Plasminogen activator inhibitor-1 in black South Africans, methodological and clinical considerations
Abstract
Introduction and aim
Black South Africans are experiencing an increase in the prevalence of cardiovascular disease
(CVD). Obesity and abnormal haemostasis are among the underlying risk factors associated
with CVD development in the African populations. Fibrinolysis and, in particular, one of its main
inhibitors, plasminogen activator inhibitor-1 (PAI-1), have been found to play an important
regulating role in the development of abnormal haemostasis and consequently, increase the risk
of CVD development. Most of the studies investigating PAI-1 provide data on individuals of
European descent. Much less information is available regarding PAI-1 in other ethnicities.
From these initial studies, two issues were identified that requires investigation in African
participants and formed the aim of this thesis. The first is a methodological issue relating to the
influence of platelets in plasma on PAI-1 and PAI-1 related assays as a possible explanation for
inconsistencies in ethnic differences reported for PAI-1. The second is a clinical issue focusing
on the relationship between PAI-1 and body fat distribution in Africans. Preliminary evidence
suggests this relationship may differ from what has been observed in European populations.
The specific objectives were to determine the effect of residual platelets in plasma on different
plasma PAI-1 and PAI-1 related assays, to investigate the relationship of PAI-1 with body fat
distribution patterns in Africans and also to review the literature reporting on the association
between body fat distribution and plasma PAI-1 levels.
Participants and methods
Methodological issues were addressed in the Sympathetic activity and Ambulatory Blood
Pressure in Africans (SABPA) study that included 151 teachers. In addition, data was also used
from a follow-up study where 20 academic staff members of a tertiary institution were recruited.
As for the clinical issues, available data from the Sarcopenic Obesity and Non-communicable
Disease Risk in African Adults (SONDRAA) study were used in which 246 African women were
included. Fasting blood samples were collected from the participants’ antebrachial vein
branches with a sterile winged infusion set before 10:00. Samples were centrifuged at different
centrifugation speeds, as stipulated by the respective study protocols and stored at -82°C until
further analysis. The following variables were analysed in the SABPA and follow-up study: PAI-
1 activity (PAI-1act), antigen (PAI-1ag), tissue plasminogen activator (tPA)/PAI-1 complex, clot
lysis time (CLT), beta thromboglobulin (βTG), and plasma platelet count and size. In the
SONDRAA study, PAI-1act, insulin, glucose, HIV status, high sensitivity C-reactive protein,
urinary albumin and creatinine were analysed. In order to determine different body fat distribution patterns in the SONDRAA study population, measurements of body weight, waist
circumference, abdominal and supraspinal skinfolds, as well as body composition by means of
dual-energy x-ray absorption were analysed. The identified clinical issues were also address by
undertaking an overview of ex vivo and in vivo studies investigating the association between
body fat distribution and plasma PAI-1 levels in order to contextualise apparent disparate
findings.
Results
Results from the methodological issues that were addressed indicated that a marker of platelet
α-granule release (plasma βTG) associated significantly with total PAI-1 content (PAI-1ag) levels
and demonstrated weak associations only with active PAI-1 (PAI-1act) and the functional marker,
clot lysis time (CLT). In the follow-up study it was indicated that plasma PAI-1ag was also
strongly affected by platelet count in a concentrated-dependent manner, and that plasma PAI-
1ag levels increased even further after complete platelet degradation. Regarding the association
of PAI-1 with different body fat distribution patterns (clinical considerations), the research
determined that the PAI-1act of sarcopenic obese women did not differ significantly from that of
the non-sarcopenic obese women (p=0.8) in this study population. Body fat distribution patterns
and degree of obesity influenced the relationship of PAI-1act with body fat percentage, insulin,
triglycerides and appendicular skeletal mass (ASM). It was also established that PAI-1act was
higher (1.65 vs 0.16 U/ml; p=0.001) in women with proportionally higher visceral adipose tissue
(VAT), compared to women with proportionally higher abdominal subcutaneous adipose tissue
(SCAT) in the total study population. This was, however, not the case in the centrally obese
sub-group (1.72 vs 0.83 U/ml; p=0.5). By applying multiple regression models, it was
established that body fat percentage as such, did not contribute markedly to the PAI-1act
variance in women with increased fat mass, but that other factors associated with obesity such
as inflammation and endothelial damage contributed to a larger extent. Additionally, in the
overview of the literature, factors that influence the relationship between body fat distribution
and plasma PAI-1 levels were identified, while the relative contribution of adipose tissue
compared to other PAI-1 source tissue was also put into perspective.
Conclusion
With regard to methodological issues, it was concluded that residual platelets in plasma
significantly influence plasma PAI-1ag levels mainly by increasing latent PAI-1 levels with limited
effects on PAI-1act, tPA/PAI-1 complex or CLT and that this is done in a platelet concentration
dependent manner. Platelet concentration should therefore be strictly monitored specifically when measuring PAI-1ag. In terms of the clinical data, it was found that patterns of fat
distribution and the degree of obesity influenced the association of PAI-1act with insulin,
triglycerides, ASM and body fat percentage in African women and that in conditions of extreme
obesity, abdominal SCAT contributes equally to plasma PAI-1act than does VAT. It was
furthermore established that the relationship between VAT and plasma PAI-1 levels is not fixed;
it rather seems to be regulated by a number of other factors such as the size of the
subcutaneous adipose tissue depot, ethnicity, possibly genetics and other obesity-related
metabolic abnormalities. Lastly, it was also determined that body fat percentage per se
contributes less to PAI-1act variance in African women than other obesity related derangements
such as endothelial dysfunction and inflammation which should be taken into account when
investigating the relationship between body composition and PAI-1.
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- Health Sciences [2060]