International council for standardisation in haematology recommendations on fibrinogen assays, thrombin clotting time and related tests in the investigation of bleeding disorders.

This guidance was prepared on behalf of the International Council for Standardisation in Haematology (ICSH) by an international working group of clinicians and scientists. The document focuses on tests and assays used for the assessment of fibrinogen function, particularly in the scenario of bleeding disorders. Thrombin clotting time (TT) is used as a screening test in some laboratories and also has some utility when direct anticoagulants are in use. The Clauss fibrinogen assay remains the method of choice for the assessment of fibrinogen function, but there are some situations where the results may be misleading. Prothrombin time derived fibrinogen assays are frequently used, but should be interpreted with caution; the results are not interchangeable between different methods and fibrinogen can be overestimated in certain clinical scenarios. Viscoelastic point of care methods may be helpful in emergency situations, while Reptilase time (and similar tests) are useful combined with TT in distinguishing heparin contamination of samples (i.e., if an incorrect blood draw is suspected) and the presence of direct thrombin inhibitors. Fibrinogen antigen assays should be used in the investigation of functional fibrinogen abnormalities; fibrinogen antigen and genetic testing are recommended in the confirmation of congenital fibrinogen disorders. The following recommendations for fibrinogen function assessment are based on published literature and expert opinion and should supplement local regulations and standards.

Metabolomic Insights on Potassium Excretion, Blood Pressure, and Glucose Homeostasis: The African-PREDICT Study.

BACKGROUND: Low-potassium intake is associated with a higher risk of type 2 diabetes and hypertension. Both conditions occur more frequently in Black populations, who also consume less potassium-rich foods. OBJECTIVES: Using metabolomics to identify dysregulated metabolic pathways associated with low-potassium excretion may procure more accurate entry points for nutritional prevention and intervention for type 2 diabetes and hypertension. METHODS: A total of 440 White and 350 Black adults from the African-PREDICT study (aged 20-30 y) were included. Twenty-four-hour blood pressure (BP) was measured. Potassium, sodium, and fasting glucose concentrations were analyzed in 24-h urine and plasma samples. Liquid chromatography-tandem mass spectrometry-based metabolomics included the analyses of amino acids and acylcarnitines in spot urine samples. RESULTS: Black participants had lower urinary potassium concentrations than Whites (36.6 compared with 51.1 mmol/d; P < 0.001). In White but not Black adults, urinary potassium correlated positively with 2-aminoadipic acid (2-AAA) (r = 0.176), C3-[propionyl]carnitine (r = 0.137), C4-[butyryl]carnitine (r = 0.169) and C5-[isovaleryl]carnitine (r = 0.167) in unadjusted and 2-AAA (r = 0.158) and C4-carnitine (r = 0.160) in adjusted analyses (all P < 0.05 and q < 0.05). Elevated C0-, C3-, and C5-carnitine in turn were positively associated with systolic BP (Black and White groups), diastolic BP (Black group), and glucose (White group) (all P < 0.05). CONCLUSIONS: Racial differences are an important consideration when investigating nutrient-metabolite relationships and the role thereof in cardiovascular disease. Only in White adults did urinary potassium associate with 2-AAA and short-chain acylcarnitines. These metabolites were positively related to BP and fasting plasma glucose concentrations. In White adults, the metabolomic profiles related to potassium excretion may contribute to BP regulation and glucose homeostasis. This trial was registered at clinicaltrials.gov as NCT03292094.

Strategies of Modelling Incident Outcomes Using Cox Regression to Estimate the Population Attributable Risk.

When the Cox model is applied, some recommendations about the choice of the time metric and the model's structure are often disregarded along with the proportionality of risk assumption. Moreover, most of the published studies fail to frame the real impact of a risk factor in the target population. Our aim was to show how modelling strategies affected Cox model assumptions. Furthermore, we showed how the Cox modelling strategies affected the population attributable risk (PAR). Our work is based on data collected in the North-West Province, one of the two PURE study centres in South Africa. The Cox model was used to estimate the hazard ratio (HR) of mortality for all causes in relation to smoking, alcohol use, physical inactivity, and hypertension. Firstly, we used a Cox model with time to event as the underlying time variable. Secondly, we used a Cox model with age to event as the underlying time variable. Finally, the second model was implemented with age classes and sex as strata variables. Mutually adjusted models were also investigated. A statistical test to the multiplicative interaction term the exposures and the log transformed time to event metric was used to assess the proportionality of risk assumption. The model's fitting was investigated by means of the Akaike Information Criteria (AIC). Models with age as the underlying time variable with age and sex as strata variables had enhanced validity of the risk proportionality assumption and better fitting. The PAR for a specific modifiable risk factor can be defined more accurately in mutually adjusted models allowing better public health decisions. This is not necessarily true when correlated modifiable risk factors are considered.

