Racial, biological sex, and geographic disparities of venous thromboembolism in the United States, 2016 to 2019.

BACKGROUND: Venous thromboembolism (VTE) stands as the leading cause of preventable death within hospitals in the United States. Although there have been some studies investigating the incidence rates of VTE, there has yet to be a large-scale study elucidating disparities in sex, race, income, region, and seasons in patients with VTE. The goal of this study was to report the disparities in race, sex, income, region, and seasons in patients with VTE, pulmonary embolism (PE), and deep vein thrombosis (DVT), in hospitalized patients from 2016 to 2019. METHODS: We used the United States National Inpatients Sample database to identify inpatients diagnosed with PE, DVT, and PE and DVT from 2016 to 2019. The inpatient incidence per thousand was calculated for sex and race using the weighted sample model. The regional and monthly incidence of DVT and PE per thousand inpatients and risk of incidence were calculated. Patients' characteristics including hospital type, bed size, median length of stay, median total charges, and mortality were also collected. RESULTS: We examined 455,111 cases of VTE, 177,410 cases of DVT, 189,271 cases of PE, and 88,430 cases of both DVT and PE combined. Over the study period, we observed a statistically significant trend among PE hospitalization incidences. There was a strong and positive correlation between DVT and PE inpatients. Black inpatients had the highest cumulative incidence of hospitalizations in all cohorts with 10.36 per 1000 in PE and 9.1 per 1000 in DVT. Asian and Pacific Islander inpatients had the lowest cumulative incidence with 4.42 per 1000 in PE and 4.28 per 1000 in DVT. Females showed the lowest cumulative incidence with 7.47 per 1000 in PE and 6.53 per 1000 in DVT. The Mountain region was the highest among PE hospitalizations with 9.62 per 1000. For DVT, the Middle Atlantic region was the highest at 8.65 per 1000. The in-hospital mortality rate was the highest among the PE hospitalizations at 7.3%. Also, the trend analysis showed significant increases among all groups. CONCLUSIONS: Over the study period (2016-2019), we report the racial, biological sex, and geographical disparities from the National Inpatient Sample database, highlighting that Black inpatients had the highest incidence of PE and DVT, whereas Asian/Pacific Islander inpatients had the lowest incidences of PE and DVT. Moreover, women had a lower incidence compared with men. The observed regional variations indicated that the incidence of PE was highest in the Mountain region, whereas the incidence of DVT was lowest in the Middle Atlantic region. There was an increase in the mortality of inpatients diagnosed with VTE reflecting the growing burden of this condition in the US health care system.

Venous thromboembolism in Black COVID-19 patients in a minority context compared to White, Asian and other racialized patients: A systematic review and meta-analysis.

