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Background: Nearly half of all Americans have hypertension, and Black adults experience a disproportionate burden. Hypercoagulability may relate to hypertension risk, and higher levels of factor VIII increase thrombosis risk. Black adults have higher factor VIII and more hypertension than other groups. Whether higher factor VIII associates with incident hypertension is unknown., Methods: The Biomarkers as Mediators of Racial Disparities in Risk Factors (BioMedioR) study measured certain biomarkers in a sex-race stratified sample of 4,400 REGARDS participants who attended both visits. We included BioMedioR participants, excluding those with prevalent hypertension, missing factor VIII level, or covariates of interest. Modified Poisson regression estimated risk ratios (RR) for incident hypertension by higher log-transformed factor VIII level per SD (SD of log-transformed factor VIII, 0.33). Weighting was applied to take advantage of REGARDS sampling design., Results: Among the 1,814 participants included (55% female, 24% Black race), the median follow-up was 9.5 years and 35% (2,146/6,138) developed hypertension. Black participants had a higher median (IQR) factor VIII level (105.6%; 87.1%-126.9%) than White participants (95.6%; 79.8%-115.9%; P < 0.001). The age- and sex-adjusted Black-White hypertension RR was 1.45 (95% CI 1.28, 1.63). Higher factor VIII was not associated with more hypertension (final model RR 1.01; 95% CI 0.94, 1.07)., Conclusions: In a prospective study of Black and White adults without prevalent hypertension, factor VIII was not associated with greater hypertension risk., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

In the United States, causes of racial differences in stroke and its risk factors remain only partly understood, and there is a long-standing disparity in stroke incidence and mortality impacting Black Americans. Only half of the excess risk of stroke in the United States Black population is explained by traditional risk factors, suggesting potential effects of other factors including genetic and biological characteristics. Here, we nonsystematically reviewed candidate laboratory biomarkers for stroke and their relationships to racial disparities in stroke. Current evidence indicates that IL-6 (interleukin-6), a proinflammatory cytokine, mediates racial disparities in stroke through its association with traditional risk factors. Only one reviewed biomarker, Lp(a) (lipoprotein[a]), is a race-specific risk factor for stroke. Lp(a) is highly genetically determined and levels are substantially higher in Black than White people; clinical and pharmaceutical ramifications for stroke prevention remain uncertain. Other studied stroke risk biomarkers did not explain racial differences in stroke. More research on Lp(a) and other biological and genetic risk factors is needed to understand and mitigate racial disparities in stroke.

Background and Objectives: Hemostatic factors have been associated with kidney function decline, and evidence suggests stronger effects among African Americans. The presence of APOL1 renal risk variants, common in African Americans, might partly underlie this risk difference., Design, Setting, Participants, & Measurements: A total of 13,337 participants in the Atherosclerosis Risk in Communities study were followed from 1987-1989 until 2010. Participants were categorized into three groups by ancestry and APOL1 risk status: European Americans (n=10,206), African Americans with zero or one APOL1 risk allele (n=2,733), and African Americans with two APOL1 risk alleles (n=398). ESRD events were ascertained through linkage to the US Renal Data System. Cox regression was used to estimate the risk for ESRD associated with hemostatic factors (factor VIIc, factor VIIIc, fibrinogen, von Willebrand factor, protein C, and antithrombin III)., Results: There were 232 cases of ESRD over 21.5 years (European Americans, 119; African Americans with zero or one APOL1 risk allele, 94; African Americans with two APOL1 risk alleles, 19). In unadjusted and adjusted analysis of the overall population, higher levels of all hemostatic factors, except antithrombin III, were significantly associated with ESRD (all P<0.05). Factor VIIc had the strongest association (per one interquartile range; adjusted hazard ratio, 1.46; 95% confidence interval, 1.21 to 1.76). With the exception of fibrinogen, the risk associated with each hemostatic factor was stronger in African Americans with two APOL1 risk alleles compared with the other two groups. Statistically significant interactions were seen for factor VIIIc and protein C (interaction between those with two APOL1 risk allele and the other two groups: P<0.02 for factor VIIIc and <0.04 for protein C)., Conclusions: Higher levels of factor VIIc, VIIIc, fibrinogen, von Willebrand factor, and protein C were associated with ESRD risk, with a significantly stronger association of factor VIIIc and protein C in African Americans with two APOL1 risk alleles., (Copyright © 2015 by the American Society of Nephrology.)

