Cold exposure promotes thrombotic risk in ischemic stroke by activating the platelet cGAS-STING pathway

BACKGROUND: Ischemic stroke (IS) incidence increases in cold periods, implicating cold exposure as a key environmental risk factor. However, the underlying biological mechanisms remain unclear. METHODS: We performed a cross-sectional study in acute IS patients (n = 623) to compare platelet and coagulation profiles between cold- and non-cold-season admissions, analyzing temperature associations using Generalized Additive Models and age-cold interactions via additive measures. Parallel rat experiments examined cold effects on platelet function, hemostasis, cerebral ischemia, and the cGAS-STING pathway. RESULTS: Patients in cold periods exhibited significantly elevated platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), ADP-induced aggregation, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, and D-dimer. Lower daily temperature correlated with increased ADP-aggregation and PDW. A significant positive additive interaction existed between cold exposure and older age (≥65 years) for PLT, MPV, PDW, ADP-aggregation, APTT and FIB. In rats, cold shortened bleeding time, enhanced platelet aggregation, spreading, clot retraction, and microvesicle release, increasing cerebral infarct volume. Mechanistically, cold upregulated platelet cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING), effects blunted by the cGAS inhibitor RU.521. CONCLUSION: Cold exposure acts as an independent risk factor and exerts a synergistic effect with aging to promote a prothrombotic state in elderly stroke patients. Our findings suggest that activation of the platelet cGAS-STING pathway may serve as a potential mechanistic link. Importantly, pharmacological inhibition of this pathway was associated with attenuated pro-thrombotic phenotype and brain injury in cold-exposed animals. These findings support the platelet cGAS-STING axis as a candidate therapeutic target for mitigating seasonal stroke risk.