IMPORTANCE: COVID-19 has disproportionately affected racialized populations, with particular impact among individuals of Black individuals. However, it is unclear whether disparities in venous thromboembolic (VTE) complications exist between Black individuals and those belonging to other racial groups with confirmed SARS-CoV2 infections. OBJECTIVE: To summarize the prevalence and moderators associated with VTE among Black COVID-19 patients in minoritized settings, and to compare this to White and Asian COVID-19 patients according to sex, age, and comorbid health conditions (heart failure, cancer, obesity, hypertension). DESIGN SETTING, AND PARTICIPANTS: A systematic search of MEDLINE, Embase, CINAHL and CENTRAL for articles or reports published from inception to February 15, 2023. STUDY SELECTION: Reports on VTE among Black individuals infected with SARS-CoV2, in countries where Black people are considered a minority population group. DATA EXTRACTION AND SYNTHESIS: Study characteristics and results of eligible studies were independently extracted by 2 pairs of reviewers. VTE prevalence was extracted, and risk of bias was assessed. Prevalence estimates of VTE prevalence among Black individuals with COVID19 in each study were pooled. Where studies provided race-stratified VTE prevalence among COVID19 patients, odds ratios were generated using a random-effects model. MAIN OUTCOMES AND MEASURES: Prevalence of VTE, comprising of deep vein thrombosis and pulmonary embolism. RESULTS: Ten studies with 66,185 Black individuals reporting the prevalence of COVID-19 associated VTE were included. Weighted median age of included studies was 47.60. Pooled prevalence of COVID-19 associated VTE was 7.2 % (95 % CI, 3.8 % - 11.5 %) among Black individuals. Among individuals with SARS-CoV2 infections, Black population had higher risks of VTE compared to their White (OR = 1.79, [95 % CI 1.28-2.53], p < .001) or Asian (OR = 2.01, [95 % CI, 1.14-3.60], p = .017) counterparts, or patients with other racial identities (OR = 2.01, [95 % CI, 1.39, 2.92]; p < .001). CONCLUSIONS AND RELEVANCE: Black individuals with COVID-19 had substantially higher risk of VTE compared to White or Asian individuals. Given racial disparities in thrombotic disease burden related to COVID-19, medical education, research, and health policy interventions are direly needed to ensure adequate disease awareness among Black individuals, to facilitate appropriate diagnosis and treatment among Black patients with suspected and confirmed VTE, and to advocate for culturally safe VTE prevention strategies, including pre-existing inequalities to the COVID-19 pandemic that persist after the crisis.

COVID-19 and Risk of VTE in Ethnically Diverse Populations.

BACKGROUND: Limited existing data suggest that the novel COVID-19 may increase risk of VTE, but information from large, ethnically diverse populations with appropriate control participants is lacking. RESEARCH QUESTION: Does the rate of VTE among adults hospitalized with COVID-19 differ from matched hospitalized control participants without COVID-19? STUDY DESIGN AND METHODS: We conducted a retrospective study among hospitalized adults with laboratory-confirmed COVID-19 and hospitalized adults without evidence of COVID-19 matched for age, sex, race or ethnicity, acute illness severity, and month of hospitalization between January 2020 and August 2020 from two integrated health care delivery systems with 36 hospitals. Outcomes included VTE (DVT or pulmonary embolism ascertained using diagnosis codes combined with validated natural language processing algorithms applied to electronic health records) and death resulting from any cause at 30 days. Fine and Gray hazards regression was performed to evaluate the association of COVID-19 with VTE after accounting for competing risk of death and residual differences between groups, as well as to identify predictors of VTE in patients with COVID-19. RESULTS: We identified 6,319 adults with COVID-19 and 6,319 matched adults without COVID-19, with mean ± SD age of 60.0 ± 17.2 years, 46% women, 53.1% Hispanic, 14.6% Asian/Pacific Islander, and 10.3% Black. During 30-day follow-up, 313 validated cases of VTE (160 COVID-19, 153 control participants) and 1,172 deaths (817 in patients with COVID-19, 355 in control participants) occurred. Adults with COVID-19 showed a more than threefold adjusted risk of VTE (adjusted hazard ratio, 3.48; 95% CI, 2.03-5.98) compared with matched control participants. Predictors of VTE in patients with COVID-19 included age ≥ 55 years, Black race, prior VTE, diagnosed sepsis, prior moderate or severe liver disease, BMI ≥ 40 kg/m2, and platelet count > 217 k/µL. INTERPRETATION: Among ethnically diverse hospitalized adults, COVID-19 infection increased the risk of VTE, and selected patient characteristics were associated with higher thromboembolic risk in the setting of COVID-19.

Should all patients receive the same prophylaxis? Racial variation in the risk of venous thromboembolism after major abdominal operations.