Objective: To assess the relationships among ABO group, factor VIII (FVIII), and incident cognitive impairment in a large, prospective cohort study of black and white adults in the United States using a nested case-control design., Methods: Incident cognitive impairment was defined using cognitive domain tests over a mean follow-up of 3.4 years. ABO blood group was measured by genotyping in a nested case-control sample of 495 cases with cognitive impairment and 587 controls., Results: Those with blood group AB and those with higher FVIII had an increased risk of cognitive impairment, adjusting for age, race, region, and sex (respective odds ratios 1.82, 95% confidence interval [CI] 1.15-2.90; and 1.24, 95% CI 1.10-1.38 for 40 IU/dL higher FVIII). Mean FVIII was higher in those with blood type AB (142 IU/dL; 95% CI 119-165) compared with O (104 IU/dL; 95% CI 101-107), and FVIII mediated 18% of the association between AB group and incident cognitive impairment (95% CI for mediation -30% to 68%)., Conclusions: Blood group AB and higher FVIII were associated with increased incidence of cognitive impairment in this prospective study. The association of blood group AB with incident cognitive impairment was not significantly mediated by FVIII levels., (© 2014 American Academy of Neurology.)

Venous thromboembolism (VTE) affects more than 300,000 people in the United States each year. However, it has been estimated that current diagnostic testing fails to identify prothrombotic risk in 50% of VTE patients. This article examines the relationship between levels of the pro-coagulant proteins factor VIII (FVIII), von Willebrand factor (VWF), and fibrinogen and risk of VTE in order to assess the impact of these novel risk factors. Data were collected from patients enrolled in the matched case-control Genetic Attributes and Thrombosis Epidemiology study. Crude and adjusted conditional logistic regression models were used to assess the impact of FVIII, VWF, and fibrinogen on risk of VTE. Before adjustment for independent predictors of VTE risk, high levels of FVIII, VWF, and fibrinogen were significantly associated with increased risk of VTE in both Blacks and Whites. After adjustment for ABO type, factor VII levels, hypertension, renal disease, recent surgery, diabetes, annual household income, alcohol use, and the other proteins of interest (FVIII, VWF, and/or fibrinogen), high FVIII and VWF levels were associated with increased risk of VTE in Blacks (OR: 1.97 [1.01-3.84] and 3.39 [1.58-7.27], respectively). High FVIII only was significantly associated with risk of VTE in Whites (OR: 2.35 [1.16-4.75]). Future research into the inclusion of these protein levels in risk models for VTE could help identify persons at highest risk.

Genotyping efforts in hemophilia A (HA) populations in many countries have identified large numbers of unique mutations in the Factor VIII gene (F8). To assist HA researchers conducting genotyping analyses, we have developed a listing of F8 mutations including those listed in existing locus-specific databases as well as those identified in patient populations and reported in the literature. Each mutation was reviewed and uniquely identified using Human Genome Variation Society (HGVS) nomenclature standards for coding DNA and predicted protein changes as well as traditional nomenclature based on the mature, processed protein. Listings also include the associated hemophilia severity classified by International Society of Thrombosis and Haemostasis (ISTH) criteria, associations of the mutations with inhibitors, and reference information. The mutation list currently contains 2,537 unique mutations known to cause HA. HA severity caused by the mutation is available for 2,022 mutations (80%) and information on inhibitors is available for 1,816 mutations (72%). The CDC Hemophilia A Mutation Project (CHAMP) Mutation List is available at http://www.cdc.gov/hemophiliamutations for download and search and will be updated quarterly based on periodic literature reviews and submitted reports., (Published 2012. This Article is a US Government work and is in the public domain in the USA.)

