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  • American Society of Hematology  (46)
  • 1
    In: Blood, American Society of Hematology, Vol. 132, No. 17 ( 2018-10-25), p. 1842-1850
    Abstract: Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry–specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; P = .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; P = 6.6 × 10−5) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the 3 fibrinogen subunit-encoding genes (FGA, FGG, and FGB) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 2
    In: Blood Advances, American Society of Hematology, Vol. 7, No. 18 ( 2023-09-26), p. 5341-5350
    Abstract: Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are associated with an increased risk of cardiovascular diseases, including venous thromboembolism (VTE). The reasons for this are complex and include obesity, smoking, and use of hormones and psychotropic medications. Genetic studies have increasingly provided evidence of the shared genetic risk of psychiatric and cardiometabolic illnesses. This study aimed to determine whether a genetic predisposition to MDD, BD, or SCZ is associated with an increased risk of VTE. Genetic correlations using the largest genome-wide genetic meta-analyses summary statistics for MDD, BD, and SCZ (Psychiatric Genetics Consortium) and a recent genome-wide genetic meta-analysis of VTE (INVENT Consortium) demonstrated a positive association between VTE and MDD but not BD or SCZ. The same summary statistics were used to construct polygenic risk scores for MDD, BD, and SCZ in UK Biobank participants of self-reported White British ancestry. These were assessed for impact on self-reported VTE risk (10 786 cases, 285 124 controls), using logistic regression, in sex-specific and sex-combined analyses. We identified significant positive associations between polygenic risk for MDD and the risk of VTE in men, women, and sex-combined analyses, independent of the known risk factors. Secondary analyses demonstrated that this association was not driven by those with lifetime experience of mental illness. Meta-analyses of individual data from 6 additional independent cohorts replicated the sex-combined association. This report provides evidence for shared biological mechanisms leading to MDD and VTE and suggests that, in the absence of genetic data, a family history of MDD might be considered when assessing the risk of VTE.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2023
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  • 3
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 934-934
    Abstract: Introduction: Among all venous thromboembolism (VTE) events, 20% occur during or in the three months following a hospitalization. Inpatient VTE prevention strategies incorporate pharmacological interventions that do not commonly continue after discharge. Recent trials of post-discharge prophylaxis have not identified benefit among recently discharged patients, probably due to lack of understanding of the relative and absolute risks of VTE after discharge. In order to better clarify the scope of the problem, we quantified the risk of VTE during hospitalizations, and up to 3 months post-discharge relative to patients without a recent hospitalization. Methods: We followed all primary care patients aged ≥18, at the University of Vermont Medical Center's primary care clinics for hospitalization and VTE using the electronic medical record. Patients entered the cohort at their first contact with the health system after 06/30/2010 and were followed until their last contact, change of primary care provider to a non-University of Vermont provider, or December 2016, whichever occurred first. First VTE during follow-up was defined as having two outpatient VTE codes 7-185 days apart or one inpatient code. Patients with a VTE code in the first 3 months of enrollment were excluded as having pre-baseline VTE. Hospital-acquired VTE was defined as VTE occurring after day 1 of hospitalization (to correctly categorize people with an outpatient VTE and admitted with VTE) and post-discharge VTE was defined as VTE occurring during successive 1-month time periods after discharge from the hospital. Age- and sex-adjusted Cox proportional hazard models were used to calculate hazard ratios (HRs) of VTE during and after hospitalization. Hospitalization and time periods after hospitalization were modeled as time-varying covariates and included the time in the hospital, and 1-30 (month 1), 31-60 (month 2), and 61-90 (month 3) days post-discharge. The reference group for this analysis was outpatients who were not within 90 days of a hospitalization. Results: From 2010-16, 87,821 patients (49,468 women, 56%) were included, with a mean age of 46 years. With 371,429 person-years of follow-up (mean follow-up 4.2 years), 749 first VTE events occurred for a rate of 2.0 per 1,000 person-years. There were 57,837 hospitalizations among 21,963 individuals for a rate 155.7 hospitalizations per 1,000 person-years. The Table presents the person-years of follow-up, the number, rate, and age- and sex-adjusted hazard of VTE for hospitalization and successive months after hospitalization. The VTE rate was 1.5 per 1,000 person-years outpatients not within 3 months of hospitalization. During hospitalization, the rate was 75.9 per 1,000 person-years, and slowly decreased over time after discharge, but remained elevated at 5.0 per 1,000 person-years event in month 3 after discharge. The age- and sex-adjusted HR for VTE was 40.3 during hospitalization and declined to 18.1, 6.0 and 2.9 over successive 1-month intervals after discharge (Table). Conclusion: In a primary care population in northern Vermont, hospitalization and time periods after hospitalization were associated with a dramatically increased incidence of and risk for VTE compared with patients not hospitalized in the past 3 months. The rate of VTE (34.4 per 1,000 person-years) in the first month post-discharge might not warrant universal post-discharge VTE prophylaxis, but suggests that if we can identify high-risk patients at low risk for bleeding, pharmacologic VTE prophylaxis may be appropriate in some patients. Further study of risk factors for post-discharge VTE is warranted. Table Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 4