BACKGROUND: Whether prevention strategy for postoperative venous thromboembolism (VTE) should be tailored across racial groups remains unknown. METHODS: Patients who underwent major abdominal operation in the Nationwide Inpatient Sample (NIS) were examined. Our primary outcome was postoperative VTE, and the secondary outcome was postoperative bleeding. Multivariable logistic regression analyses were performed and validated with the National Surgical Quality Improvement Program (NSQIP) database. RESULTS: 781,888 patients from NIS were analyzed. Overall VTE rate was 2.0%. Compared to White patients, Hispanic (OR 0.85, 95% CI 0.78-0.93, p < 0.01) and Asian patients (OR 0.49, 95% CI 0.40-0.61, p < 0.01) had significantly lower risks for VTE. In contrast, Asian patients had a significantly higher risk of bleeding (OR 1.39, 95% CI 1.24-1.56, p < 0.01). Similar trends were observed in NSQIP. CONCLUSIONS: The risk-benefit ratio of postoperative VTE prophylaxis for Asian patients is roughly three times higher than that for White patients, suggesting a tailored approach is necessary.

Incidence of Venous Thromboembolism in a Racially Diverse Population of Oklahoma County, Oklahoma.

BACKGROUND: Contemporary incidence data for venous thromboembolism (VTE) from racially diverse populations are limited. The racial distribution of Oklahoma County closely mirrors that of the United States. OBJECTIVE: To evaluate VTE incidence and mortality, including demographic and racial subgroups. DESIGN: Population-based prospective study. SETTING: We conducted VTE surveillance at all relevant tertiary care facilities and outpatient clinics in Oklahoma County, Oklahoma during 2012 to 2014, using both active and passive methods. Active surveillance involved reviewing all imaging reports used to diagnose VTE. Passive surveillance entailed identifying VTE events from hospital discharge data and death certificate records. MEASUREMENTS: We used Poisson regression to calculate crude, age-stratified, and age-adjusted incidence and mortality rates per 1,000 population per year and 95% confidence intervals (CIs). RESULTS: The incidence rate of all VTE was 3.02 (2.92-3.12) for those age ≥18 years and 0.05 (0.04-0.08) for those <18 years. The age-adjusted incidence rates of all VTE, deep vein thrombosis, and pulmonary embolism were 2.47 (95% CI: 2.39-2.55), 1.47 (1.41-1.54), and 0.99 (0.93-1.04), respectively. The age-adjusted VTE incidence and the 30-day mortality rates, respectively, were 0.63 and 0.121 for Asians/Pacific Islanders, 3.25 and 0.355 for blacks, 0.67 and 0.111 for Hispanics, 1.25 and 0.195 for Native Americans, and 2.71 and 0.396 for whites. CONCLUSION: The age-adjusted VTE incidence and mortality rates vary substantially by race. The incidence of three per 1,000 adults per year indicates an important disease burden, and is informative of the burden in the U.S.

Trends and outcomes of venous thromboembolism in adult hospitalizations with acute myeloid leukemia: analysis of nationwide inpatient sample from 2010 to 2014.

Background: Venous thromboembolism (VTE) occurs frequently in acute myeloid leukemia (AML) patients. There are no population-based studies from the United States (U.S.) analyzing this association. The study aims to analyze the trends, predictors of mortality, and outcomes of VTE in AML patients.Methods: We analyzed the publicly available Nationwide Inpatient Sample (NIS) for years 2010-2014. Hospitalizations due to AML were identified by previously validated International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes as the primary diagnosis. VTE was identified by ICD-9-CM codes as secondary diagnosis. Hospitalizations with age less than 18 years of age were excluded. The trends and outcomes were determined using Chi-squared (χ2) test and multivariate regression models.Results: From 2010 to 2014, there were 313,282 hospitalizations with a primary diagnosis of AML and 1,633 hospitalizations (0.1%) had VTE as a concurrent diagnosis. There was a significant increase in the proportion of AML hospitalizations with VTE from 0.47% in 2010 to 0.56% in 2014 (P = 0.014). Multivariable regression analysis showed that the odds of in-hospital mortality were not higher in AML hospitalizations with VTE (odds ratio [OR] 1.11; 95% confidence interval [CI] 0.81-1.52; P = 0.5) than those without VTE. Age group above 84 years carried the highest risk of mortality (OR 3.20; 95% CI 2.77-3.70; P < 0.0001) in AML-VTE patients. Black (OR 1.23; 95% CI 1.13-1.35; P < 0.0001) and uninsured patients (OR 1.50; 95% CI 1.31-1.73; P < 0.0001) were at significantly higher odds of in-hospital mortality amongst the AML-VTE hospitalizations.Conclusion: The proportion of AML hospitalizations with VTE continues to rise in the U.S. After adjusting for confounders, increasing age, Black race, and lack of insurance were found to have higher risk of in-hospital mortality in the AML-VTE cohort. The odds of in-hospital mortality in AML hospitalizations with VTE are not higher than those without VTE.

