Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) Antigen and Activity Assay in Patients With Primary Hypothyroidism

Abstract

Hypothyroidism causes a tendency for cardiovascular diseases. It was recently shown that thrombin-activatable fibrinolysis inhibitor (TAFI) attenuates fibrinolysis and also fibrin-plasminogen interaction by the removal of lysine and arginine residues from fibrin monomers. The aim of this study was to determine the effects of overt hypothyroidism on the levels of TAFI antigen (TAFI Ag) and TAFI activity (TAFIa). Thirty-one overt primary hypothyroid patients and age- and gender-matched 25 healthy controls were enrolled in the study. Patients were treated with L-thyroxine after the collection of blood samples. Thyroid functions were reevaluated following the achievement of euthyroid status. Thrombin-activatable fibrinolysis inhibitor Ag, tissue plasminogen activator (t-PA), and plasminogen activator inhibitor 1 (PAI-1) levels were measured with the enzyme-linked immunosorbent assay (ELISA). Thrombin-activatable fibrinolysis inhibitor activity was assessed with the chromogenic assay. Thrombin-activatable fibrinolysis inhibitor Ag (1.63% ± 0.42% vs 1.32% ± 0.36%, P < .01) and TAFIa (14.2 ± 4.12 vs 11.6 ± 3.49 μg/mL, P < .05) levels were elevated in hypothyroid patient compared to controls. Plasminogen activator inhibitor 1 and t-PA levels were not significantly different between both groups. In hypothyroid patients, TAFI Ag levels were correlated with free T₄ (r = -.373, P < .05) and thyroid-stimulating hormone (TSH) levels (r = .748, P < .001). Regression analysis showed that TSH levels were predictors of TAFI Ag levels (P < .001, β =.671, 95% confidence interval [CI]: 0.008-0.017). Following L-thyroxine treatment, TAFI Ag (1.63% ± 0.42%, 1.34% ± 0.33%, P < .05) and TAFIa (14.2 ± 4.12 μg/mL, 12.0 ± 2.77 μg/mL, P < .05) levels were significantly decreased, but t-PA and PAI-1 levels remained unchanged. This results point out that the fibrinolytic activity was decreased in hypothyroid patients, and therefore the achievement of euthyroid status is important in ameliorating the increased risk of cardiovascular disease.

Keywords

hypothyroidism thrombin-activatable fibrinolysis inhibitor fibrinolytic system tissue plasminogen activator plasminogen activator inhibitor L-thyroxine treatment

References

Vanderpump MP , Tunbridge WM , French JM , et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol. 1995;43(1):55-68.

Ladenson PW Recognition and management of cardiovascular disease related to thyroid dysfunction . Am J Med. 1990;88(6): 638-641.

Chadarevian R. , Bruckert E. , Leenhardt L. , Giral P. , Ankri A. , Turpin G. Components of the fibrinolytic system are differently altered in moderate and severe hypothyroidism. J Clin Endocrinol Metab. 2001;86(2):732-737.

Erem C. , Kavgaci H. , Ersöz HO , et al. Blood coagulation and fibrinolytic activity in hypothyroidism . Int J Clin Pract. 2003;57(2): 78-81.

Cesarman-Maus G. , Hajjar KA Molecular mechanisms of fibrinolysis. Br J Haematol. 2005;129(3):307-321.

Bouma BN , Mosnier LO Thrombin activatable fibrinolysis inhibitor (TAFI) at the interface between coagulation and fibrinolysis. Pathophysiol Haemost Thromb. 2003/2004;(5-6):375-381.

Bajzar L. Thrombin activatable fibrinolysis inhibitor and an antifibrinolytic pathway . Arterioscler Thromb Vasc Biol. 2000; 20(12):2511-2518.

Cappola AR , Ladenson PW Hypothyroidism and atherosclerosis. J Clin Endocrinol Metab. 2003;88(6):2438-2444.

Perk M. , O’Neill BJ The effect of thyroid hormone therapy on angiographic coronary artery disease progression. Can J Cardiol. 1997;13(3):273-276.

10.

