Implication of Free Fatty Acids in Thrombin Generation and Fibrinolysis in Vascular Inflammation in Zucker Rats and Evolution with Aging

Abstract

Background: The metabolic syndrome (MetS) and aging are associated with modifications in blood coagulation factors, vascular inflammation, and increased risk of thrombosis.Objectives: Our aim was to determine concomitant changes in thrombin generation in the blood compartment and at the surface of vascular smooth muscle cells (VSMCs) and its interplay with adipokines, free fatty acids (FFA), and metalloproteinases (MMPs) in obese Zucker rats that share features of the human MetS.Methods: Obese and age-matched lean Zucker rats were compared at 25 and 80 weeks of age. Thrombin generation was assessed by calibrated automated thrombography (CAT).Results: Endogenous thrombin potential (ETP) was increased in obese rats independent of platelets and age. Clot half-lysis time was delayed with obesity and age. Interleukin (IL)-1β and IL-13 were increased with obesity and age respectively. Addition of exogenous fibrinogen, leptin, linoleic, or palmitic acid increased thrombin generation in plasma whereas adiponectin had an opposite effect. ETP was increased at the surface of VSMCs from obese rats and addition of exogenous palmitic acid further enhanced ETP values. Gelatinase activity was increased in aorta at both ages in obese rats and MMP-2 activity was increased in VSMCs from obese rats.Conclusions: Our study demonstrated in MetS an early prothrombotic phenotype of the blood compartment reinforced by procoagulant properties of dedifferentiated and inflammatory VSMCs. Mechanisms involved (1) increased fibrinogen and impaired fibrinolysis and (2) increased saturated fatty acids responsible for additive procoagulant effects. Whether specifically targeting this hypercoagulability using direct thrombin inhibitors would improve outcome in MetS is worth investigating.

Interspecies comparison of simultaneous thrombin and plasmin generation

“…Human PH values were larger than in rat, swine and rabbit, while guinea pig PH values were the smallest. Rat and rabbit are commonly used species to study TG [3][4][5]9,[29][30][31][32] . Among these studies, several used TF concentrations consistent with our study, and subsequently PH values were also similar to those presented in our study 3,4,9,29,30 .…”

“…Rat and rabbit are commonly used species to study TG [3][4][5]9,[29][30][31][32] . Among these studies, several used TF concentrations consistent with our study, and subsequently PH values were also similar to those presented in our study 3,4,9,29,30 . Up to this time, there are no studies that report TG in rhesus macaque or Guinea pig, despite both species being used as animal models in hemostasis research [33][34][35][36][37][38] .…”

Evaluation of global haemostatic assays and fibrin structure in patients with pre‐eclampsia

“…Fibre density was determined (with a modification of the method described by Larange et al) by counting the number of fibres that cut a line of 4.44 μm placed in the image. The mean density was then calculated by dividing the distance (4.44 μm) by the number of fibres in five randomly selected images for each sample and expressed as μm/fibre …”

Source of Dietary Fat in Pig Diet Affects Adipose Expression of Genes Related to Cancer, Cardiovascular, and Neurodegenerative Diseases

“…It has been shown previously that fibrin and thrombin activity exacerbates diet-induced obesity, metabolic inflammation, and associated sequelae [9]. Interestingly, Lagrange [10] observed that linoleic and palmitic acids increased coagulation by enhancing thrombin generation in Zucker rat's plasma. The diet based on beef tallow had the highest content of palmitic acid, which is in line with previous results.…”