Coagulation Status and Venous Thromboembolism Risk in African Americans: A Potential Risk Factor in COVID-19.

Severe acute respiratory syndrome coronavirus 2 infection (COVID-19) is known to induce severe inflammation and activation of the coagulation system, resulting in a prothrombotic state. Although inflammatory conditions and organ-specific diseases have been shown to be strong determinants of morbidity and mortality in patients with COVID-19, it is unclear whether preexisting differences in coagulation impact the severity of COVID-19. African Americans have higher rates of COVID-19 infection and disease-related morbidity and mortality. Moreover, African Americans are known to be at a higher risk for thrombotic events due to both biological and socioeconomic factors. In this review, we explore whether differences in baseline coagulation status and medical management of coagulation play an important role in COVID-19 disease severity and contribute to racial disparity trends within COVID-19.

Nationwide Trends in Prevalent Cardiovascular Risk Factors and Diseases in Young Adults: Differences by Sex and Race and In-Hospital Outcomes.

OBJECTIVES: Prevalence and trends in all cardiovascular disease (CVD) risk factors among young adults (18-39 years) have not been evaluated on a large scale stratified by sex and race. The aim of this study was to establish the prevalence and temporal trend of CVD risk factors in US inpatients younger than 40 years of age from 2007 through 2014 with racial and sex-based distinctions. In addition, the impact of these risk factors on inpatient outcomes and healthcare resource utilization was explored. METHODS: A cross-sectional nationwide analysis of all hospitalizations, comorbidities, and complications among young adults from 2007 to 2014 was performed. The primary outcomes were frequency, trends, and race- and sex-based differences in coexisting CVD risk factors. Coprimary outcomes were trends in all-cause mortality, acute myocardial infarction, arrhythmia, stroke, and venous thromboembolism in young adults with CVD risk factors. Secondary outcomes were demographics and resource utilization in young adults with versus without CVD risk factors. RESULTS: Of 63 million hospitalizations (mean 30.5 [standard deviation 5.9] years), 27% had at least one coexisting CVD risk factor. From 2007 to 2014, admission frequency with CVD risk factors increased from 42.8% to 55.1% in males and from 16.2% to 24.6% in females. Admissions with CVD risk were higher in male (41.4% vs 15.9%) and white (58.4% vs 53.8%) or African American (22.6% vs 15.9%) patients compared with those without CVD risk. Young adults in the Midwest (23.9% vs 21.1%) and South (40.8% vs 37.9%) documented comparatively higher hospitalizations rates with CVD risk. Young adults with CVD risk had higher all-cause in-hospital mortality (0.4% vs. 0.3%) with a higher average length of stay (4.3 vs 3.2 days) and charges per admission ($30,074 vs $20,124). CONCLUSIONS: Despite modern advances in screening, management, and interventional measures for CVD, rising trends in CVD risk factors across all sex and race/ethnic groups call for attention by preventive cardiologists.

Resting heart rate and incident venous thromboembolism: the Multi-Ethnic Study of Atherosclerosis.

