Hypoxia and low temperature upregulate transferrin to induce hypercoagulability at high altitude

Studies have shown significantly increased thromboembolic events at high altitude. We recently reported that transferrin could potentiate blood coagulation, but the underlying mechanism for high altitude-related thromboembolism is still poorly understood. Here, we examined the activity and concentration of plasma coagulation factors and transferrin in plasma collected from long-term human residents and short-stay mice exposed to varying altitudes. We found that the activities of thrombin and factor XIIa (FXIIa) along with the concentrations of transferrin were significantly increased in the plasma of humans and mice at high altitudes. Furthermore, both hypoxia (6% O-2) and low temperature (0 degrees C), 2 critical high-altitude factors, enhanced hypoxia-inducible factor 1 alpha (HIF-1 alpha) levels to promote the expression of the transferrin gene, whose enhancer region contains HIF-1 alpha binding site, and consequently, to induce hypercoagulability by potentiating thrombin and FXIIa. Importantly, thromboembolic disorders and pathological insults in mouse models induced by both hypoxia and low temperature were ameliorated by transferrin interferences, including transferrin antibody treatment, transferrin down - regulation, and the administration of our designed peptides that inhibit the potentiation of transferrin on thrombin and FXIIa. Thus, low temperature and hypoxia upregulated transferrin expression-promoted hypercoagulability. Our data suggest that targeting the transferrin-coagulation pathway is a novel and potentially powerful strategy against thromboembolic events caused by harmful environmental factors under high-altitude conditions.

Automated summary

Studies have shown that thromboembolic events increase significantly at high altitude, but the underlying mechanism is still unclear. In this study, the activity and concentration of plasma coagulation factors and transferrin were examined in humans and mice exposed to different altitudes. The results showed that the activities of thrombin and factor XIIa, as well as the concentrations of transferrin, were significantly increased at high altitudes. Both hypoxia and low temperature, two critical factors at high altitude, enhanced the expression of hypoxia-inducible factor 1 alpha (HIF-1 alpha) and consequently promoted the expression of the transferrin gene. The upregulation of transferrin resulted in hypercoagulability by potentiating thrombin and FXIIa. Targeting the transferrin-coagulation pathway could be a novel and potentially effective strategy against thromboembolic events caused by harmful environmental factors under high-altitude conditions.