Association between cardiovascular risk factors and venous thromboembolism in the elderly.

BACKGROUND: The preponderance of the evidence supports no association between traditional cardiovascular risk factors and venous thromboembolism (VTE), other than obesity. There are limited data in older people. OBJECTIVES: To investigate whether cardiovascular risk factors (body mass index, smoking, alcohol intake, hypertension, and diabetes) are associated with the risk of VTE in elderly and to assess the combined effect between cardiovascular risk factors and genetic risk factors for VTE (factor V Leiden/prothrombin 20210A, positive family history of VTE, and non-O blood group). METHODS: The Age and Thrombosis, Acquired and Genetic risk factors in the Elderly study is a multicenter case-control study performed in Vermont, USA and Leiden, the Netherlands, comprising 401 cases with first VTE and 431 control subjects, all aged ≥70 years. To assess the risk of VTE, odds ratios (OR) with 95% confidence intervals (CIs) were calculated, adjusting for potential confounders. RESULTS: Both height and weight were positively associated with VTE risk: the ORs were 2.2 (95% CI, 1.2-3.9) and 1.5 (95% CI, 1.0-2.4) in the top quartile for height and weight separately. This risk was more pronounced for unprovoked VTE. Smoking, alcohol intake, and diabetes were not associated with VTE. Higher systolic and diastolic blood pressure and hypertension were associated with a decreased risk of VTE. In the presence of a genetic predisposition, height and weight further increased the risk of VTE. CONCLUSIONS: In the elderly, height and weight are positively associated with the risk of VTE. With genetic predisposition, higher levels of height and weight further increase the risk of VTE.

The EHA Research Roadmap: Blood Coagulation and Hemostatic Disorders.

In 2016, the European Hematology Association (EHA) published the EHA Roadmap for European Hematology Research1 aiming to highlight achievements in the diagnostics and treatment of blood disorders, and to better inform European policy makers and other stakeholders about the urgent clinical and scientific needs and priorities in the field of hematology. Each section was coordinated by 1-2 section editors who were leading international experts in the field. In the 5 years that have followed, advances in the field of hematology have been plentiful. As such, EHA is pleased to present an updated Research Roadmap, now including 11 sections, each of which will be published separately. The updated EHA Research Roadmap identifies the most urgent priorities in hematology research and clinical science, therefore supporting a more informed, focused, and ideally funded future for European hematology research. The 11 EHA Research Roadmap sections include Normal Hematopoiesis; Malignant Lymphoid Diseases; Malignant Myeloid Diseases; Anemias and Related Diseases; Platelet Disorders; Blood Coagulation and Hemostatic Disorders; Transfusion Medicine; Infections in Hematology; Hematopoietic Stem Cell Transplantation; CAR-T and Other Cell-based Immune Therapies; and Gene Therapy.

Rise of levels of von Willebrand factor and factor VIII with age: Role of genetic and acquired risk factors.

BACKGROUND: Von Willebrand factor (VWF) levels are regulated by genetic and acquired factors. The acquired factors are mostly related to age and could be mediators of the age effect on VWF levels. OBJECTIVES: To disentangle the role of genetic (sex, blood group) and acquired factors (comorbidities, body mass index, reduced kidney function, hormone use, and inflammation) in regulating von Willebrand factor antigen (VWF:Ag) and factor VIII activity (FVIII:C) levels in the normal population. METHODS: Analysis were performed in a large population sample (2923 individuals) from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study), after exclusion of individuals with active cancer and women who were pregnant or within nine months postpartum. The increase of VWF:Ag and FVIII:C with age was evaluated by linear regression after the age of 40 years. Analyses were adjusted for acquired factors and stratified for sex and blood group. RESULTS: VWF:Ag and FVIII:C increased with age: increase per decade of age for VWF:Ag 18 IU/dL (95%CI 15-20) and for FVIII:C 12 IU/dL (95%CI 10-14). After adjustment for acquired factors, the increase per decade was 13 IU/dL (95%CI 10-16) for VWF:Ag and 9 IU/dL (95%CI 6-11) for FVIII:C. The stratified analysis for blood group showed higher increase in the non-O group, but these differences were annulled after adjustment for acquired factors. CONCLUSIONS: VWF:Ag and FVIII:C increase with age. Carriers of blood group non-O present a steeper increase of VWF:Ag and FVIII:C with age, that is mediated by acquired factors.

