Cold exposure aggravates vein occlusion through non-shivering thermogenesis-induced thrombocytopoiesis.
Summary
This study demonstrates that cold exposure increases platelet production through adipose thermogenesis and circulating free fatty acids. The mechanistic pathway involves fatty-acid β-oxidation, acetyl-CoA, p300/SIRT1-dependent regulation of C/EBPα, and downstream GATA-1/NF-E2 activation in megakaryocytes. Genetic or pharmacological interruption of this pathway reduced deep venous thrombosis and retinal vein occlusion in mice, while human observations showed increased platelet counts during cold exposure and cold seasons.
Key Findings
- Cold exposure increased platelet counts and aggravated deep venous thrombosis and retinal vein occlusion in mouse models.
- Adipose thermogenesis increased circulating free fatty acids, whose β-oxidation promoted acetyl-CoA-dependent C/EBPα stabilization and megakaryocyte platelet production.
- Inhibition of adipose triglyceride lipase, megakaryocyte CPT1α, or p300 reduced cold-induced thrombocytopoiesis and venous occlusion.
- Cold exposure increased platelet counts in healthy volunteers, and cold-season platelet elevation and higher deep venous thrombosis incidence were observed in patient cohorts.
Clinical Implications
Cold exposure may represent a modifiable environmental risk factor for venous thrombotic disease, particularly in susceptible individuals. The identified fatty-acid oxidation and p300-related pathways may support future preventive or therapeutic strategies, but no clinical treatment recommendation can yet be made.
Why It Matters
The paper provides a previously unrecognized mechanistic explanation for the seasonal increase in venous occlusive disease and identifies megakaryocyte metabolism as a potentially targetable pathway. It is strengthened by concordant evidence from mouse models, genetic manipulation, pharmacological inhibition, healthy volunteers, and patient cohorts.
Limitations
- The human component is observational and cannot establish that cold-induced platelet elevation causes venous occlusion in humans.
- The therapeutic effects of pathway inhibition were demonstrated in mice and require safety and efficacy testing in humans.
Future Directions
Future studies should prospectively determine whether seasonal cold exposure modifies thrombotic risk in defined high-risk populations and evaluate selective inhibition of megakaryocyte fatty-acid oxidation or p300 without impairing normal hemostasis.
Study Information
- Study Type
- Basic/mechanistic study with human observational validation
- Research Domain
- Pathophysiology
- Evidence Level
- IV - Rigorous preclinical mechanistic evidence supported by human observational and volunteer data, but without an interventional human trial.
- Study Design
- OTHER