Association of the metabolic syndrome with PAI 1act and clot lysis time over a 10-year follow up in an African population.

BACKGROUND AND AIMS: The association between the metabolic syndrome (MetS) and plasminogen activator inhibitor-1 (PAI-1) has been well established in cross-sectional studies. It is less clear whether this translates into decreased clot lysis rates and very little information is available on non-European populations. Little is known regarding prospective associations and whether clot lysis progressively worsens in MetS individuals over time. We determined the prospective association of MetS with PAI-1 activity (PAI-1act) and clot lysis time (CLT) over a 10-year period. METHODS AND RESULTS: As many as 2010 African men and women aged ≥30 years were stratified according to MetS status and number of MetS criteria (0-5). We also determined the contribution of the PAI-1 4G/5G polymorphism to these associations and identified which MetS criteria had the strongest associations with PAI-1act and CLT. Both PAI-1act and CLT remained consistently elevated in individuals with MetS throughout the 10-year period. PAI-1act and CLT did not increase more over time in MetS individuals than in controls. The 4G/5G genotype did not influence the association of PAI-1act or clot lysis with MetS. Increased waist circumference, increased triglycerides and decreased HDL-C were the main predictors of PAI-1act and CLT. CONCLUSIONS: Black South Africans with MetS had increased PAI-1act and longer CLTs than individuals without MetS. The inhibited clot lysis in MetS did, however, not deteriorate over time compared to controls. Of the MetS criteria, obesity and altered lipids were the main predictors of PAI-1act and CLT and are thus potential targets for prevention strategies to decrease thrombotic risk.

Urinary metabolomics, dietary salt intake and blood pressure: the African-PREDICT study.

In Black populations excessive salt intake may exacerbate the genetic predisposition to hypertension and promote the early onset of cardiovascular disease. Ethnic differences in the interaction between sodium intake and the metabolome may play a part in hypertension and cardiovascular disease development. We determined (1) urinary amino acid and acylcarnitine profiles of young Black and White adults according to low, moderate, and high dietary salt intake, and (2) investigated the triad of salt intake, systolic blood pressure (SBP), and the associated metabolomics profile. This study included 447 White and 380 Black adults aged 20-30 years from the African-PREDICT study. Estimated salt intake was determined from 24-hour urinary sodium levels. Urinary amino acids and acylcarnitines were measured using liquid chromatography-tandem mass spectrometry. Black adults exhibited no significant differences in SBP, amino acids, or acylcarnitines across low (<5g/day), moderate (5-10g/day), and high (>10g/day) salt intake. White adults with a high salt intake had elevated SBP compared to those with low or moderate intakes (p < 0.001). Furthermore, gamma-aminobutyric acid (GABA) (q = 0.020), citrulline (q = 0.020), glutamic acid (q = 0.046), serine (q = 0.054) and proline (q = 0.054) were lowest in those with higher salt intake. Only in White and not Black adults did we observe inverse associations of clinic SBP with GABA (Adj. R2 = 0.34; Std. ß = -0.133; p = 0.003), serine (Adj. R2 = 0.33; Std. ß = -0.109; p = 0.014) and proline (Adj. R2 = 0.33; Std. ß = -0.109; p = 0.014). High salt intake in White, but not in black adults, were related to metabolomic changes and may contribute to pathophysiological mechanisms associated with increased BP.

Associations Between 25-Hydroxyvitamin D and Total and γ' Fibrinogen and Plasma Clot Properties and Gene Interactions in a Group of Healthy Black South African Women.