Objective: Venous thromboembolism (VTE) is associated with significant morbidity and mortality. Resting heart rate (RHR), which may be modifiable through lifestyle changes, has been shown to be associated with cardiovascular disease risk and with inflammatory markers that have been predictive of VTE incidence. Methods: We examined whether RHR is also associated with VTE incidence independent of these risk factors. We studied 6479 Multi-Ethnic Study of Atherosclerosis participants free from clinical VTE at baseline who had baseline RHR ascertained by 12-lead ECG. VTE events were recorded from hospital records and death certificates using International Classification of Diseases (ICD)-9 and ICD-10 codes. We categorised RHR as <60, 60-69, 70-79 and ≥80 bpm. We used Cox hazard models to determine the association of incident VTE by RHR. Results: Participants had mean (SD) age of 62 (10) years and RHR of 63 (10) bpm. RHR was cross-sectionally correlated with multiple inflammatory and coagulation factors. There were 236 VTE cases after a median follow-up of 14 years. Compared with those with RHR<60 bpm, the HR (95% CI) for incident VTE for RHR≥80 bpm was 2.08 (1.31 to 3.30), after adjusting for demographics, physical activity, smoking, diabetes and use of atrioventricular (AV)-nodal blockers, aspirin and anticoagulants, and remained significant after further adjustment for inflammatory markers (2.05 (1.29 to 3.26)). Results were similar after excluding those taking AV-nodal blocker medications. There was no effect modification of these associations by sex or age. Conclusion: Elevated RHR was positively associated with VTE incidence after a median of 14 years; this association was independent of several traditional VTE and inflammatory markers.

Comparison of 2013 and 2009 versions of Caprini risk assessment models for predicting VTE in Chinese cancer patients: a retrospective study.

This study aimed to compare the predictive value of 2009 and 2013 version of Caprini risk assessment models (RAM) for venous thromboembolism (VTE) in cancer patients by receiver operating characteristic (ROC) analysis. This retrospective study reviewed a total of 1439 VTE and 1439 non-VTE Chinese cancer inpatients. The baseline demographic data of these patients were recorded. 2009 and 2013 versions Caprini RAMs were applied, and cumulative risk scores were obtained by adding the scores of each risk factor. The specificity, sensitivity, positive predictive value and negative predictive value of these two models were analyzed. ROC curve was drawn to calculate the area under the curve (AUC) and the Youden index. Significant differences were observed in the risk factors between VTE and non-VTE Group. The specificity and negative predictive value of 2013 version were higher than those of 2009 version (P < 0.05). No significant differences were found in the sensitivity or positive predictive value between 2009 and 2013 versions of the Caprini RAM (P > 0.05). The AUC and Youden index of 2013 Caprini RAM were significantly higher than those of 2009 Caprini RAM (P < 0.001), whereas the Youden index of the 2009 Caprini RAM at critical point 4 was higher than that at critical point 3 (0.362 vs 0.067, P < 0.05). Compared with 2009 version, 2013 version of the Caprini RAM provides a more accurate and efficacious method for the risk assessment of VTE in Chinese cancer patients.

Black Patients Experience Highest Rates of Cancer-associated Venous Thromboembolism.

PURPOSE: Cancer patients are at a higher risk of venous thromboembolism (VTE) than the general population. In the general population, blacks are at a higher risk of VTE compared with whites. The influence of race on cancer-associated VTE remains unexplored. We examined whether black cancer patients are at a higher risk of VTE and whether these differences are present in specific cancer types. DESIGN: A retrospective study was performed in the largest safety net hospital of New England using a cohort of cancer patients characterized by a substantial number of nonwhites. RESULTS: We identified 16,498 subjects with solid organ and hematologic malignancies from 2004 to 2018. Among them, we found 186 unique incident VTE events, of which the majority of the events accrued within the first 2 years of cancer diagnosis. Overall, blacks showed a 3-fold higher incidence of VTE (1.8%) compared with whites (0.6%; P<0.001). This difference was observed in certain cancer types such as lung, gastric and colorectal. In lung cancer, the odds of developing VTE in blacks was 2.77-times greater than those in white patients (confidence interval, 1.33-5.91; P=0.007). Despite the greater incidence of cancer-associated VTE in blacks, their Khorana risk score of VTE was not higher. CONCLUSIONS: In a diverse cancer cohort, we observed a higher incidence of cancer-associated VTE in blacks compared with patients from other races. This study indicates the consideration of race in the risk assessment of cancer-associated VTE. It could also lead to future mechanistic studies aiming at identifying reasons for differential VTE risk depending on cancer type.

