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Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

This cohort study compares the sex- and age-adjusted incidence of cerebral venous sinus thrombosis before the COVID-19 pandemic with that during the first 92 days after Ad26.COV2.S vaccination.

Coronary embolism is the underlying cause of 3% of acute coronary syndromes but is often not considered in the differential of acute coronary syndromes. It should be suspected in the case of high thrombus burden despite a relatively normal underlying vessel or recurrent coronary thrombus. Coronary embolism may be direct (from the aortic valve or left atrial appendage), paroxysmal (from the venous circulation through a patent foramen ovale), or iatrogenic (following cardiac intervention). Investigations include transesophageal echocardiography to assess the left atrial appendage and atrial septum and continuous electrocardiographic monitoring to assess for paroxysmal atrial fibrillation. The authors review the historic and contemporary published data about this important cause of acute coronary syndromes. The authors propose an investigation and management strategy for work-up and anticoagulation strategy for patients with suspected coronary embolism.

Women with inherited antithrombin (AT) deficiency are at high risk for venous thromboembolism (VTE), especially during times of estrogen exposure, but little is known about patient-oriented reproductive decision-making in this population.Provider-administered survey of women with AT deficiency. Participants were asked to discuss their diagnosis of AT deficiency and questioned about (1) contraception, (2) pregnancies, and (3) menorrhagia, and the impact of their AT deficiency on each reproductive health experience.Of 31 women with inherited AT deficiency, 18 (58%) were surveyed, 8 (26%) were unreachable, and 5 (16%) were deceased. Twelve (67%) had a VTE, including two which occurred during pregnancy and five during oral contraceptive (OCP) use. Women reported using OCPs, intrauterine device (IUD), and condoms for contraception. Of five women diagnosed with AT deficiency while taking OCPs, three switched to an IUD, one to condoms, and one used no alternative method. Eighteen women reported 42 total pregnancies, with 33 (79%) resulting in live term birth, 3 (7%) in live preterm birth, and 6 (14%) in spontaneous abortion at a median of 12 weeks. Four (22%) women reported the use of anticoagulation during pregnancy. Eleven (61%) women reported menorrhagia and 4 (36%), while on anticoagulation for VTE events. Ten of 18 women (56%) reported that the diagnosis of AT had affected their reproductive health in some way.Women with AT deficiency require careful multidisciplinary management to avoid complications in the setting of contraception and pregnancy. AT deficiency impacts women's reproductive health experiences and patient-oriented reproductive decision-making is key.

The annual number of US venous thromboembolism (VTE) events, the number of potentially preventable events, and the effect of hospitalization-based prophylaxis are uncertain. We estimated VTE attack (incident plus recurrent VTE) rates and the total annual number of US VTE events related and unrelated to hospitalization using Rochester Epidemiology Project resources to identify all Olmsted County, Minnesota, residents with incident or recurrent VTE over the 6-year period 2005-2010. The average annual VTE attack rates related and unrelated to hospitalization were 282 and 8 per 10 000 person-years, respectively. The estimated average number of US VTE events was 495 669 per year (48% unrelated to hospitalization). Among Olmsted County residents hospitalized at a Mayo Clinic hospital from 2005 to 2010, the proportion of patients receiving VTE prophylaxis or with an indication that prophylaxis was unnecessary increased from ∼40% in 2005 to ∼90% by 2010. The annual age- and sex-adjusted hospitalization-related (in-hospital) VTE attack rates from 2005 to 2010 ranged from 251 to 306 (1155 to 1751) per 10 000 person-years (bed-years) and did not change significantly. The median durations of hospitalization and in-hospital prophylaxis were 3 days and 70 hours, respectively. A total of 75% of VTE events occurred after hospital discharge, with a 19.5-day median time to VTE. Additional efforts are needed to identify the individual inpatient and outpatient at high risk for incident and recurrent VTE and target (longer duration) primary and secondary prophylaxis to high-risk individuals who would benefit most.

SummaryTo identify novel single nucleotide polymorphisms (SNPs) associated with venous thromboembolism (VTE) in African-Americans (AAs), we performed a genome-wide association study (GWAS) of VTE in AAs using the Electronic Medical Records and Genomics (eMERGE) Network, comprised of seven sites each with DNA biobanks (total ~39,200 unique DNA samples) with genome-wide SNP data (imputed to 1000 Genomes Project cosmopolitan reference panel) and linked to electronic health records (EHRs). Using a validated EHR-driven phenotype extraction algorithm, we identified VTE cases and controls and tested for an association between each SNP and VTE using unconditional logistic regression, adjusted for age, sex, stroke, site-platform combination and sickle cell risk genotype. Among 393 AA VTE cases and 4,941 AA controls, three intragenic SNPs reached genome-wide significance: LEMD3 rs138916004 (OR=3.2; p=1.3E-08), LY86 rs3804476 (OR=1.8; p=2E-08) and LOC100130298 rs142143628 (OR=4.5; p=4.4E-08); all three SNPs validated using internal cross-validation, parametric bootstrap and meta-analysis methods. LEMD3 rs138916004 and LOC100130298 rs142143628 are only present in Africans (1000G data). LEMD3 showed a significant differential expression in both NCBI Gene Expression Omnibus (GEO) and the Mayo Clinic gene expression data, LOC100130298 showed a significant differential expression only in the GEO expression data, and LY86 showed a significant differential expression only in the Mayo expression data. LEMD3 encodes for an antagonist of TGF-β-induced cell proliferation arrest. LY86 encodes for MD-1 which down-regulates the pro-inflammatory response to lipopolysaccharide; LY86 variation was previously associated with VTE in white women; LOC100130298 is a non-coding RNA gene with unknown regulatory activity in gene expression and epigenetics.Supplementary Material to this article is available online at www.thrombosis-online.com.

Age is the dominant risk factor for most chronic human diseases; yet the mechanisms by which aging confers this risk are largely unknown.1 Recently, the age-related acquisition of somatic mutations in regenerating hematopoietic stem cell populations was associated with both hematologic cancer incidence2–4 and coronary heart disease prevalence.5 Somatic mutations with leukemogenic potential may confer selective cellular advantages leading to clonal expansion, a phenomenon termed ‘Clonal Hematopoiesis of Indeterminate Potential’ (CHIP).6 Simultaneous germline and somatic whole genome sequence analysis now provides the opportunity to identify root causes of CHIP. Here, we analyze high-coverage whole genome sequences from 97,691 participants of diverse ancestries in the NHLBI TOPMed program and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid, and inflammatory traits specific to different CHIP genes. Association of a genome-wide set of germline genetic variants identified three genetic loci associated with CHIP status, including one locus at TET2 that was African ancestry specific. In silico-informed in vitro evaluation of the TET2 germline locus identified a causal variant that disrupts a TET2 distal enhancer. Aggregates of rare germline loss-of-function variants in CHEK2, a DNA damage repair gene, predisposed to CHIP acquisition. Overall, we observe that germline genetic variation altering hematopoietic stem cell function and the fidelity of DNA-damage repair increase the likelihood of somatic mutations leading to CHIP.