    In: Blood, American Society of Hematology, Vol. 134, No. 19 ( 2019-11-7), p. 1645-1657
    Abstract: In this work related to familial aggregation of familial venous thromboembolism, the investigators report genomic and transcriptomic association of 16 novel susceptibility loci for venous thromboembolism.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
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  • 5
    In: Blood, American Society of Hematology, Vol. 120, No. 24 ( 2012-12-06), p. 4873-4881
    Abstract: We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P 〈 5 × 10−8) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10−10); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10−8); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10−8). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P 〈 .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
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  • 6
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 1915-1915
    Abstract: Introduction: Bleeding risk is understudied in recently discharged medical patients and often less appreciated than venous thrombosis risk. Knowledge of both absolute and relative bleeding risk in people recently discharged from medical hospitalizations is needed to balance the risks of thrombosis and bleeding. We therefore quantified the relative and absolute risk of bleeding requiring hospitalization in patients recently discharged (up to 3 months) after a bleeding-free medical admission. Methods: We followed all primary care patients aged ≥18 at the University of Vermont Medical Center's primary care clinics from July 2010 to September 2019, capturing all hospitalizations and bleeding events that followed these hospitalizations for 3 months after discharge. Using International Classification of Disease (ICD) 9 and 10 discharge diagnoses, laboratory values, current procedure terminology (CPT) codes and flowsheet data for transfusion support, we developed and validated computable phenotypes to identify bleeding events. Validation was performed manually by abstracting 150 charts with bleeding events detected by the phenotype and 40 charts without a bleeding event. Present on admission (POA)-bleeding was defined if bleeding occurred & lt;24 hours after admission, and hospital-acquired (HA) if it occurred ≥24 hours after admission. For this analysis, our outcome was POA-bleeding. Bleeding risk was estimated using successive 1-month intervals after discharge as a time-varying covariate in age- and sex-adjusted Cox proportional hazard models. The reference group was bleeding risk in people with no hospitalization in the prior 3 months. HA-bleeding occurring within 3 months of a previous hospitalization were not grouped with the prior hospitalization. Results: From 2010-2019, among 67,571 people with a mean age of 48 years (56.7% female) followed for a median of 6.2 years, there were a total of 14,266 medical hospitalizations and 1,784 hospitalized bleeding events (568 HA and 1216 POA). The bleeding computable phenotype had a positive predictive value of 79% and a negative predictive value of & gt;99%. The rate of bleeding in people with no hospitalizations within the past 3 months was 2.88 per 1000 person-years. Over the 1 month after discharge, the rate was 153.8 per 1000 person-years decreasing to 61 per 1000 person-years in the second month after discharge and 29 per 1000 person-years in the third month after discharge. The age- and sex-adjusted HR for bleeding was 26.9 the first month after discharged and decreased respectively to 15.3 and 8 over successive 1-month intervals after discharge, relative to those with no hospitalization in the past 3 months (Table). Conclusion: In this northern Vermont population, the three months after a medical hospitalization was associated with dramatically increased risk of hospitalization for bleeding compared to people with no recent hospitalizations. Findings demonstrate how common bleeding is after hospitalization and emphasize on the need to develop methods to quantify bleeding risk. Figure 1 Figure 1. Disclosures Al-Samkari: Novartis: Consultancy; Moderna: Consultancy; Argenx: Consultancy; Rigel: Consultancy; Amgen: Research Funding; Dova/Sobi: Consultancy, Research Funding; Agios: Consultancy, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 7
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 40-41