Objective: This study examines the hypothesis that chronic inflammation is associated with a higher risk of cardiac death compared to the risk of nonfatal myocardial infarction., Methods and Results: Cardiac death and nonfatal MI events were identified in the ARIC cohort during follow-up from 1987 through 2001. Markers of inflammation and hemostasis were determined at baseline using standardized procedures. Cox proportional hazard regression and polytomous logistic regression were used to estimate associations. We observed a positive gradient in incidence of sudden cardiac death (SCD), nonsudden cardiac death (NSCD), and nonfatal MI in association with decreasing levels of albumin and increasing levels of white blood cell count and of markers of hemostasis (fibrinogen, von Willebrand factor, factor VIIIc). Associations for von Willebrand factor were stronger for fatal relative to nonfatal events (3rd versus 1st tertile hazard ratios: SCD 3.11 [95% CI 2.10, 4.59], NSCD 2.12 [95% CI 1.28, 3.49], nonfatal MI 1.42 [95% CI 1.19, 1.70]). For factor VIIIc those associations were strongest for sudden cardiac death: SCD 3.16 (95% CI 2.18, 4.58), NSCD 1.44 (95% CI 0.93, 2.24), nonfatal MI 1.54 (95% CI 1.29, 1.84). Gradients of association for fibrinogen and white blood cell count, examined over tertiles of distribution and per one SD increase, were similar for the 3 end points. All associations were independent of smoking status., Conclusions: von Willebrand factor and factor VIIIc are associated with an increased risk of cardiac death as compared to the risk of nonfatal MI.

Background: Inflammation and hemostasis may increase the risk of kidney function decline; however, data from prospective studies are sparse., Study Design: The Atherosclerosis Risk in Communities (ARIC) Study, a prospective observational cohort., Setting & Participants: We used data from 14,854 middle-aged adults from 4 different US communities., Predictor: Markers of inflammation and hemostasis were examined., Outcomes & Measurements: The risk of kidney function decrease associated with these markers was studied. Glomerular filtration rate (GFR) was calculated from serum creatinine levels using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation. Chronic kidney disease (CKD) was defined as: (1) a decrease in estimated GFR to less than 60 mL/min/1.73 m2 from greater than 60 mL/min/1.73 m2 at baseline, or (2) a hospitalization discharge or death coded for CKD. Serum creatinine was measured at baseline and the 3- and 9-year follow-up visits. Hazard ratios (HRs) of CKD associated with increased levels of inflammatory and hemostatic variables were estimated by using multivariate Cox proportional hazards regression., Results: 1,787 cases of CKD developed between 1987 and 2004. After adjusting for demographics, smoking, blood pressure, diabetes, lipid levels, prior myocardial infarction, antihypertensive use, alcohol use, year of marker measurement, and baseline renal function using estimated GFR, the risk of incident CKD increased with increasing quartiles of white blood cell count (HR quartile 4 versus quartile 1, 1.30; 95% confidence interval [CI], 1.12 to 1.50; P trend = 0.001), fibrinogen (HR, 1.25; 95% CI, 1.09 to 1.44; P < 0.001), von Willebrand factor (HR, 1.46; 95% CI, 1.26 to 1.68; P < 0.001), and factor VIIIc (HR, 1.39; 95% CI, 1.20 to 1.60; P < 0.001). A strong inverse association was found between serum albumin level and risk of CKD (HR, 0.63; 95% CI, 0.55 to 0.72; P < 0.001). No independent association was found with factor VIIc level., Limitations: Although we lacked a direct measure of kidney function, associations were robust to case definitions., Conclusions: Markers of inflammation and hemostasis are associated with greater risk of kidney function decrease. Findings suggest that inflammation and hemostasis are antecedent pathways for CKD.

