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As innovative therapies for renal anemia, roxadustat and daprodustat are specifically indicated for populations with chronic kidney disease (CKD) who exhibit a significantly higher susceptibility to cardiovascular complications. Platelets are important participants in cardiovascular and cerebrovascular thrombotic diseases, and the effects of roxadustat and daprodustat on platelets have not been clarified. The study explored their modulatory effects on platelet functions (using human platelets) and antithrombotic activity in vivo (via mouse pulmonary embolism and mesenteric thrombus models). Mechanistically, thromboxane A2/cyclic adenosine monophosphate (TXA₂/cAMP) levels were measured by ELISA, and protein expression by immunoblotting. Results revealed that roxadustat and daprodustat treatment could effectively inhibit platelet functions. Roxadustat and daprodustat inhibited collagen-induced platelet aggregation ex vivo and FeCl₃-induced mesenteric arteriolar thrombosis in mice and were protective in pulmonary embolism models. Additionally, roxadustat and daprodustat caused a decrease in TXA₂ production and an increase in cAMP signaling. Western blot assay results displayed that roxadustat and daprodustat downregulated collagen-induced platelet PI3K/AKT/HIF-1α pathway. Our study revealed the pharmacological effects of roxadustat and daprodustat in inhibiting platelet activation and thrombosis. The effects may provide some insights into the physiological activity of HIF and clinical medication safety.