The role of 25-hydroxyvitamin D [25(OH)D] in reducing the risk of cardiovascular disease (CVD) has been recognized, but the mechanisms involved are unclear. Researchers have discovered a link between vitamin D and fibrinogen. Until now, data on the relationship between vitamin D and the γ' splice variant of fibrinogen and fibrin clot characteristics remain unexplored. In this study, 25(OH)D, total and γ' fibrinogen, as well as turbidimetrically determined plasma clot properties, were quantified, and fibrinogen and FXIII SNPs were genotyped in 660 Black, apparently healthy South African women. Alarmingly, 16 and 45% of the women presented with deficient and insufficient 25(OH)D, respectively. Total fibrinogen and maximum absorbance (as a measure of clot density) correlated inversely, whereas γ' fibrinogen correlated positively with 25(OH)D. γ' fibrinogen increased whereas maximum absorbance decreased over the deficient, insufficient, and sufficient 25(OH)D categories before and after adjustment for confounders. 25(OH)D modulated the association of the SNPs regarding fibrinogen concentration and clot structure/properties, but did not stand after correction for false discovery rate. Because only weak relationships were detected, the clinical significance of the findings are questionable and remain to be determined. However, we recommend vitamin D fortification and supplementation to reduce the high prevalence of this micronutrient deficiency and possibly to improve fibrinogen and plasma clot structure if the relationships are indeed clinically significant. There is a need for large cohort studies to demonstrate the relationship between vitamin D and cardiovascular and inflammatory risk factors as well as to uncover the molecular mechanisms responsible.

The Metabolic Profiles of Metabolically Healthy Obese and Metabolically Unhealthy Obese South African Adults over 10 Years.

Obesity is associated with an increased cardiometabolic risk, but some individuals maintain metabolically healthy obesity (MHO). The aims were to follow a cohort of black South African adults over a period of 10 years to determine the proportion of the group that maintained MHO over 10 years, and to compare the metabolic profiles of the metabolically healthy and metabolically unhealthy groups after the follow-up period. The participants were South African men (n = 275) and women (n = 642) from the North West province. The prevalence of obesity and the metabolic syndrome increased significantly. About half of the metabolically healthy obese (MHO) adults maintained MHO over 10 years, while 46% of the women and 43% of men became metabolically unhealthy overweight/obese (MUO) at the end of the study. The metabolic profiles of these MHO adults were similar to those of the metabolically healthy normal weight (MHNW) group in terms of most metabolic syndrome criteria, but they were more insulin resistant; their CRP, fibrinogen, and PAI-1act were higher and HDL-cholesterol was lower than the MHNW group. Although the metabolic profiles of the MUO group were less favourable than those of their counterparts, MHO is a transient state and is associated with increased cardiometabolic risk.

Lifestyle Influences Changes in Fibrin Clot Properties Over a 10-Year Period on a Population Level.

Case-control and observational studies have provided a plausible mechanistic link between clot structure and thrombosis. We aimed to identify lifestyle, demographic, biochemical, and genetic factors that influence changes in total fibrinogen concentration and clot properties over a 10-year period in 2,010 black South Africans. Clot properties were assessed with turbidimetry and included lag time, slope, maximum absorbance, and clot lysis time. Linear mixed models with restricted maximum likelihood were used to determine whether (1) outcome variables changed over the 10-year period; (2) demographic and lifestyle variables, biochemical variables, and fibrinogen single-nucleotide polymorphisms influenced the change in outcome variables over the 10-year period; and (3) there was an interaction between the exposures and time in predicting the outcomes. A procoagulant risk score was furthermore created, and multinomial logistic regression was used to determine the exposures that were associated with the different risk score categories. In this population setting, female gender, obesity, poor glycemic control, increased low-density lipoprotein cholesterol, and decreased high-density lipoprotein cholesterol contributed to the enhanced progression to prothrombotic clot properties with increasing age. Alcohol consumption on the other hand, offered a protective effect. The above evidence suggest that the appropriate lifestyle changes can improve fibrin clot properties on a population level, decreasing cardiovascular disease risk and thus alleviate the strain on the medical health care system.

The association between an energy-adjusted dietary inflammatory index and inflammation in rural and urban Black South Africans.

