TY - JOUR

T1 - Effects of Thyroid Function on Hemostasis, Coagulation, and Fibrinolysis

T2 - A Mendelian Randomization Study

AU - Ellervik, Christina

AU - Mora, Samia

AU - Kus, Aleksander

AU - Asvold, Bjorn

AU - Marouli, Eirini

AU - Deloukas, Panos

AU - Sterenborg, Rosalie B. T. M.

AU - Teumer, Alexander

AU - Burgess, Stephen

AU - Sabater-Lleal, Maria

AU - Huffman, Jennifer

AU - Johnson, Andrew D.

AU - Tregouet, David-Alexandre

AU - Smith, Nicolas L.

AU - Medici, Marco

AU - DeVries, Paul S.

AU - Chasman, Daniel I.

AU - Kjaergaard, Alisa D.

PY - 2021

Y1 - 2021

N2 - Background: Untreated hypothyroidism is associated with acquired von Willebrand syndrome, and hyperthyroidism is associated with increased thrombosis risk. However, the causal effects of thyroid function on hemostasis, coagulation, and fibrinolysis are unknown. Methods: In a two-sample Mendelian randomization (MR) study with genome-wide association variants, we assessed causality of genetically predicted hypothyroidism (N = 134,641), normal-range thyrotropin (TSH; N = 54,288) and free thyroxine (fT4) (N = 49,269), hyperthyroidism (N = 51,823), and thyroid peroxidase antibody positivity (N = 25,821) on coagulation (activated partial thromboplastin time, von Willebrand factor [VWF], factor VIII [FVIII], prothrombin time, factor VII, fibrinogen) and fibrinolysis (D-dimer, tissue plasminogen activator [TPA], plasminogen activator inhibitor-1) from the CHARGE Hemostasis Consortium (N = 2583-120,246). Inverse-variance-weighted random effects were the main MR analysis followed by sensitivity analyses. Two-sided p < 0.05 was nominally significant, and p < 0.0011[ = 0.05/(5 exposures x 9 outcomes)] was Bonferroni significant for the main MR analysis. Results: Genetically increased TSH was associated with decreased VWF [beta(SE) = -0.020(0.006), p = 0.001] and with decreased fibrinogen [beta(SE) = -0.008(0.002), p = 0.001]. Genetically increased fT4 was associated with increased VWF [beta(SE) = 0.028(0.011), p = 0.012]. Genetically predicted hyperthyroidism was associated with increased VWF [beta(SE) = 0.012(0.004), p = 0.006] and increased FVIII [beta(SE) = 0.013(0.005), p = 0.007]. Genetically predicted hypothyroidism and hyperthyroidism were associated with decreased TPA [beta(SE) = -0.009(0.024), p = 0.024] and increased TPA [beta(SE) = 0.022(0.008), p = 0.008], respectively. MR sensitivity analyses showed similar direction but lower precision. Other coagulation and fibrinolytic factors were inconclusive. Conclusions: In the largest genetic studies currently available, genetically increased TSH and fT4 may be associated with decreased and increased synthesis of VWF, respectively. Since Bonferroni correction may be too conservative given the correlation between the analyzed traits, we cannot reject nominal associations of thyroid traits with coagulation or fibrinolytic factors.

AB - Background: Untreated hypothyroidism is associated with acquired von Willebrand syndrome, and hyperthyroidism is associated with increased thrombosis risk. However, the causal effects of thyroid function on hemostasis, coagulation, and fibrinolysis are unknown. Methods: In a two-sample Mendelian randomization (MR) study with genome-wide association variants, we assessed causality of genetically predicted hypothyroidism (N = 134,641), normal-range thyrotropin (TSH; N = 54,288) and free thyroxine (fT4) (N = 49,269), hyperthyroidism (N = 51,823), and thyroid peroxidase antibody positivity (N = 25,821) on coagulation (activated partial thromboplastin time, von Willebrand factor [VWF], factor VIII [FVIII], prothrombin time, factor VII, fibrinogen) and fibrinolysis (D-dimer, tissue plasminogen activator [TPA], plasminogen activator inhibitor-1) from the CHARGE Hemostasis Consortium (N = 2583-120,246). Inverse-variance-weighted random effects were the main MR analysis followed by sensitivity analyses. Two-sided p < 0.05 was nominally significant, and p < 0.0011[ = 0.05/(5 exposures x 9 outcomes)] was Bonferroni significant for the main MR analysis. Results: Genetically increased TSH was associated with decreased VWF [beta(SE) = -0.020(0.006), p = 0.001] and with decreased fibrinogen [beta(SE) = -0.008(0.002), p = 0.001]. Genetically increased fT4 was associated with increased VWF [beta(SE) = 0.028(0.011), p = 0.012]. Genetically predicted hyperthyroidism was associated with increased VWF [beta(SE) = 0.012(0.004), p = 0.006] and increased FVIII [beta(SE) = 0.013(0.005), p = 0.007]. Genetically predicted hypothyroidism and hyperthyroidism were associated with decreased TPA [beta(SE) = -0.009(0.024), p = 0.024] and increased TPA [beta(SE) = 0.022(0.008), p = 0.008], respectively. MR sensitivity analyses showed similar direction but lower precision. Other coagulation and fibrinolytic factors were inconclusive. Conclusions: In the largest genetic studies currently available, genetically increased TSH and fT4 may be associated with decreased and increased synthesis of VWF, respectively. Since Bonferroni correction may be too conservative given the correlation between the analyzed traits, we cannot reject nominal associations of thyroid traits with coagulation or fibrinolytic factors.

KW - coagulation

KW - fibrinolysis

KW - hemostasis

KW - hyperthyroidism

KW - hypothyroidism

KW - thyroid hormone

KW - thyroid peroxidase antibody

KW - thyrotropin

KW - TISSUE-PLASMINOGEN-ACTIVATOR

KW - PARTIAL THROMBOPLASTIN TIME

KW - GENOME-WIDE ASSOCIATION

KW - CARDIOVASCULAR EVENTS

KW - VENOUS THROMBOSIS

KW - FREE-THYROXINE

KW - RISK

KW - HYPERTHYROIDISM

KW - INSTRUMENTS

KW - HYPOTHYROIDISM

U2 - 10.1089/thy.2021.0055

DO - 10.1089/thy.2021.0055

M3 - Journal article

C2 - 34210154

VL - 31

SP - 1305

EP - 1315

JO - Thyroid

JF - Thyroid

SN - 1050-7256

IS - 9

ER -