Abstract
Various abnormalities of coagulation–fibrinolytic system have been reported in patients with thyroid dysfunction. Several studies indicate that coagulation and fibrinolytic system is disturbed in the patients with hypothyroidism. Also, the influence of hypothyroidism on hemostasis is controversial; both hypocoagulable and hypercoagulable states have been reported. The levels of plasma thrombin-activatable fibrinolysis inhibitor (TAFI) antigen and tissue factor pathway inhibitor (TFPI) have been investigated only once in patients with hypothyroidism. Therefore, the main purpose of this study was to evaluate the profile of coagulation and fibrinolytic parameters including TAFI and TFPI in patients with hypothyroidism. Fifteen patients with untreated hypothyroidism and 15 age-matched healthy controls were included in the study. Factors V(FV), VII (FVII), VIII (FVIII) activities, von Willebrand factor (vWF), protein C, protein S, thrombomodulin (TM), TFPI, and TAFI were measured. The relationships between serum thyroid hormones and these hemostatic parameters were examined. Compared with the control subjects, FVII activity, and TM Ag and TAFI Ag levels were significantly increased in patients with hypothyroidism, whereas FV, FVIII, vWF, protein C and protein S activities, and TFPI Ag levels were significantly decreased. We did not find any significant correlation between serum thyroid hormones and the hemostatic parameters that we measured. In conclusion, we found some important differences in the hemostatic parameters between the patients with hypothyroidism and healthy controls. Increased FVII, TM, and TAFI and decreased FV, FVIII, vWF, protein C, protein S, and TFPI in these patients represent a potential hypercoagulable and hypofibrinolytic state, possible endothelial dysfunction, which might augment the risk for atherosclerotic and atherothrombotic complications. Thus, disturbances of the hemostatic system may contribute to the excess mortality due to cardiovascular disease seen in patients with hypothyroidism.
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References
C. Erem, H.Ö. Ersoz, S.S. Kartı, K. Ukinç, A. Hacıhasanoğlu, O. Değer, M. Telatar, Blood coagulation and fibrinolysis in patients with hyperthyroidism. J. Endocrinol. Invest. 25, 345–350 (2002)
C. Erem, H. Kavgacı, H.Ö. Ersoz, A. Hacıhasanoğlu, K. Ukinç, S.S. Kartı, O. Değer, M. Telatar, Blood coagulation and fibrinolytic activity in hypothyroidism. Int. J. Clin. Pract. 57, 78–81 (2003)
C. Erem, Blood coagulation, fibrinolytic activity and lipid profile in subclinical thyroid disease: subclinical hyperthyroidism increases plasma factor X activity. Clin. Endocrinol. 64, 323–329 (2006)
A. Squizzato, E. Romualdi, H.R. Büller, V.E. Gerdes, Clinical review: thyroid dysfunction and effects on coagulation and fibrinolysis:a systematic review. J. Clin. Endocrinol. Metab. 92, 2415–2420 (2007)
M. Franchini, Hemostasis and thyroid diseases revisited. J. Endocrinol. Invest. 27, 886–892 (2004)
F. Marongiu, C. Cauli, S. Mariotti, Thyroid, hemostasis and thrombosis. J. Endocrinol. Invest. 27, 1065–1071 (2004)
S. Gullu, H. Sav, N. Kamel, Effects of levothyroxine treatment on biochemical and hemostasis parameters in patients with hypothyroidism. Eur. J. Endocrinol. 152, 355–361 (2005)
B. Myrup, C. Bregengård, J. Faber, Primary haemostasis in thyroid disease. J. Intern. Med. 238, 59–63 (1995)
M. Franchini, Hemostatic changes in thyroid diseases. Hematology 11, 203–208 (2006)