© 2020, The Author(s), under exclusive licence to Springer Nature Limited. Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2–4 and coronary heart disease5—this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

Background Appropriate periprocedural management of the chronically anticoagulated patient with an inherited or acquired thrombophilia is uncertain. The objective of this study was to test "thrombophilia" as a potential predictor of the 3-month cumulative incidence of thromboembolism and major bleeding among chronically anticoagulated patients undergoing an invasive procedure. Methods In a prospective cohort study, consecutive chronically anticoagulated patients referred to the Mayo Thrombophilia Center for standardized periprocedural anticoagulation management who had venous thromboembolism and complete thrombophilia testing were categorized as "severe," "non-severe," or "no identifiable" thrombophilia. The 3-month cumulative incidence rates of thromboembolism, bleeding, and death were estimated using the Kaplan-Meier product limit method. Results Among 362 patients with complete thrombophilia testing, 165 (46%) had a defined thrombophilia; 76 patients had severe thrombophilia, mainly due to antiphospholipid syndrome (66%). Half of the patients in each of the 3 groups received pre- and postprocedure heparin. During follow-up, there were no thromboembolic events, rare major bleeding events (1% for each group), and 4 deaths. Due to the very low event rates for each of these outcomes, Cox proportional hazard modeling could not be performed. Conclusions Periprocedural event rates were low irrespective of thrombophilia status. Inherited or acquired thrombophilia was not a predictor of thromboembolism, major bleeding, or mortality after temporary interruption of chronic anticoagulation for an invasive procedure.

Background Independent risk factors for cancer-associated incident venous thromboembolism (VTE) and their magnitude of risk are not fully characterized. Aim To identify non-cancer and cancer-specific risk factors for cancer-associated incident VTE. Methods In a population-based retrospective case–control study, we used Rochester Epidemiology Project and Mayo Clinic Cancer Registry resources to identify all Olmsted County, MN residents with active cancer-associated incident VTE, 1973–2000 (cases; n=570) and 1–3 residents with active cancer matched to each case on age, sex, date and duration of active cancer (controls; n=604). Using conditional logistic regression, we tested cancer and non-cancer characteristics for an association with VTE, including a cancer site VTE risk score. Results In the multivariable model, higher cancer site VTE risk score (OR=1.4 per 2-fold increase), cancer stage≥2 (OR=2.2), liver metastasis (OR=2.7), chemotherapy (OR=1.8) and progesterone use (OR=2.1) were independently associated with VTE, as were BMI 2 (OR=1.9) or ≥35kg/m 2 (OR=4.0), hospitalization (OR=7.9), nursing home confinement (OR=4.7), central venous (CV) catheter (OR=8.5) and any recent infection (OR=1.7). In a subgroup analysis, platelet count≥350×10 9 /L at time of cancer diagnosis was marginally associated with VTE (OR=2.3, p=0.07). Conclusion Cancer site, cancer stage≥2, liver metastasis, chemotherapy, progesterone, being underweight or obese, hospitalization/nursing home confinement, CV catheter, and infection are independent risk factors for incident VTE in active cancer patients.

Venous thromboembolism (VTE) is categorized by the U.S. Surgeon General as a major public health problem. VTE is relatively common and associated with reduced survival and substantial health-care costs, and recurs frequently. VTE is a complex (multifactorial) disease, involving interactions between acquired or inherited predispositions to thrombosis and VTE risk factors, including increasing patient age and obesity, hospitalization for surgery or acute illness, nursing-home confinement, active cancer, trauma or fracture, immobility or leg paresis, superficial vein thrombosis, and, in women, pregnancy and puerperium, oral contraception, and hormone therapy. Although independent VTE risk factors and predictors of VTE recurrence have been identified, and effective primary and secondary prophylaxis is available, the occurrence of VTE seems to be relatively constant, or even increasing.

Nursing home (NH) residency is an independent risk factor for venous thromboembolism (VTE), but the VTE burden within the NH population is uncertain. This study estimates VTE incidence and VTE-associated mortality among NH residents. We identified all NH residents in any NH in Olmsted County, Minnesota, United States, 1 October 1998 to 31 December 2005 and all first lifetime VTE among county residents to estimate VTE incidence while resident of local NHs (NHVTE), using Centers for Medicare and Medicaid Services Minimum Data Set and Rochester Epidemiology Project resources. We tested associations between NHVTE and age, sex and time since each NH admission using Poisson modelling. Additionally, we tested incident NHVTE as a potential predictor of survival using Cox proportional hazards, adjusting for age, sex and NH residency. Between 1 October 1998 and 31 December 2005, 3,465 Olmsted County residents with ≥1 admission to a local NH, contributed 4,762 NH stays. Of the 3,465 NH residents, 111 experienced incident NHVTE (2.3% of all eligible stays), for an overall rate of 3,653/100,000 NH person-years (NH-PY). VTE incidence was inversely associated with time since each NH admission, and was highest in the first 7 days after each NH admission (18,764/100,000 NH-PY). The adjusted hazard of death for incident NHVTE was 1.90 (95% confidence interval [CI]: 1.38–2.62). In conclusion, VTE incidence among NH residents was nearly 30-fold higher than published incidence rates for the general Olmsted County population. VTE incidence was highest within 7 days after NH admission, and NHVTE was associated with significantly reduced survival. These data can inform future research and construction of clinical trials regarding short-term prophylaxis.

Platelet transmission electron microscopy (PTEM) is considered the gold standard test for assessing distinct ultrastructural abnormalities in inherited platelet disorders (IPDs). Nevertheless, PTEM remains mainly a research tool due to the lack of standardized procedures, a validated dense granule (DG) count reference range, and standardized image interpretation criteria. The aim of this study was to standardize and validate PTEM as a clinical laboratory test. Based on previously established methods, we optimized and standardized preanalytical, analytical, and postanalytical procedures for both whole mount (WM) and thin section (TS) PTEM. Mean number of DG/platelet (plt), percentage of plts without DG, platelet count (PC), mean platelet volume (MPV), immature platelet fraction (IPF), and plt light transmission aggregometry analyses were measured on blood samples from 113 healthy donors. Quantile regression was used to estimate the reference range for DG/plt, and linear regression was used to assess the association of DG/plt with other plt measurements. All PTEM procedures were standardized using commercially available materials and reagents. DG interpretation criteria were established based on previous publications and expert consensus, and resulted in improved operator agreement. Mean DG/plt was stable for 2 days after blood sample collection. The median within patient coefficient of variation for mean DG/plt was 22.2%; the mean DG/plt reference range (mid-95th %) was 1.2-4.0. Mean DG/plt was associated with IPF (p = .01, R

Background Predictors of venous thromboembolism ( VTE ) recurrence are uncertain. Objective To identify predictors of VTE recurrence, adjusted for treatments and interim exposures. Materials and Methods Using Rochester Epidemiology Project resources, all Olmsted County, MN residents with objectively-diagnosed incident VTE over the 13-year period, 1988–2000, who survived ≥1day were followed for first objectively-diagnosed VTE recurrence. For all patients with recurrence, and a random sample of all surviving incident VTE patients (n=415), we collected demographic and baseline characteristics, treatments and interim exposures. In a case-cohort study design, demographic, baseline, treatment and interim exposure characteristics were tested as potential predictors of VTE recurrence using time-dependent Cox proportional hazards modeling. Results Among 1262 incident VTE patients, 306 developed recurrence over 6,440 person-years. Five-year recurrence rates, overall and for cancer-associated, idiopathic and non-cancer secondary VTE, were 24.5%, 43.4%, 27.3% and 18.1%, respectively. In multivariable analysis, interim hospitalization, active cancer, pregnancy, central venous catheter and respiratory infection were associated with increased hazards of recurrence, and warfarin and aspirin were associated with reduced hazards. Adjusting for treatments and these interim risk factors, male sex, baseline active cancer and failure to achieve a therapeutic aPTT in the first 24hours were independently associated with increased hazards of VTE recurrence over the entire follow-up period, while the hazards of recurrence for patient age, chronic lung disease, leg paresis, prior superficial vein thrombosis and idiopathic VTE varied over the follow-up period. Conclusions Baseline and interim exposures can stratify VTE recurrence risk and may be useful for directing secondary prophylaxis.

