Zelda de Lange

Plasma Clot Lysis Time and Its Association with Cardiovascular Risk Factors in Black Africans

Studies in populations of European descent show longer plasma clot lysis times (CLT) in patients with cardiovascular disease (CVD) than in controls. No data are available on the association between CVD risk factors and fibrinolytic potential in black Africans, a group undergoing rapid urbanisation with increased CVD prevalence. We investigated associations between known CVD risk factors and CLT in black Africans and whether CLTs differ between rural and urban participants in light of differences in CVD risk. Data from 1000 rural and 1000 urban apparently healthy black South Africans (35–60 years) were cross-sectionally analysed. Increased PAI-1act, BMI, HbA1c, triglycerides, the metabolic syndrome, fibrinogen concentration, CRP, female sex and positive HIV status were associated with increased CLTs, while habitual alcohol consumption associated with decreased CLT. No differences in CLT were found between age and smoking categories, contraceptive use or hyper- and normotensive participants. Urban women had longer CLT than rural women while no differences were observed for men. CLT was associated with many known CVD risk factors in black Africans. Differences were however observed, compared to data from populations of European descent available in the literature, suggesting possible ethnic differences. The effect of urbanisation on CLT is influenced by traditional CVD risk factors and their prevalence in urban and rural communities.

The contribution of different adipose tissue depots to plasma plasminogen activator inhibitor-1 (PAI-1) levels

Increased plasma plasminogen activator inhibitor-1 (PAI-1) level is considered a mechanistic pathway through which obesity contributes to increased cardiovascular disease risk. Abdominal adipose tissue specifically, is a major PAI-1 source with visceral adipose tissue (VAT), an ectopic fat depot, generally considered to produce more PAI-1 than subcutaneous adipose tissue. However, this does not necessarily lead to increased plasma PAI-1 levels. This review provides an overview of studies investigating the association between body fat distribution and plasma PAI-1 levels. It discusses factors that influence this relationship and also considers the contribution of other tissue to plasma PAI-1 levels, placing the relative contribution of adipose tissue into perspective. In conclusion, the relationship between VAT and plasma PAI-1 levels is not fixed but can be modulated by a number of factors such as the size of the subcutaneous adipose tissue depot, ethnicity, possibly genetics and other obesity-related metabolic abnormalities.

The clinical relevance of altered fibrinogen packaging in the presence of 17β-estradiol and progesterone.

BACKGROUND The effect of endogenous hormone concentrations, specifically 17β-estradiol and progesterone, on fibrin network formation has not been established. OBJECTIVES It is essential to understand natural hormone mechanisms since these hormones are still present in circulation while hormonal contraceptives, which are associated with increased risk of venous thromboembolism, are used. METHODS Due to the fact that these hormones are known to increase hypercoagulability and the prothrombotic state scanning electron microscopy (SEM), atomic force microscopy (AFM), thromboelastography (TEG) and turbidimetry were employed to investigate the morphology, surface roughness, viscoelastic properties and formation and lysis of fibrin. RESULTS 17β-estradiol and progesterone showed hypercoagulable viscoelastic properties and decreased the diameter and surface roughness of fibrin while increasing dense matted deposit occurrence. Our results suggest that the additional burden of hormonal load, together with the presence of endogenous estrogen and progesterone, may result in a prothrombotic and hypercoagulable state in females with an inflammatory predisposition. CONCLUSION Our results are of clinical importance when considering hormones as either pathological agent or therapeutic intervention as will be assessed in future investigation.