    Abstract: Introduction Electronic health records (EHRs), allow use of large clinical databases to inform the practice of medicine. The impact of EHRs on research has been modest due to the lack of validated computable phenotypes for risk factors and outcomes. We developed and validated a computable phenotype for hospital-acquired (HA) venous thrombosis (VTE) to aid future studies about of HA-VTE. Methods The study population consisted of all admissions to the medical services (general medicine, cardiology, intensive care unit, and hematology / oncology) between 2010-19 at the University of Vermont (UVM) Medical Center, a 540-bed tertiary acute care hospital. HA-VTE was defined as a deep vein thrombosis of a lower or upper extremity or pulmonary embolism. Data used to develop the computable phenotype include International Classification of Disease (ICD) 9 or 10 discharge codes with the present on admission (POA) flag and current procedure terminology (CPT) codes with dates/times (which include imaging studies). We divided VTE into three groups; upper extremity deep venous thrombosis, lower extremity deep venous thrombosis, and pulmonary embolism, and selected CPT codes which could have diagnosed each VTE group. Our final definition consisted of a VTE ICD code not POA with a VTE site-specific CPT code (but not on the day of admission). We validated the algorithm by randomly abstracting 110 charts in 6 groups; 1) no VTE ICD codes, 2) VTE ICD code POA, 3) VTE ICD code not POA and no CPT code, 4) VTE ICD code not POA and with a CPT code on day 1 of admission, 5) VTE ICD code not POA with a CPT code on day 1 of admission and another 1+ day of admission (this group was incidentally discovered during our initial chart abstraction and validation) and 6) VTE ICD code not POA and with a CPT code after day 1 of admission (our computable phenotype of HA-VTE). We used survey methodology to determine the sensitivity and specificity of our computable phenotype for HA-VTE. Results Figure 1 shows our methodology and the results from the computable phenotype including how many admissions were analyzed and the total number of HA-VTE identified. For validation we abstracted 110 hospitalizations from the 6 identified groups using a standardized form. The results of the validation by abstraction group are presented in the Table. Using survey methodology, we estimate the incidence of HA-VTE to be 4.9 per 1000 admissions. Among the 20 patients with no VTE ICD code, there were no VTE events. Among the hospitalizations with VTE ICD codes which did not meet our computable phenotype definition of HA-VTE, 5 of 91 individuals had a HA-VTE. One individual had an incorrect POA flag, another had a non-vascular ultrasound which diagnosed the HA-VTE, and 3 admissions with HA-VTE were excluded due to having an imaging study on day 1. Among the 19 patients abstracted for our computable phenotype for HA-VTE, 16 had a HA-VTE. Among the three failures of our HA-VTE computable phenotype, 1 individual had a HA-superficial venous thrombosis (miscoded), the second individual had multiple imaging studies due to a high clinical suspicion, and the third had a VTE on admission (erroneous POA flag). The sensitivity and specificity of our computable phenotype for HA-VTE was 84.2% (CI 78.7-88.9%) and 99.8% (CI 99.77-99.84%). Conclusions We developed a computable phenotype for HA-VTE with adequate specificity and excellent sensitivity. This phenotype will be used to assess risk factors for HA-VTE and with appropriate validation to estimate the rates of HA-VTE at other institutions. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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  • 8
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 45-46
    Abstract: Introduction: Bleeding is an uncommon event but it is causes significant increase in morbidity and mortality. Identifying bleeding events using electronic health record data (both resulting from hospitalization and causing hospitalization) would allow the development of risk assessment models (RAM) to identify those at most risk. Traditional prospective cohorts for rare events are time consuming and expensive. We suggest a more efficient method using the electronic health record (EHR) data by developing and validating an algorithm to detect bleeding in hospitalized patients, ie, a "computable phenotype". Methods: We captured all admissions to the University of Vermont (UVM) Medical Center between 2010-19, a tertiary care medical center in northwest Vermont. Using International Classification of Disease (ICD) 9 and 10 discharge diagnoses, "present on admission" flags, problem lists, laboratory values, vital signs, current procedure terminology (CPT) codes, medication administration, and flowsheet data for transfusion support, we developed computable phenotypes for bleeding. Classification was based on the gold standard International Society of Thrombosis and Haemostasis definitions for clinically relevant non-major bleeding (CRNMB) and major bleeding (MB) and validated by medical record review. To improve sensitivity and specificity, algorithms were developed by bleeding site (intracerebral, intraspinal, pericardial, retroperitoneal, orbital, intramuscular, gastrointestinal, genitourinary, gynecologic, pulmonary, nasal, post-procedure, or miscellaneous). We preliminary validated the computable phenotype by randomly abstracting 10 medical records from each bleeding site. Results: Among 62,468 admissions, our computable phenotype for bleeding identified 10,202 bleeding events associated with hospitalization; 4,650 were CRNMB and 5,552 were MB. On chart abstraction, 135 of 153 hospitalizations had either a MB or CRNMB (88%, Figure). For MB, 95 of 119 (80%) of the computed MB phenytope events were