The independent effect of lipid lowering therapy (LLT) on venous thromboembolism (VTE) risk is uncertain.To test statin and non-statin LLT as potential VTE risk factors.Using Rochester Epidemiology Project resources, we identified all Olmsted County, MN residents with objectively diagnosed incident VTE (cases) over the 13-year period, 1988-2000 (n=1340), and one to two matched controls (n=1538). We reviewed their complete medical records for baseline characteristics previously identified as independent VTE risk factors, and for statin and non-statin LLT. Using conditional logistic regression, we tested the overall effect of LLT on VTE risk and also separately explored the role of statin versus that of non-statin LLT, adjusting for other baseline characteristics.Among cases and controls, 74 and 111 received statin LLT, and 32 and 50 received non-statin LLT, respectively. Univariately, and after individually controlling for other potential VTE risk factors (i.e., BMI, trauma/fracture, leg paresis, hospitalization for surgery or medical illness, nursing home residence, active cancer, central venous catheter, varicose veins, prior superficial vein thrombosis, diabetes, congestive heart failure, angina/myocardial infarction, stroke, peripheral vascular disease, smoking, anticoagulation), LLT was associated with decreased odds of VTE (unadjusted OR=0.73; p=0.03). When considered separately, statin and non-statin LLT were each associated with moderate, non-significant lower odds of VTE. After adjusting for angina/myocardial infarction, each was significantly associated with decreased odds of VTE (OR=0.63, p0.01 and OR=0.61, p=0.04, respectively).LLT is associated with decreased VTE risk after adjusting for known risk factors.

Activated platelets serve as a catalyst for thrombin generation and a source of vasoactive and mitogenic factors affecting vascular remodeling. Oral menopausal hormone treatments (MHT) may carry greater thrombotic risk than transdermal products. This study compared effects of oral and transdermal MHT on platelet characteristics, platelet proteins, and platelet-derived microvesicles (MV) in recently menopausal women. Platelets and MV were prepared from blood of a subset of women (n = 117) enrolled in the Kronos Early Estrogen Prevention Study prior to and after 48 months of treatment with either oral conjugated equine estrogen (0.45 mg/day), transdermal 17β-estradiol (50 µg/day), each with intermittent progesterone (200 mg/day for 12 days a month), or placebo pills and patch. Platelet count and expression of platelet P-selectin and fibrinogen receptors were similar across groups. An aggregate measure of 4-year change in vasoactive and mitogenic factors in platelet lysate, by principle component analysis, indicated significantly lower values in both MHT groups compared to placebo. Increases in numbers of tissue factor positive and platelet-derived MV were significantly greater in the transdermal compared to placebo group. MHT was associated with significantly reduced platelet content of vasoactive and mitogenic factors representing a potential mechanism by which MHT may affect vascular remodeling. Various hormonal compositions and doses of MHT could differentially regulate nuclear transcription in bone marrow megakaryocytes and non-genomic pathways in circulating platelets thus determining numbers and characteristics of circulating MV. Thrombotic risk associated with oral MHT most likely involves liver-derived inflammatory/coagulation proteins rather than circulating platelets per se.

Background While post thrombotic syndrome (PTS) is increasingly recognized as a frequent and potentially serious complication of deep vein thrombosis (DVT) in children, limited information is available regarding predictors of PTS. Methods Using the Mayo Clinic Master Diagnostic Index, all pediatric patients (age 0 to 18 years) with a potential DVT based on ICD-8 codes over the 15-year period, 1995 to 2009 were identified. A validated PTS survey instrument was mailed to eligible patients followed by a second mailing and three reminder phone calls for non-responders. Baseline clinical and radiographic characteristics were abstracted from patient medical records and tested as potential predictors of PTS using logistic regression. Associations were summarized by calculating odds ratios (OR) and corresponding 95% confidence intervals. Results Ninety patients agreed to participate. The mean age (± SD) at DVT diagnosis and survey completion were 12.8 (± 6.1) and 19.3 (± 7.7) years, respectively. Fifty three respondents (59%) reported mild PTS whereas 12 (13%) reported moderate-to-severe PTS. Pain (34%) and dilated blood vessels (40%) were the most frequent PTS symptom and sign, respectively. On multivariate analysis, predictors of PTS included duration between incident DVT and survey completion (OR 1.75; 95% CI: 1.08 – 2.84) and number of thrombosed vein segments (OR 1.40; 95% CI: 1.05 – 1.86). Conclusion Over 70% of children with DVT report subsequent symptoms or signs of PTS, though only 13% report clinically significant, moderate-to-severe PTS. Number of thrombosed vein segments at diagnosis and time duration between incident DVT and survey completion were independent predictors of PTS.

Background: Certain diseases can occur with and without a trigger. We use Venous Thromboembolism (VTE) as our example to identify genetic interaction with pregnancy in women with VTE during pre- or postpartum. Pregnancy is one of the major risk factors for VTE as it accounts for 10% of maternal deaths. Methods: We performed a whole genome association analysis using the Cox Proportional Hazard (CoxPH) model adjusted for covariates to identify genetic variants associated with the time-to-event of VTE related to pre- or postpartum during the childbearing age of 18–45 years using a case-only design in a cohort of women with VTE. Women with a VTE event after 45 years of age were censored and contributed only follow-up time. Results: We identified two intragenic single nucleotide polymorphisms (SNPs) at genome-wide significance in the PURB gene located on chromosome 7, and two additional intragenic SNPs, one in the LINGO2 gene on chromosome 9 and one in RDXP2 on chromosome X. Conclusions: We showed that the time-to-event model is a useful approach for identifying potential hazard-modification of the genetic variants when the event of interest (VTE) occurs due to a risk factor (pre- or post-partum).

