Antiplatelet activity of deferiprone through cyclooxygenase-1 inhibition

Thalassemia patients are susceptible to both iron overload and thromboembolism. Deferiprone is an iron chelator that shows an antiplatelet activity and thus may alleviate platelet hyperactivation in thalassemia. Therefore, this study aimed to characterize the inhibitory effects and mechanisms of deferiprone on normal human platelets. The results illustrated that deferiprone inhibited platelet aggregation at the iron chelating concentrations (0.08–0.25 mmol/l). Deferiprone inhibited human platelet aggregation stimulated by arachidonic acid and ADP more potently than epinephrine and collagen, with the IC₅₀ of 0.24 mmol/l and 0.25 mmol/l <i>vs</i>. 3.36 mmol/l and 3.73 mmol/l, respectively. Interestingly, deferiprone significantly inhibited COX-1 activity, with the IC₅₀ of 0.33 mmol/l, and slightly increased cAMP level at the high concentration of 4 mmol/l. Moreover, the results from molecular docking showed that deferiprone interacted closely with key residues in the peroxidase active site of COX-1. These results suggested that deferiprone possessed antiplatelet activity mainly through the inhibition of COX-1 activity.

地中海贫血（Thalassemia）患者易同时罹患铁过载与血栓栓塞疾病。去铁酮（Deferiprone）是一种铁螯合剂，具备抗血小板活性，因此可缓解地中海贫血患者体内的血小板过度活化状态。为此，本研究旨在明确去铁酮对正常人血小板的抑制作用及其作用机制。研究结果显示，在铁螯合浓度范围（0.08~0.25 mmol/L）内，去铁酮可抑制血小板聚集。相较于肾上腺素与胶原诱导的血小板聚集，去铁酮对花生四烯酸（arachidonic acid）和二磷酸腺苷（ADP）诱导的人血小板聚集抑制效果更强，其半数抑制浓度（IC₅₀）分别为0.24 mmol/L、0.25 mmol/L，对应肾上腺素与胶原诱导组的IC₅₀则为3.36 mmol/L、3.73 mmol/L。值得注意的是，去铁酮可显著抑制环氧合酶-1（COX-1）活性，其IC₅₀为0.33 mmol/L，且在4 mmol/L的高浓度条件下可轻度升高环磷酸腺苷（cAMP）水平。此外，分子对接实验结果表明，去铁酮可与COX-1过氧化物酶活性位点内的关键氨基酸残基紧密结合。上述结果提示，去铁酮的抗血小板活性主要通过抑制COX-1活性实现。