Impact of thyroid function on coagulation and venous thromboembolism: a two-sample mendelian randomization study

ObjectiveThe association between thyroid function, coagulation and venous thromboembolism (VTE) has been reported in observational studies with conflicting findings. This study aimed to elucidate the causal effects of thyroid function on coagulation and VTE from a genetic perspective.MethodsTwo sample Mendelian randomization analysis was conducted using summary statistics from genome-wide association studies in a European population. Coagulation status was associated with nine coagulation-related factors (F VIII, F IX, F XI, Fibrinogen, Antithrombin-III, Thrombomodulin, Plasminogen activator inhibitor-1, Protein C and Protein S). Inverse variance weighting with random effect method was used as the main analytic approach with MR-Egger, weighted median, simple mode and weighted mode methods serving as complements. Sensitivity analyses including heterogeneity test, horizontal pleiotropy test and leave-one-out analysis were conducted to further assess the reliability of results.ResultsNo genetic causal effects of thyroid function on VTE (including pulmonary embolism and deep venous thrombosis) were found. Genetically, hyperthyroidism was suggestively related to decreased Antithrombin-III (beta: -0.04 [95% CI: -0.06 to - 0.01], p = 0.010) and Protein C (beta: -0.03 [95% CI: -0.06 to 0.00], p = 0.045). No notable associations were observed between other thyroid function parameters and coagulation-related factors.ConclusionWe provide suggestive genetic evidence supporting the causal effect of hyperthyroidism on decreased level of anticoagulant factors including Antithrombin-III and Protein C. However, whether this genetic causality could lead to clinically significant hypercoagulable state and increased risk of VTE in hyperthyroid population needs to be further addressed. The impacts of thyroid function on coagulation and VTE were debated with limited evidence from observational studies. This study aimed to elucidate the causal effects of thyroid function on coagulation and VTE from a genetic perspective. In this MR analysis, no direct genetic effects of thyroid function on VTE were observed, but genetic predicted hyperthyroidism was potentially associated with decreased level of anticoagulant factors including Antithrombin-III and Protein C. However, whether this genetic causality could lead to clinically significant hypercoagulable state and increased risk of VTE in hyperthyroid population needs to be further addressed. MR, Mendelian randomization; SNP, single nucleotide polymorphism; TSH, thyroid stimulating hormone; FT4, free thyroxine; VTE, venous thromboembolism; PE, pulmonary embolism; DVT, deep venous thrombosis.