BACKGROUND Reliable biomarkers predictive of venous thromboembolism (VTE) after acute trauma are uncertain. The objective of the study was to identify risk factors for symptomatic VTE after trauma, including individual plasma coagulome characteristics as reflected by thrombin generation. METHODS In a prospective, case-cohort study, trauma patients were enrolled over the 4.5-year period, 2011 to 2015. Blood was collected by venipuncture into 3.2% trisodium citrate at 0, 6, 12, 24, and 72 hours after injury and at hospital discharge. Platelet poor plasma was stored at -80 °C until analysis. Thrombin generation, as determined by the calibrated automated thrombogram (CAT) using 5 pM tissue factor (TF)/4 μM phospholipid (PS), was reported as peak height (nM thrombin) and time to peak height (ttPeak [minutes]). Data are presented as median [IQR] or hazard ratio with 95% CI. RESULTS Among 453 trauma patients (injury severity score = 13.0 [6.0, 22.0], hospital length of stay = 4.0 [2.0, 10.0] days, age = 49 [28, 64] years, 71% male, 96% with blunt mechanism, mortality 3.2%), 83 developed symptomatic VTE within 92 days after injury (35 [42%] after hospital discharge). In a weighted, multivariate Cox model that included clinical and CAT characteristics available within 24 hours of admission, increased patient age (1.35 [1.19,1.52] per 10 years, p < 0.0001), body mass index ≥30 kg/m (4.45 [2.13,9.31], p < 0.0001), any surgery requiring general anesthesia (2.53 [1.53,4.19], p = 0.0003) and first available ttPeak (1.67 [1.29, 2.15], p < 0.00001) were independent predictors of incident symptomatic VTE within 92 days after trauma (C-statistic = 0.799). CONCLUSION The individual's plasma coagulome (as reflected by thrombin generation) is an independent predictor of VTE after trauma. Clinical characteristics and ttPeak can be used to stratify acute trauma patients into high and low risk for VTE. LEVEL OF EVIDENCE Prognostic, level III.

Coronary embolism is the underlying cause of 3% of acute coronary syndromes but is often not considered in the differential of acute coronary syndromes. It should be suspected in the case of high thrombus burden despite a relatively normal underlying vessel or recurrent coronary thrombus. Coronary embolism may be direct (from the aortic valve or left atrial appendage), paroxysmal (from the venous circulation through a patent foramen ovale), or iatrogenic (following cardiac intervention). Investigations include transesophageal echocardiography to assess the left atrial appendage and atrial septum and continuous electrocardiographic monitoring to assess for paroxysmal atrial fibrillation. The authors review the historic and contemporary published data about this important cause of acute coronary syndromes. The authors propose an investigation and management strategy for work-up and anticoagulation strategy for patients with suspected coronary embolism.

International audience; Observational studies have shown an association between obesity and venous thromboembolism (VTE) but it is not known if observed associations are causal, due to reverse causation or confounding bias. We conducted a Mendelian Randomization study of body mass index (BMI) and VTE. We identified 95 single nucleotide polymorphisms (SNPs) that have been previously associated with BMI and assessed the association between genetically predicted high BMI and VTE leveraging data from a previously conducted GWAS within the INVENT consortium comprising a total of 7507 VTE cases and 52,632 controls of European ancestry. Five BMI SNPs were associated with VTE at P < 0.05, with the strongest association seen for the FTO SNP rs1558902 (OR 1.07, 95% CI 1.02–1.12, P = 0.005). In addition, we observed a significant association between genetically predicted BMI and VTE (OR = 1.59, 95% CI 1.30–1.93 per standard deviation increase in BMI, P = 5.8 × 10−6). Our study provides evidence for a causal relationship between high BMI and risk of VTE. Reducing obesity levels will likely result in lower incidence in VTE.

Background The American Venous Forum issued a call to reduce the prevalence of venous ulcers (VUs) by 50% in 10 years. The objectives of this study were to determine the validity of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for VU and to estimate the prevalence of VU in a well-defined geographic population (Olmsted County, Minn). Methods Rochester Epidemiology Project resources and 18 VU ICD-9-CM codes were used to identify residents with possible VUs during the 2-year period 2010-2011 (n = 1551). The complete medical records in the community were reviewed for a 15% random sample (n = 227) of these residents, and on the basis of prespecified criteria, patients were categorized as a VU or non-VU case. Continuous and categorical variables were compared between groups by the two-sample t-test and χ2 test. Results Ninety-three patients (41%) had active or healed VUs, 83 had non-VUs, and 51 never had ulcers but had stasis skin changes or skin infection. ICD-9-CM code 454.0 best identified VU cases (sensitivity, 24%; specificity, 100%). VU patients were older and heavier and more frequently had bilateral ulcers. On the basis of the random sample review, an estimated 635 patients had healed or active VUs during the 2-year period of the study. The prevalence of VUs in the Olmsted County population was estimated to be 210 per 100,000 person-years, with VU incidence (newly diagnosed ulcers) of 85 per 100,000 person-years. Conclusions ICD-9-CM VU codes operated poorly for VU identification. VU surveillance for estimating trends in incidence and prevalence of VUs will require better methods. The estimated prevalence of VUs in Olmsted County is 210 per 100,000 person-years. New ulcers developed each year in 85 of 100,000 people, an incidence that seems to be higher than in the previous epidemiologic study in this population.

BACKGROUND Nursing home (NH) residents are at increased risk for both VTE and bleeding from pharmacologic prophylaxis. Construction of prophylaxis guidelines is hampered by NH-specific limitations with VTE case identification and characterization of risk. We addressed these limitations by merging detailed provider-linked Rochester Epidemiology Project (REP) medical records with Centers for Medicare and Medicaid Services Minimum Data Set (MDS) NH assessments. METHODS This population-based nested case-control study identified all Olmsted County, Minnesota, residents with first-lifetime VTE October 1, 1998, through December 31, 2005, while a resident of an NH (N = 91) and one to two age-, sex-, and calendar year-matched NH non-VTE control subjects. For each NH case without hospitalization 3 months before VTE (n = 23), we additionally identified three to four nonhospitalized NH control subjects. REP and MDS records were reviewed before index date (VTE date for cases; respective REP encounter date for control subjects) for numerous characteristics previously associated with VTE in non-NH populations. Data were modeled using conditional logistic regression. RESULTS The multivariate model consisting of all cases and control subjects identified only three characteristics independently associated with VTE: respiratory infection vs no infection (OR, 5.9; 95% CI, 2.6-13.1), extensive or total assistance with walking in room (5.6, 2.5-12.6), and general surgery (3.3, 1.0-10.8). In analyses limited to nonhospitalized cases and control subjects, only nonrespiratory infection vs no infection was independently associated with VTE (8.8, 2.7-29.2). CONCLUSIONS Contrary to previous assumptions, most VTE risk factors identified in non-NH populations do not apply to the NH population. NH residents with infection, substantial mobility limitations, or recent general surgery should be considered potential candidates for VTE prophylaxis.