Association Between Hepatic Triglyceride Content and Coagulation Factors: The Netherlands Epidemiology of Obesity Study.

OBJECTIVE: Whether hepatic triglyceride content (HTGC) contributes to hypercoagulability beyond total body fat (TBF) and visceral adipose tissue (VAT) is unclear. We, therefore, aimed to investigate the association between HTGC and coagulation factors (F)I (fibrinogen), VIII, IX, and XI while adjusting for TBF and VAT. Approach and Results: In this cross-sectional analysis of the NEO study (Netherlands Epidemiology of Obesity; n=6671), a random subset of participants underwent magnetic resonance imaging and magnetic resonance spectroscopy to assess VAT and HTGC (n=2580). We excluded participants without complete imaging and coagulation assessment, and with history of liver disease, venous thrombosis, or on anticoagulation. Mean differences in coagulation factor levels across HTGC quartiles were estimated by linear regression adjusted for age, sex, ethnicity, education, alcohol intake, physical activity, smoking, estrogen, and menopause, in addition to TBF and VAT. Among the 1946 participants included, median HTGC was 2.66% (interquartile range: 1.34%-6.27%). Coagulation factor levels increased dose-dependently across HTGC quartiles. Mean differences between the fourth and first quartiles were 14.7 mg/dL (95% CI, 2.1-27.2) for fibrinogen, 6.7 IU/dL (95% CI, 0.5-12.9) for FVIII, 26.1 IU/dL (95% CI, 22.4-29.8) for FIX, and 8.6 IU/dL (95% CI, 4.6-12.6) for FXI. With further adjustment for TBF and VAT, the dose-response association of HTGC with FIX persisted, whereas associations with other factors disappeared. CONCLUSIONS: HTGC was associated with various coagulation factors, of which FIX remained associated with HTGC after adjustment for TBF and VAT. HTGC might contribute to venous thrombosis risk beyond total body and visceral fat through FIX levels.

Prediction of recurrent venous thrombosis in all patients with a first venous thrombotic event: The Leiden Thrombosis Recurrence Risk Prediction model (L-TRRiP).

BACKGROUND: Recurrent venous thromboembolism (VTE) is common. Current guidelines suggest that patients with unprovoked VTE should continue anticoagulants unless they have a high bleeding risk, whereas all others can stop. Prediction models may refine this dichotomous distinction, but existing models apply only to patients with unprovoked first thrombosis. We aimed to develop a prediction model for all patients with first VTE, either provoked or unprovoked. METHODS AND FINDINGS: Data were used from two population-based cohorts of patients with first VTE from the Netherlands (Multiple Environment and Genetic Assessment of Risk Factors for Venous Thrombosis [MEGA] follow-up study, performed from 1994 to 2009; model derivation; n = 3,750) and from Norway (Tromsø study, performed from 1999 to 2016; model validation; n = 663). Four versions of a VTE prediction model were developed: model A (clinical, laboratory, and genetic variables), model B (clinical variables and fewer laboratory markers), model C (clinical and genetic factors), and model D (clinical variables only). The outcome measure was recurrent VTE. To determine the discriminatory power, Harrell's C-statistic was calculated. A prognostic score was assessed for each patient. Kaplan-Meier plots for the observed recurrence risks were created in quintiles of the prognostic scores. For each patient, the 2-year predicted recurrence risk was calculated. Models C and D were validated in the Tromsø study. During 19,201 person-years of follow-up (median duration 5.7 years) in the MEGA study, 507 recurrences occurred. Model A had the highest predictive capability, with a C-statistic of 0.73 (95% CI 0.71-0.76). The discriminative performance was somewhat lower in the other models, with C-statistics of 0.72 for model B, 0.70 for model C, and 0.69 for model D. Internal validation showed a minimal degree of optimism bias. Models C and D were externally validated, with C-statistics of 0.64 (95% CI 0.62-0.66) and 0.65 (95% CI 0.63-0.66), respectively. According to model C, in 2,592 patients with provoked first events, 367 (15%) patients had a predicted 2-year risk of >10%, whereas in 1,082 patients whose first event was unprovoked, 484 (45%) had a predicted 2-year risk of <10%. A limitation of both cohorts is that laboratory measurements were missing in a substantial proportion of patients, which therefore were imputed. CONCLUSIONS: The prediction model we propose applies to patients with provoked or unprovoked first VTE-except for patients with (a history of) cancer-allows refined risk stratification, and is easily usable. For optimal individualized treatment, a management study in which bleeding risks are also taken into account is necessary.

