Abstract
Thrombosis pathogenesis is closely linked to dysregulated lipid metabolism and inflammatory processes. However, the direct regulatory role of mevalonate pathway within the coagulation cascade is still not well understood. This study aimed to elucidate the regulatory effects of mevalonic acid (MVA) on the coagulation system. The effects of MVA on coagulation were measured by recalcification. Enzymatic kinetic analysis and natural substrate hydrolysis assays were performed to identify the coagulation target of MVA. Mice bleeding and thrombosis models were applied to evaluate the effects of MVA administration on hemostasis and thrombosis. Our current study reveals that MVA significantly accelerates plasma coagulation through potentiating the procoagulant activity of FXa, without influencing the platelet aggregation. Studies showed that MVA administration substantially shortened activated partial thromboplastin time, prothrombin time, and reduced bleeding time in both tail bleeding and saphenous vein injury models. Furthermore, using ferric chloride-induced thrombosis, deep vein thrombosis and cerebral infarction models, we observed that MVA markedly potentiated thrombus formation and stroke. Our findings establish for the first time that MVA directly regulates FXa procoagulant activity, while also suggesting potential crosstalk between lipid metabolic pathways and inflammatory signaling in coagulation modulation. These results provide novel mechanistic insights into coagulation abnormalities associated with metabolic disorders such as atherosclerosis and diabetes, highlighting the mevalonate pathway as a potential therapeutic target for thrombotic complications.