Association of ß-fibrinogen polymorphisms and venous thromboembolism risk: A PRISMA-compliant meta-analysis.

BACKGROUND: Venous thromboembolism (VTE) is a multifactorial disease in which genetic and acquired risk factors may contribute to disease pathogenesis. Several studies have demonstrated that ß-fibrinogen (FGB) polymorphisms are associated with the risk of VTE. However, the results of these studies were not totally consistent. In this paper, we performed a meta-analysis to further investigate the relationship between FGB polymorphisms and susceptibility to VTE. METHODS: To identify studies pertinent to the focused question, the following databases were systematically searched: PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure, and Wanfang Data. The strength of correlations was evaluated by calculating pooled odds ratios (ORs) and 95% confidence intervals (95% CIs). Subgroup analyses stratified by ethnicity, type of disorders, and source of control were also performed. RESULTS: Overall, A total of 18 relevant case-control studies met the inclusion criteria and were incorporated in this meta-analysis, involving 3033 VTE cases and 4547 healthy controls. FGB -455G>A polymorphism and -148C>T polymorphism were not significantly associated with susceptibility to VTE in overall populations. However, results of stratified analysis demonstrated that among Caucasian population, the -455G>A mutation was negatively associated with the risk of VTE under all genetic comparison models (A:G OR = 0.80 95% CI = 0.70-0.91; GA + AA:GG OR = 0.80 95% CI = 0.68-0.93; GA:GG OR = 0.84 95% CI = 0.71-0.98; AA:GG + GA OR = 0.61 95% CI = 0.43-0.87; AA:GG OR = 0.57 95% CI = 0.40-0.82), which indicates FGB -455G>A polymorphism may be a protective factor for VTE. There was no correlation between -148C>T polymorphism and susceptibility to VTE in all subgroup analyses. CONCLUSION: FGB -455G>A polymorphism was associated with a decreased risk of VTE among the Caucasian population.

Identifying mutation-driven changes in gene functionality that lead to venous thromboembolism.

Venous thromboembolism (VTE) is a common hematological disorder. VTE affects millions of people around the world each year and can be fatal. Earlier studies have revealed the possible VTE genetic risk factors in Europeans. The 2018 Critical Assessment of Genome Interpretation (CAGI) challenge had asked participants to distinguish between 66 VTE and 37 non-VTE African American (AA) individuals based on their exome sequencing data. We used variants from AA VTE association studies and VTE genes from DisGeNET database to evaluate VTE risk via four different approaches; two of these methods were most successful at the task. Our best performing method represented each exome as a vector of predicted functional effect scores of variants within the known genes. These exome vectors were then clustered with k-means. This approach achieved 70.8% precision and 69.7% recall in identifying VTE patients. Our second-best ranked method had collapsed the variant effect scores into gene-level function changes, using the same vector clustering approach for patient/control identification. These results show predictability of VTE risk in AA population and highlight the importance of variant-driven gene functional changes in judging disease status. Of course, more in-depth understanding of AA VTE pathogenicity is still needed for more precise predictions.

Racial, Ethnic, and Socioeconomic Inequities in the Prescription of Direct Oral Anticoagulants in Patients With Venous Thromboembolism in the United States.

