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Body size measures, hemostatic and inflammatory markers and risk of venous thrombosis: The Longitudinal Investigation of Thromboembolism Etiology.

ABSTRACT: OBJECTIVE:Obesity is an important venous thrombosis (VT) risk factor but the reasons for this are unclear. MATERIALS AND METHODS:In a cohort of 20,914 individuals aged 45 and older without prior VT, we calculated the relative risk (RR) of VT over 12.6years follow-up according to baseline body size measures, and studied whether associations were mediated by biomarkers of hemostasis and inflammation that are related to adiposity. RESULTS:Greater levels of all body size measures (weight, height, waist, hip circumference, calf circumference, body-mass index, waist-hip ratio, fat mass and fat-free mass) were associated with increased risk of VT, with 4th versus 1st quartile RRs of 1.5-3.0. There were no multiplicative interactions of biomarkers with obesity status. Adjustment for biomarkers associated with VT risk and body size (factors VII and VIII, von Willebrand factor, partial thromboplastin time, D-dimer, C-reactive protein and factor XI) only marginally lowered, or did not impact, the RRs associated with body size measures. CONCLUSIONS:Greater body size, by multiple measures, is a risk factor for VT. Associations were not mediated by circulating levels of studied biomarkers suggesting that body size relates to VT because of physical factors associated with blood flow, not the hypercoagulability or inflammation associated with adiposity.

SUBMITTER: Cushman M

PROVIDER: S-EPMC4980192 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Body size measures, hemostatic and inflammatory markers and risk of venous thrombosis: The Longitudinal Investigation of Thromboembolism Etiology.

Cushman Mary M O'Meara Ellen S ES Heckbert Susan R SR Zakai Neil A NA Rosamond Wayne W Folsom Aaron R AR

Thrombosis research 20160615

<h4>Objective</h4>Obesity is an important venous thrombosis (VT) risk factor but the reasons for this are unclear.<h4>Materials and methods</h4>In a cohort of 20,914 individuals aged 45 and older without prior VT, we calculated the relative risk (RR) of VT over 12.6years follow-up according to baseline body size measures, and studied whether associations were mediated by biomarkers of hemostasis and inflammation that are related to adiposity.<h4>Results</h4>Greater levels of all body size measur ...[more]

PMID: 27328432

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Project description:INTRODUCTION:Obesity is significant risk factor for venous thromboembolism (VTE); however, the related mechanisms remain unclear. Previous studies have suggested that this might be related to physical factors including anthropometric measures. We intend to conduct a systematic review and meta-analysis of prospective studies to summarise the extant literature on the associations between a set of seven measures of body size and the risk of VTE. METHODS AND ANALYSIS:The current systematic review will include prospective cohort studies assessing the association between seven measures of body size (height, weight, body mass index, waist and hip circumferences, waist-to-hip ratio, waist-to-height ratio) and the risk of VTE. We will conduct comprehensive searches of MEDLINE and Excerpta Medica Database (EMBASE) for articles published from inception through 31 August 2017, without any language restriction. Two investigators will independently screen, select studies and perform data extraction and risk of bias assessment, with discrepancies resolved by a third investigator. For each body size measure, study-specific relative risks will be pooled using random effects meta-analysis models. Statistical heterogeneity will be assessed using Cochran's Q statistic, H and the I2 statistics. Sources of heterogeneity will be investigated using subgroup and meta-regression analyses as deemed appropriate. Publication bias will be assessed with funnel plots supplemented by Egger's test. ETHICS AND DISSEMINATION:This systematic review will use data from published literature; therefore, ethical approval is not required. We expect our findings to supplement previous epidemiological studies by providing an updated and comprehensive synthesis of the available evidence on the association between body size measures and risk of VTE in the general population. Findings will be published in peer-reviewed journal and presented at scientific meetings. PROSPERO REGISTRATION NUMBER:CD CRD42017071996.

Project description:BackgroundVenous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources.MethodsWe present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations.ResultsIn our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis.ConclusionsOur cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Project description:Antiphospholipid syndrome (APS) is associated with arterial and venous thrombosis. The unfavorable fibrin clot phenotype, including formation of dense and poorly lysable clots, has been reported both in thrombotic APS and venous thromboembolism (VTE). The presence and amount of different proteins within a plasma clot, not only associated with the coagulation system, may influence clot properties. To our knowledge, there is a lack of data on plasma fibrin-clot bound proteins in patients with thrombotic APS or VTE. The aim of our study was to perform a quantitative proteomic analysis of fibrin clots prepared from citrated plasma from subjects with thrombotic APS and prior VTE, along with fibrin clot permeability (Ks) and clot lysis time (CLT) assessed ex vivo. We investigated 23 consecutive patients with APS, 18 with a history of first-ever VTE, and 20 age and sex matched healthy subjects. A multiple enzyme digestion filter aided sample preparation and a multienzyme digestion (MED) FASP method combined with LC-MS/MS analysis performed on a Proxeon Easy-nLC System coupled to the Q Exactive HF mass spectrometer were used. The proteomic analysis revealed that clot composition regarding 117 proteins in APS patients and 48 proteins in VTE patients was changed as compared to healthy controls, while 72 clot-bounded proteins differed between APS and VTE subjects. In healthy controls, Ks was associated with fibrinogen alpha and gamma chains (r=0.46 and r=0.46, both p<0.05, respectively) or apolipoprotein B-100 (r=-0.53, p<0.05), while CLT correlated with annexin A2 (r=-0.58, p<0.05), apolipoportein(a) (r=0.47, p<0.05), or platelet glycoprotein 4 (r=0.59, p<0.05). In VTE patients correlations of Ks with complement C1q and histone H2B, as factors closely linked with thrombosis, were observed (r=-0.52 and r=-0.47, both p<0.05, respectively). In patients with thrombotic APS all above-mentioned associations were not found. This study is the first to show that different proteins are able to influence the clot formation, structure, and properties. Since, prothrombotic conditions abolished associations observed in healthy subjects fibrin clots, differences in protein clot components might explain the links between prothrombotic fibrin clot phenotype and thromboembolic events.

Dataset Information

Body size measures, hemostatic and inflammatory markers and risk of venous thrombosis: The Longitudinal Investigation of Thromboembolism Etiology.

Publications

Body size measures, hemostatic and inflammatory markers and risk of venous thrombosis: The Longitudinal Investigation of Thromboembolism Etiology.

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