Hyperhomocysteinaemia and the risk of recurrent venous thrombosis: results from the MEGA follow-up study.

The measurement of homocysteine is still part of routine thrombosis or thrombophilia work-up in many thrombosis centres in the world. Previous observational studies have shown that hyperhomocysteinaemia is associated with an increased risk of first and recurrent venous thrombosis (VT). Randomised trials, however, showed no benefit of homocysteine-lowering therapy on the risk of first or recurrent VT. This discrepancy could be explained by incomplete adjustment for confounders in the observational studies. We investigated in a large population-based follow-up study whether if the levels of homocysteine and its metabolites, methionine and cysteine, were associated with recurrent VT. Approximately three months after discontinuation of anticoagulant treatment, homocysteine, methionine and cysteine concentrations were measured in 2210 patients with VT. During a median follow-up of 6·9 years, 340 patients developed a recurrence (incidence rate, 2·8/100 patient-years). We found that elevated homocysteine concentrations were not associated with an increased risk of recurrent VT, neither as a continuous variable per 5 µmol/l increase (hazard ratio [HR] 0·98 (95% confidence interval [CI], 0·90-1·04)) nor when levels were >95th (>23·0 µmol/l) percentile (HR 1·03 (95% CI, 0·65-1·64)). Similar results were obtained for cysteine and methionine values. We conclude that hyperhomocysteinaemia is not associated with an increased risk of recurrent VT.

Endogenous sex hormones and risk of venous thromboembolism in young women.

BACKGROUND: The risk of venous thromboembolism (VTE) in young women can predominantly be attributed to exogenous hormone use. The influence of (abnormalities in) endogenous sex hormones, as in polycystic ovary syndrome (PCOS) or primary ovarian insufficiency (POI), on VTE risk is uncertain. OBJECTIVES: Th assess the association between endogenous sex hormone levels and VTE risk. METHODS: Women aged ≤45 years from the MEGA case-control study who provided a blood sample in the absence of exogenous hormone exposure or pregnancy were included. Sex hormone-binding globulin (SHBG), estradiol, follicle-stimulating hormone (FSH) and testosterone were measured. The free androgen index (FAI) and estradiol to testosterone ratio (E:T) were calculated. VTE risk was assessed according to quartiles (Qs) of levels and clinical cut-offs as proxies for PCOS (FAI > 4.5) and POI (FSH > 40 U/L). Logistic regression models were used to estimate adjusted odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Six hundred and sixty-five women (369 cases; 296 controls) were eligible for the analyses. Testosterone and FSH levels, E:T and POI (FSH > 40 U/L vs FSH ≤ 40 U/L) were not associated with VTE risk. For estradiol, VTE risk was increased with levels in Q4 vs Q1 (OR 1.6; 95% CI 1.0-2.5). There was a dose-response relationship between SHBG levels and VTE risk, with the highest OR at Q4 vs Q1: 2.0 (95% CI 1.2-3.3). FAI > 4.5 (PCOS proxy) vs FAI ≤ 4.5 was associated with increased VTE risk (OR 3.3; 95% CI 0.9-11.8). CONCLUSIONS: Estradiol, SHBG and FAI were associated with VTE risk, suggesting a role for endogenous sex hormones in the pathophysiology of VTE in young women.

A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology.

Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a trans-ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring F7 messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel (REEP3 and JAZF1-AS1) and 6 known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing REEP3 in HuH7 cells upregulated FVII, whereas silencing JAZF1 downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at REEP3 and JAZF1 contribute to FVII activity by regulating F7 expression levels. FVII activity appears to contribute to the etiology of IS in the general population.

