolism. Publications with at least 10 events in total were eligible. The network meta-analysis was performed using an extension of frequentist random effects models for mixed multiple treatment comparisons. Unadjusted relative risks with 95% confidence intervals were reported. The requirement for crude numbers did not allow adjustment for potential confounding variables. RESULTS: 3110 publications were retrieved through a search strategy; 25 publications reporting on 26 studies were included. Incidence of venous thrombosis in non-users from two included cohorts was 1.9 and 3.7 per 10,000 woman years, in line with previously reported incidences of 1-6 per 10,000 woman years. Use of combined oral contraceptives increased the risk of venous thrombosis compared with non-use (relative risk 3.5, 95% confidence interval 2.9 to 4.3). The relative risk of venous thrombosis for combined oral contraceptives with 30-35 µg ethinylestradiol and gestodene, desogestrel, cyproterone acetate, or drospirenone were similar and about 50-80% higher than for combined oral contraceptives with levonorgestrel. A dose related effect of ethinylestradiol was observed for gestodene, desogestrel, and levonorgestrel, with higher doses being associated with higher thrombosis risk. CONCLUSION: All combined oral contraceptives investigated in this analysis were associated with an increased risk of venous thrombosis. The effect size depended both on the progestogen used and the dose of ethinylestradiol.

Venous thrombosis: understanding the paradoxes of recurrence.

The decision to continue anticoagulant treatment in patients with a first venous thrombosis after the initial treatment period has strong, life-long implications. Both the risk of recurrence when treatment is stopped and the risk of bleeding when it is continued are high and will persist over a patient's lifetime. For clinicians, rational strategies to stratify their patients into levels of risk of recurrence are limited. To support in the decision to continue or not, it is of the utmost importance to understand why some people develop a second event and others do not and how these people can be identified. This is not easy as, contrary to intuition, the risk profile of a recurrent event is entirely different from that of a first: Some genetic factors that have a major effect on first thrombosis only marginally predict recurrence, while, for instance, the opposite is true for male sex. These paradoxes can be explained when we understand etiology of a first event, how rates for first and second event cannot be directly compared, and how fixed risk factors cannot be predictors, while factors that are not causes can yet be predictors. Integrating all knowledge and combining the best predicting variables will ultimately lead to ways to estimate an individual's recurrence risk and hence to decide on optimal further treatment.

The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy.

BACKGROUND: Oral contraception (OC) and postmenopausal hormone therapy (HT) can be used to alleviate menopausal symptoms. However, the risk of venous thrombosis (VT) associated with OC use in women over 50 years old has never been assessed and the two preparations have not been directly compared. OBJECTIVES: To determine and compare the risk of VT associated with OC and HT use. METHODS: From a large case-control study, 2550 women aged over 50 years old, 1082 patients with a first VT and 1468 controls, were included. Odds ratios (ORs) and 95% confidence intervals for VT were calculated for OC-users (164 patients and 54 controls) and HT-users (88 patients and 102 controls) compared with non-hormone users (823 patients and 1304 controls). RESULTS: OC-users had a 6.3-fold (4.6-9.8) increased risk of VT. This ranged from 5.4 (3.3-8.9) for preparations containing levonorgestrel to 10.2 (4.8-21.7) for desogestrel. The VT-risk associated with oral HT use was 4.0 (1.8-8.2) for conjugated equine estrogen combined with medroxyprogesterone acetate and 3.9 (1.5-10.7) for micronized estradiol combined with norethisterone acetate. Non-oral HT did not increase the risk of VT: OR 1.1 (0.6-1.8). Relative risk estimates were further increased in hormone users with factor V Leiden, prothrombin G20210A or blood group non-O and hormone users with a family history of VT. CONCLUSIONS: In this study, non-oral HT seemed to be the safest hormonal preparation in women over 50 years old. OC use increased the VT risk the most, especially in women with inherited thrombophilia or a family history of VT.