BACKGROUND: Beginning in 2012, direct oral anticoagulants (DOACs) were approved for treatment and prevention of venous thromboembolism. Prior investigations have demonstrated slow rates of adoption of novel therapeutics for black patients. We assessed the association of racial/ethnic and socioeconomic factors with DOAC use among commercially insured venous thromboembolism patients. METHODS AND RESULTS: We performed a retrospective cohort analysis of adult patients with an incident diagnosis of venous thromboembolism between January 2010 and December 2016 using OptumInsight's Clinformatics Data Mart. We identified the first filled oral anticoagulant prescription within 30 days of discharge of an inpatient admission. We performed a multivariable logistic regression, adjusting for age, sex, race/ethnicity, region, zip code-linked household income, and clinical covariates to identify factors associated with the use of DOACs. Race and ethnicity were determined in this database through a combination of public records, self-report, and proprietary ethnicity code tables. There were 14 140 patients included in the analysis. Treatment with DOACs increased from <0.1% in 2010 to 65.6% in 2016. In multivariable analyses, black patients were less likely to receive a DOAC compared with white patients (odds ratio, 0.86; 95% CI, 0.77-0.97; P=0.02). There were no differences in DOAC utilization among Asian (odds ratio, 1.06; 95% CI, 0.75-1.49; P=0.74) or Hispanic patients (odds ratio, 1.04; 95% CI, 0.88-1.22; P=0.66) compared with whites. Patients with a household income over $100 000 per year were more likely to receive DOAC therapy compared with patients with a household income of <$40 000 per year (odds ratio, 1.50; 95% CI, 1.33-1.69; P<0.0001). CONCLUSIONS: Although DOAC adoption has increased steadily since 2012, among a commercially insured population, black race and low household income were associated with lower use of DOACs for incident venous thromboembolism despite controlling for other clinical and socioeconomic factors. These findings suggest the possibility of both racial and socioeconomic inequity in access to this novel pharmacotherapy.

Circulating ceruloplasmin, ceruloplasmin-associated genes and the incidence of venous thromboembolism in the Atherosclerosis Risk in Communities study.

Essentials Ceruloplasmin (CP) is an acute-phase reactant and a potential biomarker of atherothrombotic risk. We assessed associations between CP and venous thromboembolism (VTE) risk in 9933 individuals. Higher circulating CP but not CP-related genes were associated with greater incident VTE rates. Circulating CP could be considered a non-causal biomarker of VTE risk in the community. SUMMARY: Background Ceruloplasmin (CP) is an acute-phase reactant and a potential biomarker of atherothrombotic risk. We assessed the associations between CP, CP-associated genetic variants and incident venous thomboembolism (VTE) in the Atherosclerosis Risk in Communities study. Methods and results In an observational study, 9933 men and women aged 53-75 years without prevalent VTE were included in 1996-1998 and followed through 2011. Circulating CP was measured in stored blood samples obtained in 1996-1998. Polymorphisms rs11708215 and rs13072552, which have been previously associated with CP concentrations, were measured in 8439 participants. VTEs were identified from hospital discharge codes and validated by physician review of medical records and imaging reports. Over a mean of 10.5 years of follow-up, 376 cases of VTE were identified. The association between circulating CP, CP-associated polymorphisms and the incidence of VTE was estimated. After adjustment for traditional risk factors and biomarkers, higher concentrations of circulating CP were associated with greater incident VTE rates (hazard ratio 1.82, 95% confidence interval 1.12-2.95, comparing the 87.5-100th percentile with the bottom quartile). Both rs11708215 and rs13072552 were associated with CP concentrations but not with VTE risk. Conclusions Even though high CP concentrations were associated with an increased VTE risk, CP-associated genetic variants were not associated with a higher risk of VTE. Our results suggest that circulating CP concentrations may not be causally related to the risk of incident VTE.

Clinical Manifestation and Mutation Spectrum of 53 Unrelated Pedigrees with Protein S Deficiency in China.

