In this study, we aimed to use Mendelian randomization to assess whether thyroid diseases affects the incidence of DVT. The results supported that autoimmune hyperthyroidism can increase the risk of DVT occurrence and did not found reverse causal relationship between autoimmune hyperthyroidism and DVT by using bidirectional Mendelian randomization analysis. But other thyroid diseases such as subacute thyroiditis, hypothyroidism and thyroid cancer didn’t show the similar effect.
In recent years, a large number of studies have suggested that thyroid-related diseases may be related to the occurrence of deep vein thrombosis in the lower extremities, which provides us with etiological clues leading to the occurrence of DVT in our subsequent research. As early as 2006, a review mentioned the association between thyroid dysfunction and coagulation disorders[13], suggesting the presence of a hypercoagulable state in patients with hyperthyroidism. In 2011, a review further suggested a clear association between hypothyroidism and bleeding tendency, while hyperthyroidism appeared to increase the risk of thrombotic events, especially cerebral venous thrombosis[14]. A retrospective cohort study[15]supports this conclusion, but this study only observed a higher proportion of concurrent thyroid dysfunction in patients with cerebral venous thrombosis. The relationship between thyroid function and venous thromboembolism remains controversial. Krieg VJ et al[16]found that hypothyroidism has a higher incidence rate in chronic thromboembolic pulmonary hypertension patients and could be associated with more severe disease, which seemed to be different from previous views that hyperthyroidism may associated with venous thrombosis. Alsaidan AA et al[17] also figured out that the risk of developed venous thrombosis was almost 1 fold increased for cases with a mild-to-moderate elevation of thyroid stimulating hormone and FT4, whereas 2 fold increased for cases with severe elevation of thyroid stimulating hormone and FT4.
Other thyroid diseases are also reported to be associated with DVT. In a large prospective cohort study[18], the incidence of venous thromboembolism might be increased in patients with thyroid cancer over the age of 60, but other retrospective studies did not found any difference compared to general population[19], which was different from previous views on the relationship between tumors and venous thromboembolism. In the post COVID-19 era, subacute thyroiditis has received greater attention from researchers. Indeed, new evidence suggests that COVID-19 may have some relationship with subacute thyroiditis[20, 21]. Mondal S et al[22] found that out of 670 patients with COVID-19, 11 patients presented with post-COVID-19 subacute thyroiditis. Among them, painless subacute thyroiditis appeared earlier and had symptoms of hyperthyroidism. Another case report has also indicated the same situation, that is, subacute thyroiditis occured after COVID-19 infection, accompanied by thyroid function changes[23]. That leads us to hypothesize that subacute thyroiditis may affect DVT through alterations in thyroid function.
Our research comformed significance causal relationship between autoimmune hyperthyroidism and DVT(p = 0.02). Meanwhile, the data were tested for heterogeneity and gene pleiotropy using the tests with MR-Egger, Cochran’s Q and MR-PRESSO. No evidence suggested that the results were influenced by pleiotropy and heterogeneity. In Leave-one-out analysis, four out of five SNPs selected showed significant effects of autoimmune hyperthyroidism on DVT, suggesting an impact of these SNPs on the DVT outcome. Previous studies have focused on the relationship between hyperthyroidism and its secondary arrhythmias and arterial thromboembolism[24, 25]. Our study emphasizes the risk of DVT in patients with hyperthyroidism, which has certain clinical implications. Unfortunately, there is no evidence in this study that suggest a relationship between other thyroid diseases and the occurrence of DVT, possibly due to limited database. We only studied GWAS data from a subset of European populations, and larger-scale multiracial studies are needed in the future.
There are some limitations to this study. Firstly, our study is limited to participants of European descent. Therefore, further investigation is needed to confirm our findings in other ethnicities. Second, this study did not clarify the relationship between complications of hyperthyroidism and DVT. Further research is needed to supplement it. In addition, this study selected instrumental variables in the database using statistical methods, rather than selecting them in the real population, which may result in weaker effects of the screened instrumental variables and reduce the clinical significance of MR analysis. Further studies still need to construct relevant cohorts and detect GWAS for targeted prospective research.