Venous Thrombosis Risk after Arthroscopy of the Knee: Derivation and Validation of the L-TRiP(ascopy) Score.

Patients at high risk for venous thrombosis (VT) following knee arthroscopy could potentially benefit from thromboprophylaxis. We explored the predictive values of environmental, genetic risk factors and levels of coagulation markers to integrate these into a prediction model. Using a population-based case-control study into the aetiology of VT, we developed a Complete (all variables), Screening (easy to use in clinical practice) and Clinical (only environmental risk factors) model. The Clinical model was transformed into the Leiden-Thrombosis Risk Prediction (arthroscopy) score [L-TRiP(ascopy) score]. Model validation was performed both internally and externally in another case-control study. A total of 4,943 cases and 6,294 controls were maintained in the analyses, 107 cases and 26 controls had undergone knee arthroscopy. Twelve predictor variables (8 environmental, 3 haemorheological and 1 genetic) were selected from 52 candidates and incorporated into the Complete model (area under the curve [AUC] of 0.81, 95% confidence interval [CI], 0.76-0.86). The Screening model (9 predictors: environmental factors plus factor VIII activity) reached an AUC of 0.76 (95% CI, 0.64-0.88) and the Clinical (and corresponding L-TRiP(ascopy)) model an AUC of 0.72 (95% CI, 0.60-0.83). In the internal and external validation, the Complete model reached an AUC of 0.78 (95% CI, 0.52-0.98) and 0.75 (95% CI, 0.42-1.00), respectively, while the other models performed slightly less well.

Next-generation DNA sequencing to identify novel genetic risk factors for cerebral vein thrombosis.

BACKGROUND: Cerebral vein thrombosis (CVT) is a rare, life-threatening disease affecting one adult per 100,000 per year. Genetic risk factors are deficiencies of the natural anticoagulant proteins antithrombin, protein C, protein S or single nucleotide polymorphisms such as factor V Leiden and prothrombin 20210A. In 20% of patients, the cause of CVT remains unknown. AIM: To identify novel genetic risk factors for CVT using targeted next-generation DNA sequencing (NGS). METHODS: We investigated 171 CVT patients and 298 healthy controls. Patients were selected using the following criteria: objective diagnosis of CVT, no active cancer. We performed targeted NGS analysis of the protein-coding regions of 734 candidate genes related to hemostasis and inflammation, 150 ancestry informative markers and 28 thrombosis-associated variants. RESULTS: We identified 3723 common and low frequency variants with minor allele frequency (MAF) >1% in 590 genes. Single variant association testing using logistic regression analysis identified rs8176719 insertion/deletion (indel) variant in the ABO gene associated with CVT (age and sex adjusted OR 2.03; 95% CI 1.52-2.73; P = 2.07 × 10-6; Bonferroni P = 0.008). In addition, we identified 8839 rare variants (MAF ≤ 1%) in 723 genes. Gene-based association analysis of these rare variants using a burden test revealed only a tentative association of non-coding variants located in the F8 locus with CVT. CONCLUSION: Targeted NGS identified a common indel variant rs8176719 in the ABO gene. Gene-based tests of association failed to reveal genomic loci with a cumulative burden of rare variants associated with CVT.

Functional Impairment and Risk of Venous Thrombosis in Older Adults.