OBJECTIVE: To quantify the inflammatory potential of the diet of rural and urban Black South Africans using an adapted energy-adjusted dietary inflammatory index (AE-DII) and to investigate its relationship with inflammatory and cardio-metabolic disease risk markers. Dietary inflammatory potential has not been investigated in African populations. DESIGN: Cross-sectional investigation. SETTING: Rural and urban sites in the North West province of South Africa. PARTICIPANTS: 1885 randomly selected, apparently healthy Black South Africans older than 30 years. RESULTS: AE-DII scores ranged from -3·71 to +5·08 with a mean of +0·37. AE-DII scores were significantly higher in men (0·47 ± 1·19) than in women (0·32 ± 1·29), and in rural (0·55 ± 1·29) than urban participants (0·21 ± 1·19). Apart from its dietary constituents, AE-DII scores are primarily associated with age, rural-urban status and education. Contrary to the literature, alcohol consumption was positively associated with AE-DII scores. Of the four tested inflammatory and thirteen cardio-metabolic biomarkers, the AE-DII was only significantly negatively associated with albumin and HDL cholesterol, and positively with waist circumference and fasting glucose, upon full adjustment. CONCLUSION: Rural men consumed the most pro-inflammatory diet, and urban women the least pro-inflammatory diet. The diet of the participants was not overtly pro- or anti-inflammatory and was not associated with measured inflammatory markers. The inflammatory potential of alcohol at different levels of intake requires further research. Understanding dietary inflammatory potential in the context of food insecurity, unhealthy lifestyle practices and lack of dietary variety remains limited.

Automated Fiber Diameter and Porosity Measurements of Plasma Clots in Scanning Electron Microscopy Images.

Scanning Electron Microscopy (SEM) is a powerful, high-resolution imaging technique widely used to analyze the structure of fibrin networks. Currently, structural features, such as fiber diameter, length, density, and porosity, are mostly analyzed manually, which is tedious and may introduce user bias. A reliable, automated structural image analysis method would mitigate these drawbacks. We evaluated the performance of DiameterJ (an ImageJ plug-in) for analyzing fibrin fiber diameter by comparing automated DiameterJ outputs with manual diameter measurements in four SEM data sets with different imaging parameters. We also investigated correlations between biophysical fibrin clot properties and diameter, and between clot permeability and DiameterJ-determined clot porosity. Several of the 24 DiameterJ algorithms returned diameter values that highly correlated with and closely matched the values of the manual measurements. However, optimal performance was dependent on the pixel size of the images-best results were obtained for images with a pixel size of 8-10 nm (13-16 pixels/fiber). Larger or smaller pixels resulted in an over- or underestimation of diameter values, respectively. The correlation between clot permeability and DiameterJ-determined clot porosity was modest, likely because it is difficult to establish the correct image depth of field in this analysis. In conclusion, several DiameterJ algorithms (M6, M5, T3) perform well for diameter determination from SEM images, given the appropriate imaging conditions (13-16 pixels/fiber). Determining fibrin clot porosity via DiameterJ is challenging.

The effect of plant-based diets on thrombotic risk factors.

Plant­based diets are considered to improve cardiometabolic health and to protect against cardiovascular disease. Although they center around plant­based foods, they do not necessarily exclude all animal products and comprise of a range of intakes that vary according to the type and the proportion of animal products included. Numerous metabolic pathways have been identified through which plant­based diets can exert beneficial effects including improved body composition, lipid profile, and glucose metabolism and decreased inflammation and blood pressure. Their effects on thrombosis as a cardiovascular disease pathway are, however, less clear. Ample evidence for the effects of individual dietary components of plant­based diets on thrombotic risk factors exists, but the effect of whole diets and / or dietary patterns remains less­well explored with the existing literature reporting inconsistent and inconclusive findings. Here we aim to review the literature describing the effect of different plant­based diets (vegan, lacto­vegetarian, lacto­ovo­vegetarian, pescatarian, and flexitarian) and dietary patterns (Mediterranean, Nordic, Portfolio, and DASH) on specific thrombotic risk factors (fibrinogen, platelets, factor VII, fibrinolysis) in order to better clarify these relationships and to try to explain the apparent discrepant findings. We demonstrate that a one­size­fits-all conclusion cannot be drawn and that the potential antithrombotic effect of different plant­based diets depends on the nutrient composition, the content of active antithrombotic dietary components, the relative absence of prothrombotic dietary factors as well as the degree of total caloric restriction.