Genetic polymorphisms influencing total and γ' fibrinogen levels and fibrin clot properties in Africans

Inter‐ethnic variation in fibrinogen levels is hypothesized to be the result of differences in genetic background. No information is available regarding the contribution of genetics to fibrinogen γ′ in Africans. Only limited information is available regarding the interaction between genotypes and total and γ′ fibrinogen concentration in determining fibrin clot properties. Our aim was to investigate the effect of polymorphisms in the fibrinogen and Factor XIII genes on total and γ′ fibrinogen and clot properties (turbidimetry) in 2010 black Africans as well as to determine their interactions. Significant associations were observed between rs1049636 (FGG gene), with total fibrinogen levels and between rs2070011 (FGA promoter area) and fibrinogen γ′ levels. Significant associations were observed between single nucleotide polymorphisms (SNPs) in the FGA (rs2070011), FGB (rs1800787) and FGG (rs1049636) genes and fibre size. Significant interactions were found between total and/or γ′ fibrinogen levels and SNPs in the FGA (rs2070011), FGB (rs2227385, rs1800787, rs1800788, rs4220) and F13A1 genes (rs5985) in determining clot properties. The different SNPs influenced the relationships between total and γ′ fibrinogen levels with clot properties in opposing directions. Genetic influences may be ethnic‐specific and should not only focus on fibrinogen concentration, but also on functionality in determining its role in CVD.

Triglyceride concentration and waist circumference influence alcohol-related plasminogen activator inhibitor-1 activity increase in black South Africans

We investigated the association between alcohol consumption and plasminogen activator inhibitor-1 activity (PAI-1act) and fibrinogen concentration in a black South African population presenting with lower PAI-1act and higher fibrinogen than what is typically observed in white populations. We, furthermore, wanted to investigate the effect of urbanization, sex, central obesity, increased triglycerides, 4G/5G polymorphism (PAI-1 only) and BMI on the association of alcohol with PAI-1act and fibrinogen. Data from 2010 apparently healthy, randomly collected black South African volunteers from the Prospective Urban and Rural Epidemiological (PURE) study were cross-sectionally analyzed. Alcohol consumption was recorded using quantitative food frequency questionnaires and fasting blood samples were collected for biochemical analysis including PAI-1act and fibrinogen. Heavy alcohol consumption is associated with significantly increased PAI-1act, in the total population as well as in the women separately, and tended to be so in men. This alcohol-related PAI-1act increase was observed in volunteers with increased triglycerides and central obesity but not in volunteers with normal levels and waist circumference. Urbanization, the 4G/5G polymorphism and BMI did not affect the association of alcohol with PAI-1act. Moderate alcohol consumption is associated with decreased fibrinogen concentration. Sex and level of urbanization did not affect the association of alcohol with fibrinogen. Fibrinogen decreased in normal and overweight volunteers but not in obese and centrally obese volunteers following moderate alcohol consumption. Triglyceride levels and waist circumference influence alcohol-related PAI-1act increase potentially through modulating adipocyte and triglyceride-induced PAI-1 production. Obesity prevented alcohol-related fibrinogen decrease possibly by counteracting the anti-inflammatory effect of moderate alcohol consumption.

In black South Africans from rural and urban communities, the 4G/5G PAI-1 polymorphism influences PAI-1 activity, but not plasma clot lysis time.

Data on genetic and environmental factors influencing PAI-1 levels and their consequent effect on clot lysis in black African populations are limited. We identified polymorphisms in the promoter area of the PAI-1 gene and determined their influence on PAI-1act levels and plasma clot lysis time (CLT). We also describe gene-environment interactions and the effect of urbanisation. Data from 2010 apparently healthy urban and rural black participants from the South African arm of the PURE study were cross-sectionally analysed. The 5G allele frequency of the 4G/5G polymorphism was 0.85. PAI-1act increased across genotypes in the urban subgroup (p = 0.009) but not significantly in the rural subgroup, while CLT did not differ across genotypes. Significant interaction terms were found between the 4G/5G polymorphism and BMI, waist circumference and triglycerides in determining PAI-1act, and between the 4G/5G polymorphism and fibrinogen and fibrinogen gamma prime in determining CLT. The C428T and G429A polymorphisms did not show direct relationships with PAI-1act or CLT but they did influence the association of other environmental factors with PAI-1act and CLT. Several of these interactions differed significantly between rural and urban subgroups, particularly in individuals harbouring the mutant alleles. In conclusion, although the 4G/5G polymorphism significantly affected PAI-1act, it contributed less than 1% to the PAI-1act variance. (Central) obesity was the biggest contributor to PAI-1act variance (12.5%). Urbanisation significantly influenced the effect of the 4G/5G polymorphism on PAI-1act as well as gene-environment interactions for the C428T and G429A genotypes in determining PAI-1act and CLT.