Active cancer is the major predictor of venous thromboembolism (VTE) recurrence, but further stratification of recurrence risk is uncertain. In a population-based cohort study of all Olmsted County, Minnesota, residents with active cancer-related incident VTE during the 35-year period from 1966 to 2000 who survived 1 day or longer, we estimated VTE recurrence, bleeding on anticoagulant therapy, and survival and tested cancer and noncancer characteristics and secondary prophylaxis as predictors of VTE recurrence and bleeding, using Cox proportional hazards modeling. Of 477 patients, 139 developed recurrent VTE over the course of 1533 person-years of follow-up. The adjusted 10-year cumulative VTE recurrence rate was 28.6%. The adjusted 90-day cumulative incidence of major bleeding on anticoagulation was 1.9%. Survival was significantly worse for patients with cancer who had recurrent VTE (particularly pulmonary embolism) and with bleeding on anticoagulation. In a multivariable model, brain, lung, and ovarian cancer; myeloproliferative or myelodysplastic disorders; stage IV pancreatic cancer; other stage IV cancer; cancer stage progression; and leg paresis were associated with an increased hazard, and warfarin therapy was associated with a reduced hazard, of recurrent VTE. Recurrence rates were significantly higher for cancer patients with 1 or more vs no predictors of recurrence, suggesting these predictors may be useful for stratifying recurrence risk.

Author(s): Go, Alan S; Mozaffarian, Dariush; Roger, Veronique L; Benjamin, Emelia J; Berry, Jarett D; Blaha, Michael J; Dai, Shifan; Ford, Earl S; Fox, Caroline S; Franco, Sheila; Fullerton, Heather J; Gillespie, Cathleen; Hailpern, Susan M; Heit, John A; Howard, Virginia J; Huffman, Mark D; Judd, Suzanne E; Kissela, Brett M; Kittner, Steven J; Lackland, Daniel T; Lichtman, Judith H; Lisabeth, Lynda D; Mackey, Rachel H; Magid, David J; Marcus, Gregory M; Marelli, Ariane; Matchar, David B; McGuire, Darren K; Mohler, Emile R; Moy, Claudia S; Mussolino, Michael E; Neumar, Robert W; Nichol, Graham; Pandey, Dilip K; Paynter, Nina P; Reeves, Matthew J; Sorlie, Paul D; Stein, Joel; Towfighi, Amytis; Turan, Tanya N; Virani, Salim S; Wong, Nathan D; Woo, Daniel; Turner, Melanie B; American Heart Association Statistics Committee and Stroke Statistics Subcommittee

Case Presentation 1: A healthy 19-year-old man presented with new chest pain and near syncope. Computed tomography pulmonary angiography showed a saddle pulmonary embolus. The patient denied recent travel, trauma, surgery, or hospitalization. His mother had 2 miscarriages at 10 weeks of gestation, and his maternal grandfather had deep venous thrombosis at 60 years of age. Case Presentation 2: A healthy 45-year-old woman reported new dyspnea and left calf pain. Computed tomography pulmonary angiography and compression venous duplex ultrasonography showed bilateral pulmonary emboli and acute left leg deep vein thrombosis, respectively. The patient denied exogenous hormone use, recent travel, trauma, surgery, or hospitalization. Her health maintenance was current, and she gave a family history of pernicious anemia, Grave disease, and amyotrophic lateral sclerosis. Laboratory analyses showed reduced hemoglobin (11.4 g/dL; normal, 12.0–15.5 g/dL), increased red blood cell distribution width (18.9%; normal, 11.9%–15.5%), and mild thrombocytopenia. Neither patient had previous venous thromboembolism, and both were referred to the Mayo Clinic Thrombophilia Center for apparent idiopathic venous thromboembolism. Thrombophilia is defined as a predisposition (susceptibility) to thrombosis. Thrombophilia is not a disease per se, but may be associated with a disease (eg, cancer), drug exposure (eg, oral contraceptives) or condition (eg, pregnancy or postpartum, secondary thrombophilia; Table 1), and thrombophilia may be inherited (Table 2).1 This concept is important because disease susceptibility does not imply an absolute requirement for primary or secondary prevention, or for treatment. Most persons with a thrombophilia do not develop thrombosis. Thus, thrombophilia must be considered in the context of other risk factors for incident thrombosis, or predictors of recurrent thrombosis, when estimating the need for primary or secondary prophylaxis, respectively. View this table: Table 1. Secondary Thrombophilia1 View this table: Table 2. Inherited Thrombophilia1 The role of special coagulation testing for an acquired or inherited thrombophilia is controversial. Thrombophilia testing should only be done if …

Black women have an increased risk of adverse pregnancy outcomes and the characteristics of thrombotic risk factors in this population are unknown. The objective of this study was to examine the racial differences in thrombotic risk factors among women with adverse pregnancy outcomes.Uniform data were collected in women with adverse pregnancy outcomes (pregnancy losses, intrauterine growth restriction (IUGR), prematurity, placental abruption and preeclampsia) referred to Thrombosis Network Centers funded by the Centers for Disease Control and Prevention (CDC).Among 343 white and 66 black women seen for adverse pregnancy outcomes, protein S and antithrombin deficiencies were more common in black women. The prevalence of diagnosed thrombophilia was higher among whites compared to blacks largely due to Factor V Leiden mutation. The prevalence of a personal history of venous thromboembolism (VTE) did not differ significantly by race. A family history of VTE, thrombophilia, and stroke or myocardial infarction (MI) was higher among whites. Black women had a higher body mass index, and a higher prevalence of hypertension, while the prevalence of sickle cell disease was approximately 27 fold higher compared to the general US black population.Thrombotic risk factors differ significantly in white and black women with adverse pregnancy outcomes. Such differences highlight the importance of considering race separately when assessing thrombotic risk factors for adverse pregnancy outcomes.

Objective While post-thrombotic syndrome (PTS) is increasingly recognized in children with a history of deep vein thrombosis (DVT), its impact on the health-related quality of life (HRQoL) is unknown. Our objective was to evaluate the association between the PTS and HRQoL by surveying a cohort of patients treated at our institution for DVT. Materials/Methods All unique pediatric patients (0–18 years) treated for a DVT at the Mayo Clinic during the 15-year period, 1995–2009 were identified. A previously validated PTS survey instrument and age appropriate Pediatric Quality of Life inventory, version 4 (PedsQL 4.0) were mailed to eligible patients. Linear regression models were fit to compare the HRQoL scores between PTS groups (none, mild, moderate/severe), after adjusting for the presence of potential covariates. Results Of the 90 respondents, 65 (72%) reported signs and/or symptoms of PTS. Mean age (±SD) at DVT diagnosis and survey completion were 12.8 (±6.1) and 19.3 (±7.7) years, respectively. Self-report PedsQL 4.0 module was completed by 79 patients, and 34 guardians completed the parent-proxy module. Patients with moderate to severe PTS reported significantly worse total HRQoL score (mean ± SD, 71.3 ± 13.4) as compared to patients with mild PTS (84.8 ± 14.2) and no PTS (83.4 ± 14) (P = 0.001). Conclusion Moderate to severe PTS has a significant impact on self-reported HRQoL as measured using the generic PedsQL 4.0. Further research is warranted to develop a venous disease-specific quality of life measure for children with a history of DVT. Pediatr Blood Cancer 2014;61:546–551. © 2013 Wiley Periodicals, Inc.