Certain Associations Between Iron Biomarkers and Total and γ' Fibrinogen and Plasma Clot Properties Are Mediated by Fibrinogen Genotypes.

Introduction: Evidence for the relationship between body iron and cardiovascular disease (CVD) is inconsistent and mechanisms involved remain poorly understood. Therefore, we first investigated whether there are linear or non-linear relationships between iron status and total and γ' fibrinogen as well as plasma fibrin clot properties and, second, determined whether there are interactions with iron biomarkers and fibrinogen and FXIII single nucleotide polymorphisms (SNPs) in relation to fibrinogen concentration and functionality. Methods: In this cross-sectional analysis of 2,010 apparently healthy Black South Africans we quantified total and γ' fibrinogen, serum iron, ferritin and transferrin using standardized methods and calculated transferrin saturation (TS). Clot architecture and lysis were explored with a global analytical turbidity assay. The SNPs were determined through an Illumina BeadXpress® platform. Results: Total, but not %γ', fibrinogen negatively correlated with serum iron concentrations, although both decreased over iron tertiles. %γ' fibrinogen correlated negatively with transferrin and decreased over the transferrin tertiles. A weak negative association between total fibrinogen and TS was detected with fibrinogen decreasing over the TS tertiles and categories based on TS. Lag time correlated positively with transferrin and increased over transferrin tertiles, when adjusting for fibrinogen. Before adjusting for fibrinogen, lag time was shorter in those with adequate iron status based on TS than other iron subcategories. Clot lysis time (CLT) negatively correlated with ferritin and was longer in the first than in the third ferritin tertile. Among iron status categories based on ferritin, only CLT differed and was longer in those with adequate iron than with iron-overload. CLT negatively correlated with TS, albeit weakly, shortened over the TS tertiles and was shorter in those with adequate iron based on TS categories. Interactions were observed between FGB SNPs and some of the markers of iron status investigated, in relation to the clot properties with the most prominent associations detected in homozygous carriers of the variant alleles for whom increased iron status was more beneficial than for those harboring the wild-type alleles. Iron modulated the influence of the SNPs so that for the majority iron was beneficial in respect of clot properties, but even more so for a minority group harboring specific variant alleles. Conclusion: This is the first large-scale epidemiological study to relate fibrinogen concentration and functionality to markers of iron status and to take genetic factors into consideration. We have detected a relationship between iron biomarkers and fibrinogen as well as clot characteristics that are influenced by the genetic make-up of an individual.

Lifestyle factors associated with the transition from healthy to unhealthy adiposity among black South African adults over 10 years.

BACKGROUND AND AIMS: Obesity is associated with an increasing prevalence of cardiovascular diseases in Africa, but some obese individuals maintain cardiometabolic health. The aims were to track metabolically healthy overweight or obesity (MHO) over 10 years in African adults and to identify factors associated with a transition to metabolically unhealthy overweight or obesity (MUO). METHODS AND RESULTS: The participants were the South African cohort of the international Prospective Urban and Rural Epidemiological study. From the baseline data of 1937 adults, 649 women and 274 men were followed for 10 years. The combined overweight and obesity prevalence of men (19.2%-23.8%, p = .02) and women (58%-64.7%, p < .001), and the prevalence of the metabolic syndrome in all participants (25.4%-40.2%, p < .001) increased significantly. More than a quarter (26.2%) of the women and 10.9% of men were MHO at baseline, 11.4% of women and 5.1% of men maintained MHO over 10 years, while similar proportions (12.3% of women, 4.7% of men) transitioned to MUO. Female sex, age, and total fat intake were positively associated with a transition to MUO over 10 years, while physical activity was negatively associated with the transition. HIV positive participants were more likely to be MHO at follow-up than their HIV negative counterparts. CONCLUSIONS: One in two black adults with BMI ≥25 kg/m2 maintained MHO over 10 years, while a similar proportion transitioned into MUO. Interventions should focus on lower fat intakes and higher physical activity to prevent the transition to MUO.