OBJECTIVES: To determine the role of age-specific risk factors for thrombosis in older age, such as functional impairment. DESIGN: Case-control study. SETTING: The Age and Thrombosis-Acquired and Genetic risk factors in the Elderly Study, a two-center study conducted in the Netherlands and the United States from 2008 to 2011. PARTICIPANTS: Individuals aged 70 and older with a first-time deep venous thrombosis in the leg or pulmonary embolism (n = 401) and controls aged 70 and older (n = 431) without a history of thrombosis. Exclusion criteria were active malignancy and severe cognitive disorders. MEASUREMENTS: The thrombotic risk associated with functional impairment, defined as impairment in two or more activities of daily living (ADLs), impaired mobility (inability to walk outside), sedentary lifestyle (≥20 h/d sleeping or sitting), and low handgrip strength (<15th percentile), was assessed. Odds ratios (ORs) adjusted for age, sex, and study center with 95% confidence intervals (95% CI) and population attributable risks (PAR) were calculated. RESULTS: Risk of venous thrombosis was 2.9 times greater (OR = 2.9, 95% CI = 1.6-5.3) in individuals with impairment in ADLs, three times as great (OR = 3.0, 95% CI = 1.9-4.7) in those with impaired mobility, four times as great (OR = 4.0, 95% CI = 2.5-6.3) in those with a sedentary life style, and 2.3 times as great (OR = 2.3, 95% CI = 1.5-3.4) in those with weak handgrip strength. PARs were 8% for ADL disability, 13% for inability to walk outside for 15 minutes, 29% for sedentary lifestyle, and 13% for weak hand grip strength. CONCLUSION: In individuals aged 70 and older, functional impairments are a major risk factor for venous thrombosis. These findings may help providers caring for older people be more aware of venous thrombosis risk.

Genome-wide association study with additional genetic and post-transcriptional analyses reveals novel regulators of plasma factor XI levels.

Coagulation factor XI (FXI) has become increasingly interesting for its role in pathogenesis of thrombosis. While elevated plasma levels of FXI have been associated with venous thromboembolism and ischemic stroke, its deficiency is associated with mild bleeding. We aimed to determine novel genetic and post-transcriptional plasma FXI regulators.We performed a genome-wide association study (GWAS) for plasma FXI levels, using novel data imputed to the 1000 Genomes reference panel. Individual GWAS analyses, including a total of 16,169 European individuals from the ARIC, GHS, MARTHA and PROCARDIS studies, were meta-analysed and further replicated in 2,045 individuals from the F5L family, GAIT2 and MEGA studies. Additional association with activated partial thromboplastin time (aPTT) was tested for the top SNPs. In addition, a study on the effect of miRNA on FXI regulation was performed using in silico prediction tools and in vitro luciferase assays.Three loci showed robust, replicating association with circulating FXI levels: KNG1 (rs710446, P-value = 2.07 × 10-302), F11 (rs4253417, P-value = 2.86 × 10-193), and a novel association in GCKR (rs780094, P-value = 3.56 ×10-09), here for the first time implicated in FXI regulation. The two first SNPs (rs710446 and rs4253417) also associated with aPTT. Conditional and haplotype analyses demonstrated a complex association signal, with additional novel SNPs modulating plasma FXI levels in both the F11 and KNG1 loci. Finally, eight miRNAs were predicted to bind F11 mRNA. Over-expression of either miR-145 or miR-181 significantly reduced the luciferase activity in cells transfected with a plasmid containing FXI-3'UTR.These results should open the door to new therapeutic targets for thrombosis prevention.

Venous Thrombosis Risk after Cast Immobilization of the Lower Extremity: Derivation and Validation of a Clinical Prediction Score, L-TRiP(cast), in Three Population-Based Case-Control Studies.

