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 J o u r n a l P r e -p r o o f Journal Pre-proof 2 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.