Retinal vasodilatory responses are inversely associated with plasminogen activator inhibitor-1: The African-PREDICT study.

AIMS: Plasminogen activator inhibitor-1 (PAI-1), traditionally associated with fibrinolysis, is increasingly implicated in impaired vascular function. However, studies on its association with microvascular function are limited to the cutaneous and coronary microvascular beds in older and diseased individuals. To better understand its potential involvement in the early stages of disease development, we investigated the associations of retinal vasodilatory responses to flicker light with PAI-1 activity (PAI-1act) in young and healthy individuals. METHODS: We included healthy Black and White women and men (n = 518; aged 20-30 years), and measured plasma PAI-1act and retinal vasodilatory responses to flicker light provocation. We also collected demographic and lifestyle data, measured blood pressure, anthropometry, blood lipids, inflammatory and other biomarkers. RESULTS: In multivariate regression analyses, maximal retinal venular dilation associated independently and inversely with PAI-1act (adj. R2 = 0.11; ß = -0.15; p = 0.001) in the total group. In exploratory subgroup analyses, this association remained in White women (adj. R2 = 0.07; ß = -0.23; p = 0.005), and was more robust with younger age and lower blood pressure and in non-smokers, but also with greater central adiposity, higher low-density lipoprotein cholesterol and inflammation (all p < 0.05). CONCLUSIONS: Our data suggest that in young individuals, PAI-1 may already be associated with subclinical microvascular dysfunction.

The Relationship of Circulating Homocysteine with Fibrinogen, Blood Pressure, and Other Cardiovascular Measures in African Adolescents.

OBJECTIVES: To evaluate the associations between homocysteine (Hcy) and cardiovascular health in South African adolescents. STUDY DESIGN: Circulating Hcy concentrations of 172 South African adolescents (105 girls, ages 13 to <18 years) were measured. Anthropometric and cardiovascular factors were also included and cross-sectionally analyzed through general linear models. RESULTS: Hcy correlated positively with body weight (P = .03; after adjusting for multiple testing, it was not regarded as significant) and muscle mass (P = .01), but negatively with fibrinogen concentrations (P = .001). Across Hcy tertiles, blood pressure produced approximating U-shaped curves, with differences between the middle and upper tertiles (all P < .02). Forty percent of the adolescents had elevated blood pressure, of whom 37% fell in the lowest and 38% in the highest Hcy tertiles. Hcy differed between the sexes (with boys having higher Hcy), but not between subgroups based on puberty, weight, stunting, smoking, or alcohol consumption. CONCLUSIONS: Both high and low Hcy could be early contributing risk factors to cardiovascular health. The associations between Hcy and blood pressure suggest that dietary and lifestyle manipulation, to achieve the optimal range of Hcy, may be beneficial in preventing Hcy-related hypertension in adulthood. The inverse relationship between Hcy and fibrinogen remains to be clarified.

Comparison of DNA methylation clocks in Black South African men.

Aims: DNA methylation clocks are widely used to estimate biological age, although limited data are available on non-European ethnicities. This manuscript characterizes the behavior of five DNA methylation clocks in 120 older Black South African men. Methods: The age estimation accuracy of the Horvath, Hannum and skin and blood clocks and the relative age-related mortality risk and predicted time to death portrayed by the PhenoAge and GrimAge biomarkers are investigated, respectively. Results: The results confirm the tendency of DNA methylation clocks to underestimate the biological age of older individuals. GrimAge more accurately characterizes biological decline in this African cohort compared with PhenoAge owing to the unique inclusion of smoking-related damage in the GrimAge estimate. Conclusions: Each clock provides a different fraction of information regarding the aging body. It is essential to continue studying under-represented population groups to ensure methylation-derived indicators are robust and useful in all populations.

Epigenetic age acceleration in the emerging burden of cardiometabolic diseases among migrant and non-migrant African populations: the population based cross-sectional RODAM study.