BACKGROUND: Guidelines and clinical practice vary considerably with respect to thrombosis prophylaxis during plaster cast immobilization of the lower extremity. Identifying patients at high risk for the development of venous thromboembolism (VTE) would provide a basis for considering individual thromboprophylaxis use and planning treatment studies. The aims of this study were (1) to investigate the predictive value of genetic and environmental risk factors, levels of coagulation factors, and other biomarkers for the occurrence of VTE after cast immobilization of the lower extremity and (2) to develop a clinical prediction tool for the prediction of VTE in plaster cast patients. METHODS AND FINDINGS: We used data from a large population-based case-control study (MEGA study, 4,446 cases with VTE, 6,118 controls without) designed to identify risk factors for a first VTE. Cases were recruited from six anticoagulation clinics in the Netherlands between 1999 and 2004; controls were their partners or individuals identified via random digit dialing. Identification of predictor variables to be included in the model was based on reported associations in the literature or on a relative risk (odds ratio) > 1.2 and p ≤ 0.25 in the univariate analysis of all participants. Using multivariate logistic regression, a full prediction model was created. In addition to the full model (all variables), a restricted model (minimum number of predictors with a maximum predictive value) and a clinical model (environmental risk factors only, no blood draw or assays required) were created. To determine the discriminatory power in patients with cast immobilization (n = 230), the area under the curve (AUC) was calculated by means of a receiver operating characteristic. Validation was performed in two other case-control studies of the etiology of VTE: (1) the THE-VTE study, a two-center, population-based case-control study (conducted in Leiden, the Netherlands, and Cambridge, United Kingdom) with 784 cases and 523 controls included between March 2003 and December 2008 and (2) the Milan study, a population-based case-control study with 2,117 cases and 2,088 controls selected between December 1993 and December 2010 at the Thrombosis Center, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy. The full model consisted of 32 predictors, including three genetic factors and six biomarkers. For this model, an AUC of 0.85 (95% CI 0.77-0.92) was found in individuals with plaster cast immobilization of the lower extremity. The AUC for the restricted model (containing 11 predictors, including two genetic factors and one biomarker) was 0.84 (95% CI 0.77-0.92). The clinical model (consisting of 14 environmental predictors) resulted in an AUC of 0.77 (95% CI 0.66-0.87). The clinical model was converted into a risk score, the L-TRiP(cast) score (Leiden-Thrombosis Risk Prediction for patients with cast immobilization score), which showed an AUC of 0.76 (95% CI 0.66-0.86). Validation in the THE-VTE study data resulted in an AUC of 0.77 (95% CI 0.58-0.96) for the L-TRiP(cast) score. Validation in the Milan study resulted in an AUC of 0.93 (95% CI 0.86-1.00) for the full model, an AUC of 0.92 (95% CI 0.76-0.87) for the restricted model, and an AUC of 0.96 (95% CI 0.92-0.99) for the clinical model. The L-TRiP(cast) score resulted in an AUC of 0.95 (95% CI 0.91-0.99). Major limitations of this study were that information on thromboprophylaxis was not available for patients who had plaster cast immobilization of the lower extremity and that blood was drawn 3 mo after the thrombotic event. CONCLUSIONS: These results show that information on environmental risk factors, coagulation factors, and genetic determinants in patients with plaster casts leads to high accuracy in the prediction of VTE risk. In daily practice, the clinical model may be the preferred model as its factors are most easy to determine, while the model still has good predictive performance. These results may provide guidance for thromboprophylaxis and form the basis for a management study.

Genetic variants in Cell Adhesion Molecule 1 (CADM1): a validation study of a novel endothelial cell venous thrombosis risk factor.

INTRODUCTION: In a protein C deficient family, we recently identified a candidate gene, CADM1, which interacted with protein C deficiency in increasing the risk of venous thrombosis (VT). This study aimed to determine whether CADM1 variants also interact with protein C pathway abnormalities in increasing VT risk outside this family. MATERIALS AND METHODS: We genotyped over 300 CADM1 variants in the population-based MEGA case-control study. We compared VT risks between cases with low protein C activity (n=194), low protein S levels (n=23), high factor VIII activity (n=165) or factor V Leiden carriers (n=580), and all 4004 controls. Positive associations were repeated in all 3496 cases and 4004 controls. RESULTS: We found 22 variants which were associated with VT in one of the protein C pathway risk groups. After mutual adjustment, six variants remained associated with VT. The strongest evidence was found for rs220842 and rs11608105. For rs220842, the odds ratio (OR) for VT was 3.2 (95% CI 1.2-9.0) for cases with high factor VIII activity compared with controls. In addition, this variant was associated with an increased risk of VT in the overall study population (OR: 1.5, 95% CI 1.0-2.2). The other variant, rs11608105, was not associated with VT in the overall study population (OR: 1.0, 95% CI 0.8-1.1), but showed a strong effect on VT risk (OR: 21, 95% CI 5.1-88) when combined with low protein C or S levels. CONCLUSIONS: In a population-based association study, we confirm a role for CADM1 variants in increasing the risk of VT by interaction with protein C pathway abnormalities.

Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens.

