The relationship between the metabolites of the dietary flavonoid quercetin, and haemostasis and thrombosis: an integrated systems approach

Quercetin is one of the most widely consumed flavonoids worldwide, and exerts numerous effects protective against cardiovascular disease, including the inhibition of platelet function. However, quercetin is extensively metabolised, and current data is limited regarding these metabolites. In this study, the anti-platelet effects of quercetin, and two methylated metabolites, tamarixetin and isorhamnetin, were investigated, to examine how anti-platelet efficacy is altered upon metabolism. Quercetin, tamarixetin and isorhamnetin inhibited collagen-stimulated platelet aggregation, and aggregation stimulated by ADP, thrombin and the thromboxane A2 mimetic U46619, at physiologically achievable concentrations. Granule secretion, integrin aIIbb3 activation and outside-in signalling, adhesion and spreading and calcium mobilisation were inhibited in a concentrationdependent manner; metabolism of quercetin can enhance or reduce anti-platelet effect. Due to high plasma binding, anti-platelet effects in platelet rich plasma and whole blood were investigated; significant inhibitory effects were maintained, with inhibition of clot retraction and thrombus formation under arterial flow conditions. The potential pharmacological importance of quercetin intake was investigated, with in vitro anti-platelet effects of novel quercetin formulations and an in vivo anti-thrombotic effect of an isoquercetin formulation after oral administration being demonstrated for the first time, and the identification of an interaction between the methylated metabolites and aspirin. To identify and predict important flavonoid interactions and potential inhibitory mechanisms, mathematical models of platelet aggregation and thrombus formation were developed, as was a pharmacokinetic/pharmacodynamic model of the dynamic anti-thrombotic actions of quercetin, which predicted optimal dosing regimens and highlighted the potential for increased anti-thrombotic effects upon altering quercetin metabolism. In summary, this study provided evidence for the potential of quercetin and its methylated metabolites in the inhibition of platelet function and thrombus formation, and identified interactions with aspirin, highlighting the potential of quercetin as an anti-platelet dietary compound or supplement, and identified some of the mechanisms underlying these actions