BACKGROUND: African populations are experiencing health transitions due to rapid urbanization and international migration. However, the role of biological aging in this emerging burden of cardiometabolic diseases (CMD) among migrant and non-migrant Africans is unknown. We aimed to examine differences in epigenetic age acceleration (EAA) as measured by four clocks (Horvath, Hannum, PhenoAge and GrimAge) and their associations with cardiometabolic factors among migrant Ghanaians in Europe and non-migrant Ghanaians. METHODS: Genome-wide DNA methylation (DNAm) data of 712 Ghanaians from cross-sectional RODAM study were used to quantify EAA. We assessed correlation of DNAmAge measures with chronological age, and then performed linear regressions to determine associations of body mass index (BMI), fasting blood glucose (FBG), blood pressure, alcohol consumption, smoking, physical activity, and one-carbon metabolism nutrients with EAA among migrant and non-migrants. We replicated our findings among 172 rural-urban sibling pairs from India migration study and among 120 native South Africans from PURE-SA-NW study. FINDINGS: We found that Ghanaian migrants have lower EAA than non-migrants. Within migrants, higher FBG was positively associated with EAA measures. Within non-migrants, higher BMI, and Vitamin B9 (folate) intake were negatively associated with EAA measures. Our findings on FBG, BMI and folate were replicated in the independent cohorts. INTERPRETATION: Our study shows that migration is negatively associated with EAA among Ghanaians. Moreover, cardiometabolic factors are differentially associated with EAA within migrant and non-migrant subgroups. Our results call for context-based interventions for CMD among transitioning populations that account for effects of biological aging. FUNDING: European Commission.

Fibrinogen and Fibrin.

Fibrinogen is a large glycoprotein, synthesized primarily in the liver. With a normal plasma concentration of 1.5-3.5 g/L, fibrinogen is the most abundant blood coagulation factor. The final stage of blood clot formation is the conversion of soluble fibrinogen to insoluble fibrin, the polymeric scaffold for blood clots that stop bleeding (a protective reaction called hemostasis) or obstruct blood vessels (pathological thrombosis). Fibrin is a viscoelastic polymer and the structural and mechanical properties of the fibrin scaffold determine its effectiveness in hemostasis and the development and outcome of thrombotic complications. Fibrin polymerization comprises a number of consecutive reactions, each affecting the ultimate 3D porous network structure. The physical properties of fibrin clots are determined by structural features at the individual fibrin molecule, fibrin fiber, network, and whole clot levels and are among the most important functional characteristics, enabling the blood clot to withstand arterial blood flow, platelet-driven clot contraction, and other dynamic forces. This chapter describes the molecular structure of fibrinogen, the conversion of fibrinogen to fibrin, the mechanical properties of fibrin as well as its structural origins and lastly provides evidence for the role of altered fibrin clot properties in both thrombosis and bleeding.

Biomarker association with cardiovascular disease and mortality - The role of fibrinogen. A report from the NHANES study.

BACKGROUND: While fibrinogen is a known cardiovascular disease (CVD) risk marker, its quantitative input to mortality risk is a topic of debate. METHODS: We investigated the contribution of fibrinogen, among that of other biomarkers, to prevalent CVD and incident CVD mortality in 4487 participants of the US National Health and Nutrition Examination Survey (NHANES). Participants were observed for a median period of 14 years, resulting in more than 58,000 person-years. RESULTS: At baseline 551 participants had CVD and during follow up, 1339 all-cause deaths occurred, 321 (24%) of which were due to CVD. Hierarchical cluster analysis and principal component analysis (PCA) were performed to derive clusters of association between biomarkers. Next, structural equation modelling was performed to investigate the association of these clusters with baseline CVD and all-cause and CVD mortality during follow-up. Mediation analysis was used to determine which biomarkers played a mediatory role between prevalent CVD and future mortality. Fibrinogen clustered with C-reactive protein only and was associated with CVD at baseline (p < 0.0001) and with all-cause (p < 0.001) and CVD (p < 0.001) mortality at follow-up. Only fibrinogen (4.7%), followed by gamma-glutamyl transferase (GGT) (3.5%) and uric acid (2.3%) were identified as possible mediators between CVD status and all-cause mortality, with fibrinogen (3.2%) and GGT (3.1%) the only mediators between CVD status and CVD mortality. CONCLUSION: This data shows that fibrinogen is not only cross-sectionally associated with CVD, but also contributes to all-cause and CVD mortality at follow-up. It furthermore appears to mediate the association between prevalent CVD and both all-cause and CVD mortality.