IMPORTANCE: Little is known about the comparative cardiovascular safety of oral hormone therapy products, which impedes women from making informed safety decisions about hormone therapy to treat menopausal symptoms. OBJECTIVE: To compare the relative clinical cardiovascular safety of 2 commonly used oral estrogen drugs-conjugated equine estrogens (CEEs) and estradiol. DESIGN, SETTING, AND PARTICIPANTS: Population-based, case-control study from January 1, 2003, to December 31, 2009, comparing cardiovascular event risk associated with current CEEs and estradiol use in a large health maintenance organization in which the preferred formulary estrogen changed from CEEs to estradiol during the course of data collection. Participants were 384 postmenopausal women aged 30 to 79 years using oral hormone therapy. MAIN OUTCOMES AND MEASURES: Incident venous thrombosis was the primary clinical outcome, and incident myocardial infarction and ischemic stroke were secondary outcomes. As validation, an intermediate clotting phenotype, the endogenous thrombin potential-based normalized activated protein C sensitivity ratio, was measured in plasma of controls. RESULTS: We studied 68 venous thrombosis, 67 myocardial infarction, and 48 ischemic stroke cases, with 201 matched controls; all participants were current users of oral CEEs or estradiol. In adjusted analyses, current oral CEEs use compared with current oral estradiol use was associated with an increased venous thrombosis risk (odds ratio, 2.08; 95% CI, 1.02-4.27; P = .045) and an increased myocardial infarction risk that did not reach statistical significance (odds ratio, 1.87; 95% CI, 0.91-3.84; P = .09) and was not associated with ischemic stroke risk (odds ratio, 1.13; 95% CI, 0.55-2.31; P = .74). Among 140 controls, CEEs users compared with estradiol users had higher endogenous thrombin potential-based normalized activated protein C sensitivity ratios (P < .001), indicating a stronger clotting propensity. CONCLUSIONS AND RELEVANCE: In an observational study of oral hormone therapy users, CEEs use was associated with a higher risk of incident venous thrombosis and possibly myocardial infarction than estradiol use. This risk differential was supported by biologic data. These findings need replication and suggest that various oral estrogen drugs may be associated with different levels of cardiovascular risk.

The risk of venous thrombosis in individuals with a history of superficial vein thrombosis and acquired venous thrombotic risk factors.

Superficial vein thrombosis (SVT) increases the risk of venous thrombosis fourfold to sixfold. As most individuals with SVT do not develop venous thrombosis, additional risk factors may explain the risk of developing a venous thrombosis. In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis study, we assessed the risk of venous thrombosis in individuals with previous SVT and a mild thrombotic risk factor (smoking or overweight/obesity), a strong risk factor (surgery, hospitalization, plaster cast immobilization, or malignancy), or a reproductive factor in women (oral contraception, postmenopausal hormone therapy, or pregnancy/puerperium). Individuals with previous SVT alone had a 5.5-fold (95% confidence interval [CI], 4.4-6.8) increased risk of venous thrombosis. This was 9.3 (95% CI, 7.2-12.1) combined with a mild thrombotic risk factor, 31.4 (95% CI, 14.6-67.5) with a strong risk factor, and 34.9 (95% CI, 19.1-63.8) in women with a reproductive risk factor. The highest separate risk estimates were found for SVT with surgery (42.5; 95% CI, 10.2-177.6), hospitalization (49.8; 95% CI, 11.9-209.2), or oral contraception (43.0; 95% CI, 15.5-119.3 in women). In conclusion, the risk of venous thrombosis is markedly increased in individuals with previous SVT who have an acquired thrombotic risk factor.

Long-term survival in a large cohort of patients with venous thrombosis: incidence and predictors.