ObjectiveThe aim of this study was to determine the incidence and the risk factors of venous thromboembolism (VTE) within 30 days after primary surgery for epithelial ovarian cancer (EOC).MethodsIn a historical cohort study, we estimated the postoperative 30-day cumulative incidence of VTE among consecutive Mayo Clinic patients undergoing primary cytoreduction for EOC between January 2, 2003, and December 29, 2008. We tested perioperative patient characteristics and process-of-care variables (defined by the National Surgical Quality Improvement Program, >130 variables) as potential predictors of postoperative VTE using the Cox proportional hazards modeling.ResultsAmong 569 cases of primary EOC cytoreduction and/or staging and no recent VTE, 35 developed symptomatic VTE within 30 days after surgery (cumulative incidence = 6.5%; 95% confidence interval, 4.4%–8.6%). Within the cohort, 95 (16.7%) received graduated compression stockings (GCSs), 367 (64.5%) had sequential compression devices + GCSs, and 69 (12.1%) had sequential compression devices + GCSs + postoperative heparin, with VTE rates of 1.1%, 7.4%, and 5.8%, respectively (P= 0.07, χ2test). The remaining 38 (6.7%) received various other chemical and mechanical prophylaxis regimens. In the multivariate analysis, current or past tobacco smoking, longer hospital stay, and a remote history of VTE significantly increased the risk for postoperative VTE.ConclusionsVenous thromboembolism is a substantial postoperative complication among women with EOC, and the high cumulative rate of VTE within 30 days after primary surgery suggests that a more aggressive strategy is needed for VTE prevention. In addition, because longer hospital stay is independently associated with a higher risk for VTE, methods to decrease length of stay and minimize factors that contribute to prolonged hospitalization are warranted.

Summary Background The incidence of symptomatic venous thromboembolism (VTE) after knee arthroscopy is uncertain. Objectives To estimate the incidence of symptomatic VTE after arthroscopic knee surgery. Methods In a population-based historical cohort study, all Olmsted County, MN, USA, residents undergoing a first arthroscopic knee surgery during the 18-year period of 1988–2005 were followed for incident deep venous thrombosis or pulmonary embolism. The cumulative incidence of VTE after knee arthroscopy was determined using the Kaplan–Meier product limit estimator. Patient age at surgery, sex, calendar year of surgery, body mass index, anesthesia characteristics, and hospitalization were tested as potential predictors of VTE using Cox proportional hazards modeling, both univariately and adjusted for age and sex. Results Among 4833 Olmsted County residents with knee arthroscopy, 18 developed postoperative VTE, all within the first 6 weeks after surgery. The cumulative incidence rates of symptomatic VTE at 7, 14, and 35 days were 0.2%, 0.3%, and 0.4%, respectively. The hazard for postoperative VTE was significantly increased for older patient age (hazard ratio = 1.34 for each 10-year increase in patient age; P = 0.03) and hospitalization either before or after knee arthroscopy (hazard ratio = 14.1; P

Synthetic κ-opioid receptor (KOR) agonists induce dysphoric and pro-depressive effects and variations in the KOR (OPRK1) and prodynorphin (PDYN) genes have been shown to be associated with alcohol dependence. We genotyped 23 single nucleotide polymorphisms (SNPs) in the PDYN and OPRK1 genes in 816 alcohol-dependent subjects and investigated their association with: (1) negative craving measured by a subscale of the Inventory of Drug Taking Situations; (2) a self-reported history of depression; (3) the intensity of depressive symptoms measured by the Beck Depression Inventory-II. In addition, 13 of the 23 PDYN and OPRK1 SNPs, which were previously genotyped in a set of 1248 controls, were used to evaluate association with alcohol dependence. SNP and haplotype tests of association were performed. Analysis of a haplotype spanning the PDYN gene (rs6045784, rs910080, rs2235751, rs2281285) revealed significant association with alcohol dependence (p = 0.00079) and with negative craving (p = 0.0499). A candidate haplotype containing the PDYN rs2281285-rs1997794 SNPs that was previously associated with alcohol dependence was also associated with negative craving (p = 0.024) and alcohol dependence (p = 0.0008) in this study. A trend for association between depression severity and PDYN variation was detected. No associations of OPRK1 gene variation with alcohol dependence or other studied phenotypes were found. These findings support the hypothesis that sequence variation in the PDYN gene contributes to both alcohol dependence and the induction of negative craving in alcohol-dependent subjects.

Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10(-13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.

Menopausal hormone treatment (MHT) may limit progression of cardiovascular disease (CVD) but poses a thrombosis risk. To test targeted candidate gene variation for association with subclinical CVD defined by carotid artery intima-media thickness (CIMT) and coronary artery calcification (CAC), 610 women participating in the Kronos Early Estrogen Prevention Study (KEEPS), a clinical trial of MHT to prevent progression of CVD, were genotyped for 13,229 single nucleotide polymorphisms (SNPs) within 764 genes from anticoagulant, procoagulant, fibrinolytic, or innate immunity pathways. According to linear regression, proportion of European ancestry correlated negatively, but age at enrollment and pulse pressure correlated positively with CIMT. Adjusting for these variables, two SNPs, one on chromosome 2 for MAP4K4 gene (rs2236935, β = 0.037, P value = 2.36 × 10−06) and one on chromosome 5 for IL5 gene (rs739318, β = 0.051, P value = 5.02 × 10−05), associated positively with CIMT; two SNPs on chromosome 17 for CCL5 (rs4796119, β = −0.043, P value = 3.59 × 10−05; rs2291299, β = −0.032, P value = 5.59 × 10−05) correlated negatively with CIMT; only rs2236935 remained significant after correcting for multiple testing. Using logistic regression, when we adjusted for waist circumference, two SNPs (rs11465886, IRAK2, chromosome 3, OR = 3.91, P value = 1.10 × 10−04; and rs17751769, SERPINA1, chromosome 14, OR = 1.96, P value = 2.42 × 10−04) associated positively with a CAC score of >0 Agatston unit; one SNP (rs630014, ABO, OR = 0.51, P value = 2.51 × 10−04) associated negatively; none remained significant after correcting for multiple testing. Whether these SNPs associate with CIMT and CAC in women randomized to MHT remains to be determined.

Author(s): Go, Alan S; Mozaffarian, Dariush; Roger, Veronique L; Benjamin, Emelia J; Berry, Jarett D; Borden, William B; Bravata, Dawn M; Dai, Shifan; Ford, Earl S; Fox, Caroline S; Franco, Sheila; Fullerton, Heather J; Gillespie, Cathleen; Hailpern, Susan M; Heit, John A; Howard, Virginia J; Huffman, Mark D; Kissela, Brett M; Kittner, Steven J; Lackland, Daniel T; Lichtman, Judith H; Lisabeth, Lynda D; Magid, David; Marcus, Gregory M; Marelli, Ariane; Matchar, David B; McGuire, Darren K; Mohler, Emile R; Moy, Claudia S; Mussolino, Michael E; Nichol, Graham; Paynter, Nina P; Schreiner, Pamela J; Sorlie, Paul D; Stein, Joel; Turan, Tanya N; Virani, Salim S; Wong, Nathan D; Woo, Daniel; Turner, Melanie B; American Heart Association Statistics Committee and Stroke Statistics Subcommittee

