Thyroid function and cardiovascular disease: the mediating role of coagulation factors.

Bano, Arjola; Chaker, Layal; de Maat, Moniek P M; Atiq, Ferdows; Kavousi, Maryam; Franco, Oscar H; Mattace-Raso, Francesco U S; Leebeek, Frank W G; Peeters, Robin P (2019). Thyroid function and cardiovascular disease: the mediating role of coagulation factors. The Journal of clinical endocrinology and metabolism, 104(8), pp. 3203-3212. The Endocrine Society 10.1210/jc.2019-00072

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CONTEXT

Mechanisms linking high and high-normal thyroid function to an increased cardiovascular risk remain unclear. Hypothetically, coagulation can play a role.

OBJECTIVE

To investigate: (i) the association of thyroid function with coagulation factors, (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 MEASUREMENTS

In 5918 participants (mean age, 69.1 years), we measured thyrotropin, free thyroxine (FT4) and coagulation factors (von Willebrand factor antigen [VWF:Ag], ADAMTS13 activity, fibrinogen). Participants were followed 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 hazard models, adjusted for potential confounders. We performed causal mediation analyses to evaluate if 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% confidence interval [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, indicating a procoagulant state. VWF:Ag and fibrinogen explained up to 10% of the link between FT4 with CVD.

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