Effect of quinolinic acid - A uremic toxin from tryptophan metabolism - On hemostatic profile in rat and mouse thrombosis models

Abstract

Purpose: We aimed to determine the effect of quinolinic acid (QA) on hemostasis in rat and mouse models of thrombosis.

Material and methods: Wistar rats (male, n = 72) received QA dissolved in drinking water in doses of 3, 10, 30 mg/kg or pure drinking water (vehicle control group -VEH) for 14 days. On the 14^th day of the experiment the effect of QA on hemostasis was evaluated using electrically induced arterial thrombosis model. The following parameters were measured: thrombus weight, hematology, thromboelastometric (ROTEM) parameters, TXA₂ and 6-keto-PGF_1α concentration, coagulation and fibrinolytic markers activity and concentration. GFP mice (male, n = 30) were assigned to the group receiving QA (30 mg/kg) or VEH for 14 days and to the group receiving: single intravenous dose of QA (30 mg/kg) or VEH or the same dose of QA and anti-CD31 (platelet endothelial cell adhesion molecule-1, PECAM-1) antibody conjugated with Alexa Fluor 647. The effect of QA on hemostasis was evaluated in the model of laser-induced injury of mesentery vein using intravital confocal microscopy.

Results: Administering QA for 14 days resulted in a divergent, depending on dose, increase in concentration of active form of tPA and PAI-1 and concentration of total PAI-1 and PAP complexes in rats' plasma. In turn, administering QA for 14 days in mice revealed its prothrombotic activity, while single-dose IV administration revealed its antithrombotic activity, through the up-regulation of PECAM-1 expression.

Conclusions: We demonstrated the first evidence for the opposite biological effects of QA on hemostasis in rat and mouse thrombosis models.

Keywords: Chronic kidney disease; Fibrinolysis; Hemostasis; Quinolinic acid; Thrombosis.