M.A. Ozcan, A. Comlekci, F. Demirkan, F. Yuksel, I. Sari, T. Demir, G.H. Ozsan, G. Oruk, S. Yesil, B. Undar, Plasma levels of free tissue factor pathway inhibitor in patients with various thyroid disorders. Thromb. Res. 110, 243–247 (2003)
F. Marongiu, G. Biondi, M. Conti, M.L. Murtas, G. Mameli, G.G. Sorano, E. Martino, Is a hypercoagulable state present in hypothyroidism? Thromb. Haemost. 67, 729 (1992)
R. Chadarevian, E. Bruckert, A. Ankri, I. Beucler, P. Giral, G. Turpin, Relationship between thyroid hormones and plasma D-dimer levels. Thromb. Haemost. 79, 99–103 (1998)
R. Chadarevian, E. Bruckert, L. Leenhardt, P. Giral, A. Ankri, G. Turpin, Components of the fibrinolytic system are differently altered in moderate and severe hypothyroidism. Clin. Endocrinol. Metab. 86, 732–737 (2001)
B. Müller, D.A. Tsakiris, C.B. Roth, M. Guglielmetti, J.J. Staub, G.A. Marbet, Haemostatic profile in hypothyroidism as potential risk factor for vascular or thrombotic disease. Eur. J. Clin. Invest. 31, 131–137 (2001)
E. Rooth, H. Wallen, A. Antovic, M. von Arbin, G. Kaponides, N. Wahlgren, M. Blombäck, J. Antovic, Thrombin activatable fibrinolysis inhibitor and its relationship to fibrinolysis and inflammation during the acute and convalescent phase of ischemic stroke. Blood Coagul. Fibrinolysis 18, 365–370 (2007)
A. Redlitz, A.K. Tan, D.L. Eaton, E.F. Plow, Plasma carboxypeptidases as regulators of the plasminogen system. J. Clin. Invest. 96, 2534–2538 (1995)
N.H. van Tilburg, F.R. Rosendaal, R.M. Bertina, Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis. Blood 95, 2855–2859 (2000)
S. Eichinger, V. Schönauer, A. Weltermann, E. Minar, C. Bialonczyk, M. Hirschl, B. Schneider, P. Quehenberger, P.A. Kyrle, Thrombin-activatable fibrinolysis inhibitor and the risk for recurrent venous thromboembolism. Blood 103, 3773–3776 (2004)
F.W. Leebeek, M.P. Goor, A.H. Guimaraes, G.J. Brouwers, M.P. Maat, D.W. Dippel, D.C. Rijken, High functional levels of thrombin-activatable fibrinolysis inhibitor are associated with an increased risk of first ischemic stroke. J. Thromb. Haemost. 3, 2211–2218 (2005)
J. Montaner, M. Ribó, J. Monasterio, C.A. Molina, J. Alvarez-Sabín, Thrombin-activable fibrinolysis inhibitor levels in the acute phase of ischemic stroke. Stroke 34, 1038–1040 (2003)
T.M. Ravindranath, M. Goto, O. Iqbal, M. Florian-Kujawski, D. Hoppensteadt, R. Hammadeh, M.M. Sayeed, J. Fareed, Plasma thrombin activatable fibrinolysis inhibitor and tissue factor pathway inhibitor changes following sepsis. Clin. Appl. Thromb. Hemost. 13, 362–368 (2007)
G.J. Broze Jr., The role of tissue factor pathway inhibitor in a revised coagulation cascade. Semin. Hematol. 29, 159–169 (1992)
T. Abumiya, T. Yamaguchi, T. Terasaki, T. Kokawa, K. Kario, H. Kato, Decreased plasma tissue factor pathway inhibitor activity in ischemic stroke patients. Thromb. Haemost. 74, 1050–1054 (1995)
M. Kobayashi, H. Wada, Y. Wakita, M. Shimura, T. Nakase, K. Hiyoyama, S. Nagaya, N. Minami, T. Nakano, H. Shiku, Decreased plasma tissue factor pathway inhibitor levels in patients with thrombotic thrombocytopenic purpura. Thromb. Haemost. 73, 10–14 (1995)
G.M. Harris, C.L. Stendt, B.J. Vollenhoven, T.E. Gan, P.G. Tipping, Decreased plasma tissue factor pathway inhibitor in women taking combined oral contraceptives. Am. J. Hematol. 60, 175–180 (1999)
B. Akinci, A. Comlekci, M. Ali Ozcan, T. Demir, S. Yener, F. Demirkan, F. Yuksel, S. Yesil, Elevated thrombin activatable fibrinolysis inhibitor (TAFI) antigen levels in overt and subclinical hypothyroid patients were reduced by levothyroxine replacement. Endocr. J. 54, 45–52 (2007)
