To our knowledge, this was the first study to enroll the largest sample of CVT patients at HA and revealed the characteristic distinctions between plateau and plain regions as well. The more severe clinical and imaging manifestations along with prominent inflammation and hypercoagulable state were observed in plateau CVT patients, probably due to exposure to the hypoxic environment at HA. Pregnancy or puerperium were more common in patients at HA. The overall prognosis of CVT patients from both groups were favorable.
In our study, no significant difference was found in the demographic characteristics of CVT between highlands and plains, with female patients and young patients being more common, which was consistent with other studies13. Headache was the most frequent symptoms in both groups, in accordance with previous studies1, 14. Patients at HA majorly presented as acute or subacute onset and altered consciousness was more common. In addition, the imaging of CVT patients at HA showed a remarkably higher incidence of bleeding and venous infarction. The results suggested that the overall symptoms and radiological manifestations were more severe in high-altitude patients. One possible explanation is that exposure to high-altitude environments may lead to a higher substantial thrombus burden for CVT, which needs to be confirmed in future clinical and imaging studies. Another reason is that the diagnosis of CVT might be more difficult at HA, as some specific neurological disorders arising at HA can mimic CVT, including acute mountain sickness and high-altitude cerebral edema. Patients with mild clinical symptoms, such as isolated headache, might be misdiagnosed because brain imaging is not routinely performed. We also found that cortical veins were less frequently involved in HA areas. Since the identification of cortical vein thrombosis acquires experienced physicians and largely relies on SWI or GRE sequences15, 16, we suspect that he inadequate imaging diagnostic workup and lack of experience may lead to some missed diagnosis of cortical vein thrombosis in high-altitude patients.
HA exposure is an important risk factor for venous thromboembolism, including deep venous thrombosis, pulmonary thromboembolism, CVT and etc11, 17. Although the mechanism of HA on venous thromboembolism remains unclear, so far, it is believed that multiple physiological alterations induced by hypobaric hypoxia such as vascular endothelial damage, polycythemia, inflammation and hypercoagulable states, are associated with an increased probability of thrombosis11. In our study, coagulation markers including D-Dimer and Fbg as well as HGB were significantly higher in patients at HA compared with those at plains, further confirming the presence of more severe hypercoagulable state in CVT patients at HA, similar to previous studies8. One recent study has found that harmful environmental factors in high-altitude areas can upregulate transferrin, leading to hypercoagulable states and thromboembolic events, which suggests that targeting the transferrin-coagulation pathway is a potentially powerful strategy against thromboembolic events at HA7. More studies are required in the future to clarify the mechanism of hypercoagulation related to HA and provide promising strategies for the treatment of thromboembolic disorders at HA.
In addition to high-altitude exposure, other established risk factors of CVT should be systematically studied, including genetic or acquired prothrombotic conditions, infections, malignancy, oral contraceptives, and pregnancy, to better understand the etiology of CVT at HA and provide more effective prevention. We have found various risks factors of CVT at HA, including infection, hematological disorders, pregnant or postpartum, and etc. The spectrum of risk factors is quite different from that at plain. Among the major findings in this study, the notable one was that patients with CVT at HA exhibited significantly higher inflammatory state, reflected by higher levels of leukocytes and hsCPR in blood test. Recently increasing evidence supports the important role of inflammation in the occurrence and development of CVT. Several studies have reported that leukocytes, proinflammatory cytokines, and adherence molecules had significant effect on the CVT-related inflammatory process18. Several identified risk factors of CVT, such as infection and systematic autoimmune diseases, are linked with inflammatory condition, also indicating that inflammation is involved in cerebral venous thrombogenesis. Although about one-third of CVT patients at HA are complicated with recent infections, there is no significant difference in the proportion of infections compared to patients at plains. In addition, the prevalence of autoimmune diseases in CVT patients at plateau is significantly lower than that in plain areas, although the prevalence might be underestimated considering incomplete etiological workup. The above results seem insufficient to explain the high inflammatory status in high-altitude areas. Therefore, we speculate that the inflammation induced by exposure to the high-altitude environment itself is probably involved in the pathogenesis of high-altitude CVT. Although the mechanism of high inflammatory state in CVT at HA has not yet been clear, we believe that detecting potential infections and autoimmune diseases through a standardized etiological diagnosis workup and implementing effective treatment are essential strategies to improve the prognosis of CVT at HA. Further exploration on the effectiveness and safety of anti-inflammatory therapy is also needed.
Previous studies have rarely focused on the clinical characteristics and risk factors of female patients with CVT in high-altitude areas, mainly because most studies included soldiers and mountaineers at high altitudes, with almost all of them being males. In our study, the rate of pregnant or postpartum patients was notably higher in plateau (25%) than plain areas (5.8%), also higher than that reported in ASCVT (17%)14. Pregnancy may induce alterations in the coagulation state and elevate the risk of CVT19. Exposure to highland climate may aggravate hypercoagulable state and increase the susceptibility to CVT in pregnant and postpartum women11. Therefore, the screening and management of high-risk pregnant and postpartum women in plateau areas are quite important.
With the improvement of medical conditions, the treatment in CVT has been improving gradually, especially in high-altitude regions, however the proportion of anticoagulation therapy was significant lower in plateau areas in our study. Further investigation is needed to develop targeted treatment and prevention strategies in CVT at HA. Meantime, follow-up should be strengthened to improve adherence with anticoagulant drug usage in patients at HA. Overall, the outcome at discharge and at follow-up were favorable in both groups, indicating that outcome of CVT is generally benign even at HA.
Limitations
However, there are several limitations in this study. As an observational and retrospective study, the sample is not large enough to completely represent plateau and plain areas and some selection bias may exist. Some laboratory tests were incomplete in plateau patients due to poor medical conditions. We did not differentiate travelers and long-term residents in plateau concerning the small sample. Several patients lost follow up. In the future, large sample prospective cohort study is required to further investigate the impact of HA on CVT and the mechanisms.