Simvastatin administration reduces thromboxane production in subjects taking aspirin: Links between aspirin resistance and thrombin generation

Abstract

BackgroundGrowing evidence indicates that statins may reduce thromboxane A2 synthesis and thrombin generation. We investigated the relationships between thromboxane production, thrombin generation, and oxidative stress in patients receiving aspirin before and after statin administration. MethodsAn open-label study was conducted in 112 men, aged 54.4±7.3years, at an increased cardiovascular risk receiving aspirin (75mg/d). Prior to and following a 3-month simvastatin treatment (40mg/d), we evaluated circulating thromboxane B2 (TXB2), inflammatory markers, 8-isoprostane, and prothrombin fragment 1.2 (F1.2), a marker of thrombin generation, which was also measured in blood collected every 60s at the site of standardized skin incisions. ResultsSubjects (n=28) with pretreatment TXB2 concentrations in the highest quartile (“aspirin-resistant patients”) were more frequently current smokers and had elevated C-reactive protein (CRP), interleukin-6, 8-isoprostane, shorter bleeding time, and increased F1.2 production in a model of microvascular injury, when compared with the 3 remaining quartiles (all, p<0.001). Simvastatin decreased serum TXB2 in the whole group (by 20%, p=0.0008). Patients in the highest quartile of the baseline TXB2 had still higher posttreatment TXB2, CRP, interleukin-6, and F1.2 formation following injury (all, p<0.001). Simvastatin-induced change in TXB2 correlated with the magnitude of changes in maximum levels and the velocity of F1.2 formation (all p<0.001) but not with changes in inflammatory markers or lipid profile. ConclusionsThe study shows that statins significantly reduce platelet TXA2 formation in patients taking low-dose aspirin and this effect is associated with attenuated thrombin formation in response to vascular injury.