The association of clot lysis time with total obesity is partly independent from the association of PAI-1 with central obesity in African adults

INTRODUCTION Preliminary evidence indicates that the association of fibrinolytic potential, measured as clot lysis time (CLT), with body composition may differ from that of plasminogen activator inhibitor type-1 (PAI-1). We therefore investigated the association between fibrinolytic markers (plasminogen activator inhibitor type-1 activity (PAI-1act) and CLT) and body composition using detailed body composition analyses. MATERIALS AND METHODS Data from 1288 Africans were cross-sectionally analyzed. Body composition analysis included BMI, waist circumference (WC); waist to height ratio (WHtR), skinfolds and body fat percentage measured with air-displacement plethysmography and bioelectrical impedance analysis. RESULTS PAI-1act and CLT were significantly higher in women than in men, despite adjustment for differences in body composition. PAI-1act and CLT showed similar linear positive relationships with body composition (BMI, WC, WHtR, skinfolds) in men. In women CLT also showed a linear relationship with body composition, while PAI-1act levels plateaued at higher BMI and did not differ across skinfold categories. PAI-1act showed stronger correlations with body composition markers in men than it did in women, while no sex differences existed for CLT. PAI-1act associated more strongly with central obesity, while CLT associated with total body fat. CONCLUSIONS Observed differences may be related to differences in adipose tissue type, distribution and sequence of accumulation between sexes. PAI-1act is strongly influenced by accumulation of visceral adipose tissue, whereas CLT is associated with obesity independent of type and sequence of body fat accumulation in this African adult study population.

Nutrition leadership in Africa: making the change

Only a small number of truly exceptional international leaders have emanated from Africa. One of these is the South African Nobel Prize winner, Nelson Mandela. In reality, Africa is poorly led and most African countries still carry the burden of neo-patrimonial leaders who cling to their own knowledge, ideas, judgments and leadership positions, while rarely accepting advice from followers. 1 Africa is known to have well-intended reforms, but without the necessary galvanising action. While improved leadership in Africa might not be the only answer to addressing nutritional problems, it would definitely be a first step in the right direction. 2

Fibrinogen and clot-related phenotypes determined by fibrinogen polymorphisms: independent and IL-6-interactive associations

Interleukin-6 (IL-6) induces the expression of fibrinogen, and polymorphic variation within the fibrinogen genes is believed to alter the magnitude of this expression. The identification of the functional relevance of individual fibrinogen single nucleotide polymorphisms (SNPs) has been hindered by the high linkage disequilibrium (LD) reported in the European fibrinogen gene locus. This study investigated two novel and 12 known fibrinogen SNPs of potential functional relevance, in 2010 Tswana individuals known to have low LD. We aimed to identify functional polymorphisms that contribute to clot-related phenotypes and total and γ’ fibrinogen concentrations independently and through their interaction with IL-6, by taking advantage of the high fibrinogen and IL-6 concentrations and the low LD reported in black South Africans. Fibrinogen was significantly associated with IL-6, thereby mediating associations of IL-6 with clot formation and structure, although attenuating the association of IL-6 with clot lysis time. None of the common European fibrinogen haplotypes was present in this study population. Putative functional fibrinogen SNPs FGB–rs7439150, rs1800789 (–1420G/A) and rs1800787 (–148C/T) were significantly associated with fibrinogen concentration and altered clot properties, with several associations significantly influenced by IL-6 concentrations. The impact of harbouring several minor fibrinogen SNP alleles on the association of IL-6 and fibrinogen concentration was cumulative, with possession of each additional minor allele showing a stronger relationship of IL-6 with fibrinogen. This was also reflected in differences in clot properties, suggesting potential clinical relevance. Therefore, when investigating the effect of fibrinogen genetics on fibrinogen concentrations and CVD outcome, the possible interactions with modulating factors and the fact that SNP effects seem to be additive should be taken into account.