BACKGROUND: Venous thrombosis is a common disease with a high mortality rate shortly after the event. However, details on long-term mortality in these patients are lacking. The aim of this study was to determine long-term mortality in a large cohort of patients with venous thrombosis. METHODS AND FINDINGS: 4,947 patients from the Multiple Environmental and Genetic Assessment study of risk factors for venous thrombosis (MEGA study) with a first nonfatal venous thrombosis or pulmonary embolism and 6,154 control individuals without venous thrombosis, aged 18 to 70 years, were followed up for 8 years. Death and causes of death were retrieved from the Dutch death registration. Standardized mortality ratios (SMRs) were calculated for patients compared with control individuals. Several subgroups were studied as well. 736 participants (601 patients and 135 controls) died over a follow-up of 54,948 person-years. The overall mortality rate was 22.7 per 1,000 person-years (95% CI 21.0-24.6) for patients and 4.7 per 1,000 person-years (95% CI 4.0-5.6) for controls. Patients with venous thrombosis had a 4.0-fold (95% CI 3.7-4.3) increased risk of death compared with controls. The risk remained increased up to 8 years after the thrombotic event, even when no additional comorbidities were present. The highest risk of death was found for patients with additional malignancies (SMR 5.5, 95% CI 5.0-6.1). Main causes of death were diseases of the circulatory system, venous thrombosis, and malignancies. Main limitation was a maximum age of 70 at time of inclusion for the first event. Therefore results can not be generalized to those in the highest age categories. CONCLUSIONS: Patients who experienced a first venous thrombosis had an increased risk of death which lasted up to 8 years after the event, even when no comorbidities were present at time of thrombosis. Future long-term clinical follow-up could be beneficial in these patients. Please see later in the article for the Editors' Summary.

Abdominal scar recurrences of cervical cancer: incidence and characteristics: a case-control study.

BACKGROUND: Tumor recurrence in the surgical scar after radical hysterectomy for cervical cancer has been reported, but the incidence is unknown. Facts about patient and tumor characteristics and follow-up are lacking. The objective of this study was to analyze the incidence and characteristics of cervical cancer scar recurrences. METHODS: All patients who were surgically treated for cervical cancer in our center between 1984 and 2007 were reviewed for scar recurrences. For each case, 5 random controls were selected. Clinical characteristics were compared between the cases and controls. RESULTS: Eleven (1.3%) of 842 patients developed a scar recurrence. Mean time between surgery and scar recurrence was 16 months (range, 2-45 months). For 8 patients (73%), the scar recurrence was the first disease recurrence. Five patients (45%) died, and 2 (18%) were lost to follow-up. Mean time between scar recurrence and death was 9 months. Ninety-one percent of the cases had recurrent disease besides the scar recurrence during follow-up. The case group had a higher percentage of advanced FIGO (International Federation of Gynecology and Obstetrics) stage and postoperatively found involvement of parametria or resection margins and tumor diameter greater than 4 cm, whereas lymph nodes were more often involved in the control group. CONCLUSIONS: The incidence of scar recurrences after primary surgery for cervical cancer was 1.3%. Time to development was variable, and prognosis was poor. Besides higher FIGO stage and concurrent unfavorable pathological characteristics, we found no outstanding characteristics of patients with scar recurrence. Scar recurrences go hand in hand with recurrent disease at other locations and seem a manifestation of tumors with extensive metastatic potential.

Venous thrombosis of the upper extremity: effect of blood group and coagulation factor levels on risk.

Venous thrombosis of the upper extremity is a rare form of thrombosis, accounting for around 4% of all venous thromboses, and for which only a few risk factors are known. This case-control study investigated the effect of coagulation factors on risk of venous thrombosis of the upper extremity. Patients with venous thrombosis of the arm and partner controls were selected from the Multiple Environmental and Genetic Assessment study, a large population-based case-control study. Participants with a malignancy were excluded. Odds ratios (OR) were estimated for elevated levels of factor II, VII, VIII, IX, X, XI, von Willebrand Factor (VWF), and fibrinogen, low levels of protein C, protein S, and antithrombin, and for blood group non-O. Substantially increased risks of venous thrombosis of the upper extremity were found for patients with high levels (above 90th percentile versus below) of factor VIII (OR: 4.2, 95% confidence interval (CI): 2.2-7.9), VWF (OR: 4.0, 95% CI: 2.1-7.8), fibrinogen (OR: 2.9, 95% CI, 1.5-5.7), and for blood group non-O compared to O (OR: 2.1, 95% CI, 1.3-3.6). The other factors were not associated with an increased risk. Elevated levels of several procoagulant factors are associated with a strongly increased risk of venous thrombosis of the upper extremity.