Background and Purpose: The purpose of this study was to identify novel risk factors for intracerebral hemorrhagic stroke (ICH)., Methods: Risk factors were assessed at baseline in a pooled cohort of the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) involving 21,680 adults aged 45 or over. Over 263,489 person-years of follow-up, we identified 135 incident ICH events., Results: In multivariable models, for each SD higher baseline level of fibrinogen, the relative rate of incident ICH increased 35% (95% CI, 17% to 55%). Fibrinogen was more strongly related to ICH in ARIC than in CHS. In multivariable models, those with von Willebrand factor levels above the median were 1.72 (95% CI, 0.97 to 3.03) times more likely to have an incident ICH as those below the median. Factor VIII was significantly positively related to ICH in ARIC (relative rate per standard deviation of 1.31; 95% CI, 1.07 to 1.62), but not in CHS. There was no relation in multivariable models between lipoprotein (a), Factor VII, white blood cell count, or C-reactive protein and ICH., Conclusions: Greater plasma fibrinogen and, to some degree, von Willebrand factor were associated with increased rates of ICH in these prospective studies, whereas Factor VIII was related to ICH in younger ARIC study participants only.

Unlabelled: The coagulation cascade plays a critical role in the development of cardiovascular disease (CVD). Elevated plasma prothrombin fragment 1 + 2 (F1 + 2) and factor VIII antigen (FVIII:Ag) levels have been associated with a hypercoagulable state, enhancing the risk for vascular thrombotic events. Aerobic training is known to reduce CVD risk, and an improved coagulation profile may contribute to this reduction., Purpose: To analyze the effect of 6 months of standardized aerobic exercise training on resting F1 + 2 and FVIII:Ag levels in men and postmenopausal women aged 50-75 while accounting for several possibly confounding factors., Materials and Methods: Sedentary men (N=16) and women (N=31) underwent supervised aerobic training 3 d x wk(-1) for 6 months while maintaining the American Heart Association step 1 diet. Baseline and final testing included measurement of F1 + 2, FVIII:Ag, plasma lipoprotein-lipid levels, body composition, and VO2max., Results: When adjusted for baseline values and changes in diastolic blood pressure with training, F1 + 2 was found to decrease significantly with exercise training from 1.493 +/- 0.058 to 1.422 +/- 0.059 nM (P=0.014). FVIII:Ag levels were found to increase significantly with training when adjusted for baseline values, from 152.5 +/- 6.7% of standard at baseline to 156.0 +/- 6.1% of standard at final testing (P=0.005). Training-induced changes in coagulation markers were independent of changes in blood lipids, aerobic capacity, and body composition., Conclusions: : These results indicate that endurance training has a significant impact on the coagulation cascade, reducing coagulation activity in the common pathway and thrombin formation at rest while increasing the activation potential of the intrinsic pathway.

The authors summarize their experience with detection of the carrier state in classic hemophilia. Their test depends upon the observation that the plasma of patients with classic hemophilia, deficient in functional antihemophilic factor, contains normal amounts of precipitating antigenic material. By inference, the plasma of carriers should be relatively deficient in functional antihemophilic factor, but should contain normal amounts of antihemophilic factor-like antigenic material. Data obtained from 81 obligate carriers suggest that at least 90% of these women can be identified as carriers in the laboratory by demonstrating that there is an excess of antihemophilic factor-like antigenic material in plasma relative to functional antihemophilic factor. Further, at least two-thirds of mothers of individuals with isolated cases of hemophilia are carriers, suggesting that mutation is a relatively rare cause of hemophilia. Only about one-third of daughters of carriers who had no sons can be identified as carriers, a result due to the systematic exclusion of those daughters who had already had a hemophilic son.