SummaryThe demographic and clinical characteristics of adults and children with lower extremity deep-vein thrombosis and/or pulmonary embolism (LE DVT/PE) may differ from those with abdominal vein thrombosis (abdominal VT). Abdominal VT can be a presenting sign of an underlying prothrombotic state, and its presence in the setting of known disease might have prognostic implications different from LE DVT/PE. This study describes clinical presentations of abdominal VT compared to LE DVT/PE in adults and children. We analysed prospec-tively-collected data from consecutive consenting patients enrolled in one of seven Centers for Disease Control and Prevention (CDC) funded Thrombosis and Hemostasis Network Centers from August 2003 to April 2011 to compare the demographic and clinical characteristics of adults and children with abdominal VT. Both adults and children with abdominal VT tended to be younger and have a lower body mass index (BMI) than those with LE DVT/PE. Of patients with abdominal V T, children were more likely to have inferior vena cava (IVC) thrombosis than adults. For adults with venous thromboembolism (VTE), relatively more women had abdominal VT than LE DVT/PE, while the proportions with LE DVT/PE and abdominal VT by sex were similar in children. Children with abdominal VT were more likely to have diagnosed inherited thrombophilia, while trauma was more common in children with LE DVT/PE. In conclusion, both children and adults with abdominal VT were younger with a lower BMI than those with LE DVT/ PE. Significant differences exist between children and adults in respect to abdominal VT compared to LE DVT/PE.Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

Essentials We evaluated antibody status, thromboembolism and survival after cardiac surgery. Positive antibody tests are common - over 50% are seropositive at 30 days. Seropositivity did not increase thromboembolism or impair survival after cardiac surgery. Results show heparin induced thrombocytopenia antibody screening after surgery is not warranted.Background Heparin-induced thrombocytopenia (HIT) is a prothrombotic response to heparin therapy with platelet-activating, anti-platelet factor 4 (PF4)/heparin antibodies leading to thrombocytopenia associated with thromboembolism. Objective We tested the hypothesis that anti-PF4/heparin antibodies are associated with thromboembolism after cardiac surgery. Methods This multicenter, prospective cohort study collected laboratory and clinical data up to 30 days after surgery and longer-term clinical follow-up data. The primary outcome variable combined new arterial or venous thromboembolic complications (TECs) with all-cause death until 90 days after surgery. Laboratory analyses included platelet counts and anti-PF4/heparin antibody titers (GTI ELISA), with a confirmatory excess heparin step and serotonin release assay. Chi-square testing was used to test the relationship between our outcome and HIT antibody seropositivity. Results Initially, 1021 patients were enrolled between August 2006 and May 2009, and follow-up was completed in December 2014. Seropositivity defined by OD0.4 was common, being almost 20% preoperatively,30% by discharge, and60% by day 30. Death (1.7% within 30 days) or TECs (69 in total) were more likely if the partient was seronegative (OD0.4), but positivity defined by OD1.0 or including an excess heparin confirmatory step resulted in equal incidence of death or TECs, whether the patient was seronegative or seropositive. Incorporating the serotonin release assay for platelet-activating antibodies did not alter these findings. Conclusions Seropositivity for anti-PF4/heparin antibodies does not increase the risk of death or thromboembolism after cardiac surgery. Screening is not indicated, and seropositivity should only be interpreted in the context of clinical evidence for HIT.Duke IRB Protocol #00010736.

Background Predictors of venous thromboembolism (VTE) after trauma are uncertain. Objective To identify independent predictors of VTE after acute trauma. Methods Using Rochester Epidemiology Project (REP) resources, we identified all Olmsted County, MN residents with objectively-diagnosed incident VTE within 92 days after hospitalization for acute trauma over the 18-year period, 1988–2005. We also identified all Olmsted County residents hospitalized for acute trauma over this time period and chose one to two residents frequency-matched to VTE cases on sex, event year group and ICD-9-CM trauma code predictive of surgery. In a case-cohort study, demographic, baseline and time-dependent characteristics were tested as predictors of VTE after trauma using Cox proportional hazards modeling. Results Among 200 incident VTE cases, the median (interquartile range) time from trauma to VTE was 18 (6, 41) days. Of these, 62% cases developed VTE after hospital discharge. In a multiple variable model including 370 cohort members, patient age at injury, male sex, increasing injury severity as reflected by the Trauma Mortality Prediction Model (TMPM) Mortality Score, immobility prior to trauma, soft tissue leg injury, and prior superficial vein thrombosis were independent predictors of VTE (C-statistic = 0.78). Conclusions We have identified clinical characteristics which can identify patients at increased risk for VTE after acute trauma, independent of surgery. Almost two thirds of all incident VTE events occurred after initial hospital discharge (18 day median time from trauma to VTE) which questions current practice of not extending VTE prophylaxis beyond hospital discharge.

The purpose of this study is to estimate medical costs attributable to venous thromboembolism among patients with active cancer.In a population-based cohort study, we used Rochester Epidemiology Project (REP) resources to identify all Olmsted County, Minn. residents with incident venous thromboembolism and active cancer over the 18-year period, 1988-2005 (n = 374). One Olmsted County resident with active cancer without venous thromboembolism was matched to each case on age, sex, cancer diagnosis date, and duration of prior medical history. Subjects were followed forward in REP provider-linked billing data for standardized, inflation-adjusted direct medical costs from 1 year prior to index (venous thromboembolism event date or control-matched date) to the earliest of death, emigration from Olmsted County, or December 31, 2011, with censoring on the shortest follow-up to ensure a similar follow-up duration for each case-control pair. We used generalized linear modeling to predict costs for cases and controls and bootstrapping methods to assess uncertainty and significance of mean adjusted cost differences. Outpatient drug costs were not included in our estimates.Adjusted mean predicted costs were 1.9-fold higher for cases ($49,351) than for controls ($26,529) (P .001) from index to up to 5 years post index. Cost differences between cases and controls were greatest within the first 3 months (mean difference = $13,504) and remained significantly higher from 3 months to 5 years post index (mean difference = $12,939).Venous thromboembolism-attributable costs among patients with active cancer contribute a substantial economic burden and are highest from index to 3 months, but may persist for up to 5 years.

To provide nursing home (NH)-specific estimates to assess whether venous thromboembolism (VTE) risk factors identified for the general population apply to NH residents.Population-based case-control study.Olmsted County, Minnesota.All county residents with symptomatic objectively diagnosed incident VTE while resident in a NH from 1988 through 2000 (N = 182) and two age-, sex-, calendar-year-matched non-VTE Olmsted County NH residents per case (N = 364).Provider-linked medical records were reviewed to obtain information on active malignancy and recent hospitalization, surgery, trauma, or fracture as of index date (case's VTE date; respective provider registration date for controls). Risk factor prevalence and VTE-associated odds ratios (OR) were estimated and compared with previously obtained data for all Olmsted County residents from 1988 through 2000. For analyses, both groups were limited to individuals aged 65 and older.In NH residents, active malignancy, recent hospitalization, and recent surgery significantly increased VTE risk, but the magnitude of risk appeared much lower than general population estimates (e.g., for major surgery, OR = 2.5, 95% confidence interval (CI) = 1.4-4.3 for NH residents vs OR = 11, 95% CI = 7.0-17 for general population). In general, the prevalence of all evaluated VTE risk factors appeared much higher in NH controls than in general population controls. Thromboprophylaxis rates appeared higher for NH cases and controls than in the general population; disconcertingly, 47% of NH cases received prophylaxis.Although general population VTE risk factors (active cancer and recent hospitalization or surgery) can identify NH residents at higher risk for VTE, these exposures do not adequately stratify VTE risk for thromboprophylaxis recommendations. Further research into NH-specific risk factors and prophylaxis effectiveness is required.