Holvoet P. , Collen D. Thrombosis and atherosclerosis. Curr Opin Lipidol. 1997;8(5):320-328.

11.

Ford HC , Carter JM Haemostasis in hypothyroidism. Postgrad Med J. 1990;66(774):280-284.

12.

Cantürk Z. , Cetinarslan B. , Tarkun I. , Cantürk NZ , Ozden M. , Duman C. Hemostatic system as a risk factor for cardiovascular disease in women with subclinical hypothyroidism. Thyroid . 2003;13(10):971-977.

13.

Guldiken S. , Demir M. , Turgut B. , Altun BU , Arikan E. , Kara M. Global fibrinolytic capacity in patients with subclinical hypothyroidism. Endocr J. 2005 ;52(3):363-367.

14.

Chadarevian R. , Jublanc C. , Bruckert E. , et al. Effect of levothyroxine replacement therapy on coagulation and fibrinolysis in severe hypothyroidism. J Endocrinol Invest. 2005;28(5):398-404.

15.

Eaton DL , Malloy BE , Tsai SP , Henzel W. , Drayna D. Isolation, molecular cloning, and partial characterization of a novel carboxypeptidase B from human plasma. J Biol Chem. 1991;266(32): 21833-21838.

16.

Bajzar L. , Manuel R. , Nesheim ME. Purification and characterization of TAFI, a thrombin-activable fibrinolysis inhibitor. J Biol Chem. 1995;270(24):14477-14484.

17.

Guven GS , Kiliçaslan A. , Oz SG , et al. Decrements in the thrombin activatable fibrinolysis inhibitor (TAFI) levels in association with orlistat treatment in obesity. Clin Appl Thromb Hemos. 2006;12(3):364-368.

18.

Kitagawa N. , Yano Y. , Gabazza EC , et al. Different metabolic correlations of thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 in non-obese type 2 diabetic patients. Diabetes Res Clin Pract . 2006;73(2):150-157.

19.

Erem C. , Ucuncu O. , Yilmaz M. , Kocak M. , Nuhoglu I. , Ersoz HO Increased thrombin-activatable fibrinolysis inhibitor and decreased tissue factor pathway inhibitor in patients with hypothyroidism. Endocrine. 2009;35(1):75-80.

20.

Akinci B. , Comlekci A. , Ali Ozcan M. , et al. Elevated thrombin activatable fibrinolysis inhibitor (TAFI) antigen levels in overt and subclinical hypothyroid patients were reduced by levothyroxine replacement. Endocr J. 2007 ;54(1):45-52.

21.

Cetinkalp S. , Tobu M. , Karadeniz M. , Buyukkeçeci F. , Yilmaz C. The effect of hormone replacement treatment on thrombin-activatable fibrinolysis inhibitor activity levels in patients with Hashimoto thyroiditis. Intern Med . 2009;48(5):281-285.

22.

Morris MS , Bostom AG , Jacques PF , Selhub J. , Rosenberg IH Hyperhomocysteinemia and hypercholesterolemia associated with hypothyroidism in the third US National Health and Nutrition Examination Survey. Atherosclerosis. 2001;155(1): 195-200.

23.

Thompson GR , Soutar AK , Spengel FA , Jadhav A. , Gavigan SJ , Myant NB Defects of receptor-mediated low density lipoprotein catabolism in homozygous familial hypercholesterolemia and hypothyroidism in vivo. Proc Natl Acad Sci U S A. 1981;78(4): 2591-2595.

24.

Aso Y. , Wakabayashi S. , Yamamoto R. , Matsutomo R. , Takebayashi K. , Inukai T. Metabolic syndrome accompanied by hypercholesterolemia is strongly associated with proinflammatory state and impairment of fibrinolysis in patients with type 2 diabetes: synergistic effects of plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor. Diabetes Care. 2005;28(9):2211-2216.

25.

Guven GS , Atalar E. , Yavuz B. , et al. Simvastatin treatment improves endothelial function and increases fibrinolysis in patients with hypercholestrolemia. J Natl Med Assoc. 2006; 98(4):627-630.