High-concentration estradiol promotes platelet activation and thrombosis through Src-ADP axis

BACKGROUND: Pregnant women, as well as patients with endometriosis and some ovarian tumors, may experience a state of high estrogen levels. However, the role of high estrogen in platelet function and thrombosis remains controversial, which directly affects the prevention and clinical treatment of related diseases. METHODS: First, we conducted a retrospective analysis of clinical data from 108 pregnant women. Then, the effects of high estrogen levels on thrombosis were examined using the FeCl3-induced mouse mesenteric artery thrombosis model, as well as mouse stroke and pulmonary embolism models. We isolated platelets from patients and a mouse model exhibiting elevated estradiol levels to evaluate platelet activity. Finally, we explored the mechanism with mouse thrombosis models and plasma samples from pregnant women and patients with endometriosis. RESULTS: High estradiol levels enhanced thrombus formation in the mouse mesenteric artery thrombosis model. Furthermore, platelet aggregation, activation of integrin αIIbβ3, granule release, and phosphatidylserine (PS) exposure were significantly increased in platelets from pregnant women and endometriosis patients, or in mouse models with high E2 levels. We demonstrated that estrogen activates the Src/PKC/Akt signaling pathway, leading to increased ADP release. Clopidogrel abrogated the enhancing effects of estrogen on platelet activation and thrombosis in vivo. CONCLUSIONS: Our findings indicate that high-concentration estradiol promotes platelet hyperactivity and thrombogenesis through enhancing ADP release. Elimination of ADP with clopidogrel represents a novel therapeutic strategy for thrombotic disorders associated with elevated estradiol levels.