Cold exposure aggravates vein occlusion through non-shivering thermogenesis-induced thrombocytopoiesis.

Summary

Using mouse models, human volunteers, and retrospective clinical cohorts, this study demonstrated that cold exposure aggravates venous occlusion by increasing platelet production. Adipose thermogenesis elevated circulating free fatty acids, which enhanced acetyl-CoA production and activated the C/EBPα-GATA-1/NF-E2 megakaryocyte maturation pathway. Inhibition of adipose lipolysis, CPT1α, or p300 reduced thrombocytopoiesis and venous thrombosis in experimental models.

Key Findings

• Cold exposure increased platelet counts and aggravated deep venous thrombosis and retinal vein occlusion in mouse models.
• Adipose thermogenesis increased free fatty acids, promoting acetyl-CoA production and C/EBPα stabilization through p300-SIRT1 balance.
• Inhibition of PNPLA2, CPT1α, or p300 reduced cold-induced thrombocytopoiesis and venous occlusion.
• Healthy volunteers and retrospective patient cohorts showed increased platelet counts or venous thrombosis during cold exposure or cold seasons.

Clinical Implications

The findings support consideration of seasonal and environmental cold exposure as potential modifiers of venous thrombotic risk, particularly in susceptible individuals. CPT1α, p300, adipose lipolysis, and megakaryocyte metabolic pathways are investigational targets and should not yet be used clinically for thrombosis prevention.

Limitations

• The causal intervention experiments were performed primarily in mice, and human observational data cannot establish clinical causality.
• The human retrospective cohorts were relatively small and may be affected by seasonal, demographic, and behavioral confounding.

Future Directions

Prospective human studies should test whether cold exposure independently increases venous thromboembolism risk and should evaluate platelet and metabolic biomarkers. Translation of CPT1α or p300 inhibition into clinical prevention will require rigorous safety, dosing, and target-specificity studies.