Protein S (PS) deficiency is associated with a 10-fold increased risk of venous thromboembolism (VTE), but its diagnosis is quite difficult and complicated. In this study, we identified 53 unrelated pedigrees with PS deficiency in China. Data of their clinical characteristics and laboratory examinations were collected. Genetic analysis of PROS1 including direct sequencing, copy number variant detection and messenger ribonucleic acid analysis was performed in probands and related family members. Of these 53 probands, 52.8% (28/53) experienced multi-site and/or recurrent thrombotic episodes, mainly manifested as deep venous thrombosis and/or pulmonary embolism (82.7%). Additional risk factors of VTE were observed in 39.6% (21/53) probands who exhibited a significantly higher rate of recurrent VTE compared with those not, in which 7 probands were complicated by anti-phospholipid syndrome. Most probands and family members exhibited quantitative PS deficiency with impairment of both activated protein C and tissue factor pathway inhibitor cofactor activities. Note that 87.2% (34/39) PROS1 detectable mutation rate was obtained through comprehensive phenotypic and genetic analysis. A total of 36 PROS1 causative mutations including 16 novel mutations were identified in 48 probands, whereas no PROS1 mutations were detected in the other 5 probands. Three hotspot mutations (Glu67Ala, Arg561Trp and Tyr560*) were identified in the Chinese population for the first time. This article provides a framework for correlating the clinical pathogenesis of PS deficiency to genetic backgrounds in the Chinese population.

Association study of miR-146a, miR-149, miR-196a2, and miR-499 polymorphisms with venous thromboembolism in a Korean population.

Despite much progress in microRNA (miRNA) research, information regarding the association between miRNAs and venous thromboembolism (VTE), especially in Asian patients, remains limited. This case-control study sought to determine the correlation between the presence of polymorphisms in the genes encoding the miRNAs miR-146a, miR-149, miR-196a2, miR-499, and VTE in Korean patients. We observed no statistically significant differences in the genotype frequency of miRNA polymorphisms between 300 control individuals and 203 VTE patients. However, we observed a significant association between three allelic combinations of miRNA polymorphisms and VTE risk. Overall, our findings suggest that specific miRNA polymorphisms are associated with the risk of VTE in a Korean population.

A large-scale exome array analysis of venous thromboembolism.

Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.

Correlations between methylenetetrahydrofolate reductase gene polymorphisms and venous thromboembolism: A meta-analysis of 99 genetic association studies.

We performed this meta-analysis to better assess the relationship between methylenetetrahydrofolate reductase gene ( MTHFR) polymorphisms and the risk of venous thromboembolism. Eligible studies were searched in PubMed, Medline, Embase, and Web of Science. Odds ratios with 95% confidence intervals were used to assess associations of MTHFR polymorphisms with venous thromboembolism. A total of 99 genetic association studies were enrolled for analyses. Although no positive results were detected in overall analyses for the rs1801131 polymorphism. Further subgroup analyses according to ethnicity of participants and type of disease revealed that the rs1801131 polymorphism was significantly correlated with the risk of pulmonary embolism. For the rs1801133 polymorphism, significant association with the risk of venous thromboembolism was found in the dominant, recessive, and allele models. Further subgroup analyses according to ethnicity of participants revealed that the rs1801133 polymorphism was significantly associated with the risk of venous thromboembolism in Caucasians, East Asians, and West Asians. When we stratified available data according to type of disease, we found that the rs1801133 polymorphism was also significantly correlated with the risk of deep vein thrombosis and pulmonary embolism. In conclusion, our findings indicate that the MTHFR rs1801133 polymorphism may serve as a potential biological marker for venous thromboembolism in Caucasians, East Asians, and West Asians. Moreover, the MTHFR rs1801133 polymorphism may be implicated in the development of deep vein thrombosis and pulmonary embolism, while the MTHFR rs1801131 polymorphism may contribute to the development of pulmonary embolism.