validated. Of the 24 of 119 (20%) not validated, 14% (16) were CRNMB and 7% (8) the bleeding was present on coding but was not detected by chart review. Only 29%(10/34) of the CRNMB were validated. The most common error in the CRNMB computable phenotype was misclassification of 14 MB as CRNMB (41% of CRNMB. For individual bleeding sites, (figure), the algorithms performed well for most sites including intracerebral hemorrhage, gastrointestinal, and intramuscular bleeding, but performed less well for unusual and rarer bleeding sites (i.e. nasal). Conclusion: We developed a computable phenotype for bleeding which can be applied to our EHR system. The computable phenotype was specific for MB, but underestimated the severity of potential CRNMB. Importantly, we correctly classified specific important bleeding sites such as intracerebral, gastrointestinal, and retroperitoneal. This computable phenotype forms the basis for further refinement, and provides a road map for future studies on epidemiology of hospital-acquired bleeding and hospitalization for bleeding. Figure: Major and Clinically relevant non-major bleeding as detected by Electronic Health Record compared to the chart validation Figure 1 Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 829-829
    Abstract: Introduction: Multiple regulatory agencies and professional societies recommend risk assessment of hospitalized medical patients for hospital-acquired (HA) venous thromboembolism (VTE) and provision of pharmacologic prophylaxis to those at risk. Extant risk assessment models (RAMs) include risk factors not knowable or difficult to assess at admission and often do not include risk factors reflecting illness acuity (such as laboratory studies and vital signs at admission). We developed a RAM for HA-VTE that reports absolute VTE risk, as opposed to arbitrary risk categories, using only objective risk factors measured within the first 24 hours of admission. Methods: The study setting was a combined academic and community 540-bed teaching hospital in northwest Vermont (The University of Vermont Medical Center). Using validated electronic health record (EHR) derived phenotypes (computable phenotypes), we captured all medical admissions between 2010-2019 and examined patient demographics, past medical history, and presenting vital and laboratory measures as potential risk factors for HA-VTE. As risk assessment should happen within 24 hours of admission, we only assessed risk factors knowable within this timeframe. Individuals with VTE at admission were excluded. Key outcome and risk factor definitions were validated using chart review. Bayesian logistic regression with a least absolute shrinkage and selection operator (LASSO) prior probability distribution was used to select risk factors for the model. Variables with a t-statistic ≥1.5 or ≤-1.5 were included in the final model. Full or prophylactic anticoagulation use was adjusted for in the final model. Model performance was assessed using bootstrap resampling to estimate area under the receiver operating characteristic (AUC) curve and calibration slope with 95% confidence interval (CI). Results: There were 62,468 medical admissions in the study period with 219 HA-VTE events. Chart review demonstrated the positive predictive value of our HA-VTE computable phenotype to be 84% and the negative predictive value 99%. Mean age was 65 years and 51% were male. Comorbid conditions were common in this hospitalized population, including active cancer (29%), congestive heart failure (25%), diabetes (27%), hypertension (59%), and prior myocardial infarction (13%). Seven risk factors met the criteria for inclusion in the final model: prior history of VTE (OR 2.7; 95% CI 1.8, 3.8), red cell distribution width ≥14.7% (OR 1.6; 95% CI 1.2, 2.2), creatinine ≥2.0 mg/dL or on dialysis (OR 2.0; 95% CI 1.4, 2.8), serum sodium & lt;136 MEq/L (OR 1.5; 95% CI 1.1, 2.1), active cancer (OR 1.4; 95% CI 1.1, 2.0), malnutrition based on prior reported weight loss (OR 2.1; 95% CI 1.3, 3.3), and low hemoglobin ( & lt;13.6 g/dL in men, & lt;12.1 g/dL in women; OR 1.5; 95% CI 1.0, 2.1). The unadjusted AUC of the RAM was 0.73 with an unadjusted calibration slope 1.09 (Figure 1). The optimism-adjusted AUC was 0.68 (95% CI 0.64, 0.71) and the optimism-adjusted calibration slope was 0.87 (95% CI: 0.72, 1.03). Discussion: We developed and internally validated a RAM for HA-VTE during medical hospitalization which incorporates simple, objective risk factors knowable within the first 24 hours of admission. Unlike most prior RAMs, this model also incorporates risk factors reflecting illness severity such as laboratory results. The RAM has good fit and calibration and will be moved forward to external validation. Future applications include incorporating the RAM into hospital admission workflows and assessing VTE prophylaxis rates and the incidence of HA-VTE and HA-bleeding. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
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  • 10
    In: Blood, American Society of Hematology, Vol. 126, No. 11 ( 2015-09-10), p. e19-e29
    Abstract: Twelve independent, novel, low-frequency (n = 2) and rare (n = 10) genetic variants were associated with fibrinogen, FVII, FVIII, or vWF. Nine were within previously associated genes, and 3 novel candidate genes (KCNT1, HID1, and KATNB1) were confined to cohorts of African ancestry.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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