https://orcid.org/0000-0001-6167-8278
Key Points
Sodium/potassium ATPase α1 attaches to specific platelet receptors and helps regulate platelet activation and clot formation.
Male hormones decrease sodium/potassium ATPase α1 in platelets, contributing to differences in blood clot risk between men and women.
Sex differences are well-recognized in thrombotic diseases, but the underlying mechanisms remain unclear. The sodium/potassium ATPase (NKA), composed of α and β subunits, regulates ion homeostasis and plays a key role in cardiovascular function. We investigated whether the NKA α1 subunit influences platelet activation and thrombosis. Using the FeCl3-induced carotid artery injury thrombosis model in wild-type (WT, α1+/+) and NKA α1 heterozygous (α1+/-) mice, we found that NKA α1 haploinsufficiency significantly inhibited thrombosis in males but not females, without affecting hemostasis. Platelet NKA α1 expression was halved in α1+/- mice, but sodium homeostasis remained unchanged. Transfusion of α1+/- platelets into thrombocytopenic WT mice prolonged the time to occlusive thrombus formation. Low-dose ouabain or marinobufagenin, which bind NKA α1, suppressed thrombosis. Mechanistically, α1 interacted with P2Y12, and this interaction was disrupted by an LGL→SFT mutation in either partner or by the LGL peptide. NKA α1 haploinsufficiency, ouabain, and LGL peptide treatment all reduced ADP-induced platelet aggregation. Female mice exhibited higher platelet α1 expression and shorter thrombosis times than males. Gonadectomy had no effect in females but abolished the anti-thrombotic phenotype in α1+/- males, while orchiectomy increased platelet α1 expression. Although α1 haploinsufficiency did not affect thrombosis in the 10% FeCl3 model, it prolonged thrombosis time in mice treated with low-dose clopidogrel or prasugrel, which alone had no effect. These findings identify NKA α1 as a key regulator of sex-specific platelet activation and thrombosis, suggesting its potential as a biomarker for thrombotic risk and a therapeutic target for antiplatelet and antithrombotic therapy.