To further explore reports of association of alcohol dependence and response to acamprosate treatment with the GATA4 rs13273672 single nucleotide polymorphism (SNP), we genotyped this and 10 other GATA4 SNPs in 816 alcohol-dependent cases and 1248 controls. We tested for association of alcohol dependence with the 11 SNPs individually and performed a global test for association using a principle components analysis. Our analyses demonstrate significant association between GATA4 and alcohol dependence at the gene level (P = 0.009) but no association with rs13273672. Further studies are needed to identify potential causal GATA4 variation(s) and the functional mechanism(s) contributing to this association.

Summary. Objectives: To identify venous thromboembolism (VTE) disease-susceptibility genes. Patients and methods: We performed in silico genome wide association scan (GWAS) analyses using genotype data imputed to approximately 2.5 million single-nucleotide polymorphisms (SNPs) from adults with objectively-diagnosed VTE (n = 1503), and controls frequency matched on age and gender (n = 1459; discovery population). Single-nucleotide polymorphisms exceeding genome-wide significance were replicated in a separate population (VTE cases, n = 1407; controls, n = 1418). Genes associated with VTE were re-sequenced. Results: Seven SNPs exceeded genome-wide significance (P

Clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) was detected using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells (>5–10%) with the same abnormal karyotype (presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (

Venous thromboembolism (VTE) is a chronic disease with a 30% ten-year recurrence rate. The highest incidence of recurrence is in the first 6 months. Active cancer significantly increases the hazard of early recurrence, and the proportions of time on standard heparin with an APTT ≥ 0.2 anti-X(a) U/mL, and on warfarin with an INR ≥ 2.0, significantly reduce the hazard. The acute treatment duration does not affect recurrence risk after treatment is stopped. Independent predictors of late recurrence include increasing patient age and body mass index, leg paresis, active cancer and other persistent VTE risk factors, idiopathic VTE, antiphospholipid antibody syndrome, antithrombin, protein C or protein S deficiency, hyperhomocysteinemia and a persistently increased plasma fibrin D-dimer. A recommendation for secondary prophylaxis should be individualized based on the risk for recurrent VTE (especially fatal pulmonary embolism) and bleeding. The appropriateness of secondary prophylaxis should be continuously reevaluated, and the prophylaxis stopped if the benefit no longer exceeds the risk.

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e3 1. About These Statistics. . . . . . . . . . . . . . . . . . . . . . . . . .e7 2. American Heart Association's 2020 Impact Goals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e10 3. Cardiovascular Diseases . . . . . . . . . . . . . . . . . . . . . . .e21 4. Subclinical Atherosclerosis . . . . . . . . . . . . . . . . . . . . .e45 5. Coronary Heart Disease, Acute Coronary Syndrome, and Angina Pectoris . . . . . . . . . . . . . . . . . .e54 6. Stroke (Cerebrovascular Disease). . . . . . . . . . . . . . . . .e68 7. High Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . .e88 8. Congenital Cardiovascular Defects. . . . . . . . . . . . . . . .e97 9. Cardiomyopathy and Heart Failure. . . . . . . . . . . . . . .e102 10. Disorders of Heart Rhythm . . . . . . . . . . . . . . . . . . . .e107 11. Other Cardiovascular Diseases. . . . . . . . . . . …

Patients with rheumatoid arthritis (RA) have an increased incidence of cardiovascular disease (CVD) compared to the general population (1, 2). Patients with RA also have increased premature mortality, some of which is due to this increased risk of CVD (3). Like CVD, noncardiac vascular disease may be a manifestation of systemic involvement in RA, and may have important impact on the health of patients with RA. While there is a considerable body of literature regarding the risk of heart disease as a component of the overall CVD risk burden in patients with RA, there is very little known about the incidence, risk, and outcome of noncardiac vascular disease among these patients. The primary focus of interest in vascular disease in the study of patients with RA has been on coronary artery disease, but it is likely that the entire vasculature is affected. Less well studied is noncardiac vascular disease in RA, including venous thromboembolism (VTE) (4–7), transient ischemic attack (8, 9), stroke (10–13), aortic aneurysm (14), arterial thromboembolism (6), and peripheral artery disease (15–17). Little is known regarding the potential risk factors for noncardiac vascular disease and what influence the traditional cardiovascular risk factors of previous myocardial infarction, obesity, diabetes, hypertension, and smoking have on development of these events in patients with RA. The contribution of these risk factors has been examined in relation to ischemic stroke (11), but as yet no study has addressed these risk factors in relation to other noncardiac vascular diseases. There are some data regarding the effect of RA therapies on ischemic stroke in patients with RA (11, 18), but there is little information about how medications used to treat RA might influence the incidence of other noncardiac vascular diseases (6). The purpose of this study was to investigate the incidence of noncardiac vascular disease events in a community-based incidence cohort of patients with RA and to compare this incidence to that in the general population in the same community. Among patients with RA, the incidence of noncardiac vascular disease events was also compared to that found in an earlier decade in a previous study by our group (10). In addition, we examined risk factors that may be associated with development of these events in patients with RA.

OBJECTIVE To create a cohort for cost-effective genetic research, the Mayo Genome Consortia (MayoGC) has been assembled with participants from research studies across Mayo Clinic with high-throughput genetic data and electronic medical record (EMR) data for phenotype extraction. PARTICIPANTS AND METHODS Eligible participants include those who gave general research consent in the contributing studies to share high-throughput genotyping data with other investigators. Herein, we describe the design of the MayoGC, including the current participating cohorts, expansion efforts, data processing, and study management and organization. A genome-wide association study to identify genetic variants associated with total bilirubin levels was conducted to test the genetic research capability of the MayoGC. RESULTS Genome-wide significant results were observed on 2q37 (top single nucleotide polymorphism, rs4148325; P =5.0 × 10 −62 ) and 12p12 (top single nucleotide polymorphism, rs4363657; P =5.1 × 10 −8 ) corresponding to a gene cluster of uridine 5′-diphospho-glucuronosyltransferases (the UGT1A cluster ) and solute carrier organic anion transporter family, member 1B1 ( SLCO1B1 ), respectively. CONCLUSION Genome-wide association studies have identified genetic variants associated with numerous phenotypes but have been historically limited by inadequate sample size due to costly genotyping and phenotyping. Large consortia with harmonized genotype data have been assembled to attain sufficient statistical power, but phenotyping remains a rate-limiting factor in gene discovery research efforts. The EMR consists of an abundance of phenotype data that can be extracted in a relatively quick and systematic manner. The MayoGC provides a model of a unique collaborative effort in the environment of a common EMR for the investigation of genetic determinants of diseases.