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

  • Thromb Res. 2026 Apr:260:109663. doi: 10.1016/j.thromres.2026.109663.
Yuchen Li  1 ,  Miaomiao Wei  2 ,  Yumeng Gu  2 ,  Jin Deng  2 ,  Xiaokun Guo  1 ,  Lin Wang  3 ,  Xin Li  4
Affiliations
  • 1. Department of Geriatric, The Second Hospital of Tianjin Medical University, Tianjin, China.
  • 2. Department of Neurology, The Second Hospital of Tianjin Medical University, Tianjin, China.
  • 3. Department of Geriatric, The Second Hospital of Tianjin Medical University, Tianjin, China; Tianjin Interdisciplinary Innovation Centre for Health and Meteorology, Tianjin, China.
  • 4. Department of Geriatric, The Second Hospital of Tianjin Medical University, Tianjin, China; Department of Neurology, The Second Hospital of Tianjin Medical University, Tianjin, China; Tianjin Interdisciplinary Innovation Centre for Health and Meteorology, Tianjin, China. Electronic address: [email protected].
PMID: 41926906 DOI: 10.1016/j.thromres.2026.109663
Abstract

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.

Keywords
Cold exposure; Ischemic stroke; Platelet activation; cGAS-STING.
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