Thyroid Function and Cardiovascular Disease: The Mediating Role of Coagulation Factors

CONTEXT: Mechanisms linking high and high-normal thyroid function to increased cardiovascular risk remain unclear. Hypothetically, coagulation can play a role. OBJECTIVE: To investigate (i) the association of thyroid function with coagulation factors and (ii) whether coagulation factors mediate the association of thyroid function with cardiovascular disease (CVD). DESIGN AND SETTING: Rotterdam Study, a population-based prospective study. PARTICIPANTS AND MAIN OUTCOME MEASURES: In 5918 participants (mean age, 69.1 years), we measured TSH, free T4 (FT4), and coagulation factors [von Willebrand factor antigen (VWF:Ag), ADAMTS13 activity, fibrinogen]. Participants were followed up for the occurrence of cardiovascular events and deaths. Associations of thyroid function with coagulation factors (standardized z scores) and CVD were assessed through linear regression and Cox proportional hazards models, adjusted for potential confounders. We performed causal mediation analyses to evaluate whether the effect of thyroid function on CVD is mediated by coagulation. RESULTS: Higher FT4 levels were associated with higher VWF:Ag (β = 0.34; 95% CI = 0.22, 0.47), lower ADAMTS13 activity (β = -0.22; 95%CI = -0.35, -0.09), and higher fibrinogen (β = 0.26; 95% CI = 0.13, 0.39); 857 incident cardiovascular events and 690 cardiovascular deaths occurred. FT4 levels were positively associated with cardiovascular events and deaths. The effect of FT4 on incident cardiovascular events was minimally mediated by fibrinogen (1.6%) but not by VWF:Ag and ADAMTS13. VWF:Ag and fibrinogen together mediated 10.0% of the effect of FT4 on cardiovascular deaths. CONCLUSIONS: Higher FT4 levels were associated with higher VWF:Ag, lower ADAMTS13 activity, and higher fibrinogen levels, indicating a procoagulant state. VWF:Ag and fibrinogen explained up to 10% of the link between FT4 and CVD.