Elevated Circulating Tissue Factor Procoagulant Activity, Factor VII, Plasminogen Activator Inhibitor-1 and VCAM-1 in Childhood Obesity: Evidence of a Procoagulant State and Endothelial Dysfunction?,
Authors: Singh Anamika , Gunawardana Jay , McCoy Tara Alexis , Nguyen Tina , Veur Stephanie Vander , Stephens Treasure , Martinez Darnice , Komaroff Eugene , Foster Gary D. , Rao A. Koneti 
Published: October 2019

Abstract
Abstract 3338
Childhood obesity is increasing in prevalence and associated with risk of type 2 diabetes (T2DM) and coronary disease. Adult obesity and T2DM are associated with alterations in the coagulation and fibrinolytic systems. Tissue Factor (TF) is the principal initiator of blood coagulation and is both prothrombotic and proinflammatory. In mouse models of obesity, TF and plasminogen activator inhibitor (PAI)-1 genes are upregulated. We tested the hypothesis that childhood obesity is associated with elevated levels of circulating TF and markers of coagulation, fibrinolysis, and endothelial dysfunction. Forty-seven children were recruited and classified based on Body Mass Index (BMI) percentile (CDC growth curves) as underweight (≤5th percentile; n=1), healthy weight (>5–84.9th percentile; n=22), overweight (≥85%-94.9th percentile; n=3) and obese (≥95th percentile; n=21). We compared the findings in 21 obese children (10.1±1.5 years, mean age ± SD) and 22 healthy weight children (9.9±1.6 years). Circulating membrane bound TF procoagulant activity (TF-PCA), measured in whole blood lysates by a two-stage clotting assay (Key et al, Blood;1998:91), was elevated in obese compared to healthy weight children (60.6±32.5 vs 34.0±13.5 U/ml, mean ± SD, p=0.005). TF-PCA levels in obese children were comparable to levels observed by us in adults with T2DM (69.5±11.5; n=18). Plasma factor (F) VIIC (1.00±0.20 vs 0.90±0.20 U/ml; p=0.03) was elevated in obese group. Plasma FVIIa, FVIII, TF antigen, fibrinogen, and thrombin-antithrombin III, and microparticles (MP) were not different between groups. In fibrinolytic system, plasma PAI-1 was elevated in obese group (37.3±18.0 vs 25.6±15.0 ng/ml; p=0.03), and tissue plasminogen activator (tPA) antigen (6.7±3.4 vs 5.1±2.0 ng/ml, p=0.07) showed a similar trend. Endothelial markers, soluble vascular cell adhesion molecule-1 (sVCAM-1; 709.2±444.5 vs 526.5±184.8 ng/ml; p=0.05) and von-Willebrand Factor (VWF; 1057.4±139.8 vs 987.9±130.8 mU/ml; p=0.07) showed a trend towards higher levels in obesity, suggesting endothelial dysfunction. BMI correlated with circulating TF-PCA (r=0.36; p=0.01), FVIIC (r=0.36; p=0.01), and PAI-1 (r=0.38; p=0.009). TF-PCA correlated with sVCAM-1 (r=0.36; p=0.01), suggesting a potential endothelial contribution to the circulating TF-PCA. Plasma FVIIa (r=−0.29; p=0.053) appeared to be inversely related to TF-PCA possibly related to removal of FVIIa from plasma by binding to membrane TF. There was an inverse relationship between MP and FVIII (r= −0.42; p=0.004) and VWF (r=−0.37; p=0.01), which may reflect binding of FVIII and vWF to microparticles.

Conclusions:
Obesity, even in children, causes a potential procoagulant state characterized by increased circulating TF-PCA, FVIIC and PAI-1, and is associated with evidence suggesting endothelial dysfunction. Elevated levels of endothelial markers have been shown to predict development of T2DM, and elevated FVIIC has been associated with carotid intima-media thickness in young adults. Overall, these alterations may be basis for the increased risk of cardiovascular disease now documented in childhood obesity as well. Larger studies are needed to define the effect of childhood obesity on the hemostatic systems and the impact of intervention with weight reduction on the observed changes.

Disclosures:
No relevant conflicts of interest to declare.