R. Jorde, Y. Figenschau, J.B. Hansen, Haemostatic function in subjects with mild subclinical hypothyroidism. The Tromsø study. Thromb. Haemost. 95, 750–751 (2006)
L.C. Hofbauer, A.E. Heufelder, Coagulation disorders in thyroid diseases. Eur. J. Endocrinol. 136, 1–7 (1997)
M. Homoncik, A. Gessl, A. Ferlitsch, B. Jilma, H. Vierhapper, Altered platelet plug formation in hyperthyroidism and hypothyroidism. J. Clin. Endocrinol. Metab. 92, 3006–3012 (2007)
R.G. Dalton, M.S. Dewar, G.F. Savidge, P.B. Kernoff, K.B. Matthews, M. Greaves, F.E. Preston, Hypothyroidism as a cause of acquired von Willebrand’s disease. Lancet 1, 1007–1009 (1987)
S.R. Smith, M.J. Anger, Hypothyroidism and von Willebrand’s disease. Lancet 1, 1314 (1987)
J.J. Michiels, W. Schroyens, Z. Berneman, M. van der Planken, Acquired von Willebrand syndrome type 1 in hypothyroidism: reversal after treatment with thyroxine. Clin. Appl. Thromb. Hemost. 7, 113–115 (2001)
M.L. Tachman, G.P. Guthrie Jr., Hypothyroidism: diversity of presentation. Endocr. Rev. 5, 456–465 (1984)
D. Feinbloom, K.A. Bauer, Assessment of hemostatic risk factors in predicting arterial thrombotic events. Arterioscler. Thromb. Vasc. Biol. 25, 2043–2053 (2005)
T.W. Meade, S. Mellows, M. Brozovic, G.J. Miller, R.R. Chakrabarti, W.R. North et al., Haemostatic function and ischaemic heart disease: principal results of the Northwick Park heart study. Lancet 2, 533–537 (1986)
R. Junker, J. Heinrich, H. Schulte, J. van de Loo, G. Assmann, Coagulation factor VII and the risk of coronary heart disease in healthy men. Arterioscler. Thromb. Vasc. Biol. 17, 1539–1544 (1997)
P. Broadhurst, C. Kelleher, L. Hughes, J.D. Imeson, E.B. Raftery, Fibrinogen, factor VII clotting activity and coronary artery disease severity. Atherosclerosis 85, 169–173 (1990)
V. Ruddock, T.W. Meade, Factor VII activity and ischaemic heart disease: fatal and non-fatal events. QJM 87, 403–406 (1994)
B. Dahlback, B.O. Villoutreix, The anticoagulant protein C pathway. FEBS Lett. 579, 3310–3316 (2005)
M.L. Moster, Coagulopathies and arterial stroke. J. Neuroophthalmol. 23, 63–71 (2003)
B. Dahlbäck, Blood coagulation. Lancet 355, 1627–1632 (2000)
Y. Morikawa, A. Morikawa, I. Makino, Relationship of thyroid states and serum thrombomodulin (TM) levels in patients with Graves’ disease: TM, a possible new marker of the peripheral activity of thyroid hormones. J. Clin. Endocrinol. Metab. 76, 609–614 (1993)
M. Soma, Y. Maeda, R. Matsuura, I. Sasaki, S. Kasakura, Y. Saeki, K. Ikekubo, T. Ishihara, H. Kurahachi, S. Sasaki, T. Tagami, K. Nakao, Study of serum Thrombomodulin (TM) levels in patients with hyper-or hypo-thyroidism. Rinsho Byori 45, 77–81 (1997)
T. Nagasaki, M. Inaba, Y. Hiura, H. Tahara, Y. Kumeda, K. Shirakawa, N. Onoda, T. Ishikawa, E. Ishimura, Y. Nishizawa, Plasma levels of adiponectin and soluble thrombomodulin in hypothyroid patients with normal thyroid function following levothyroxine replacement therapy. Biomed. Pharmacother. 59, 571–577 (2005)
B.A. Lwaleed, P.S. Bass, Tissue factor pathway inhibitor: structure, biology and involvement in disease. J. Pathol. 208, 327–339 (2006)
M. Hoke, P.A. Kyrle, E. Minar, C. Bialonzcyk, M. Hirschl, B. Schneider, M. Kollars, A. Weltermann, S. Eichinger, Tissue factor pathway inhibitor and the risk of recurrent venous thromboembolism. Thromb. Haemost. 94, 787–790 (2005)
J. Monasterio, P. Bermúdez, D. Quiroga, E. Francisco, B. Meneses, J. Montaner, Plasma thrombin-activatable fibrinolytic inhibitor (TAFI) among healthy subjects and patients with vascular diseases: a validation study. Pathophysiol. Haemost. Thromb. 33, 382–386 (2003)
L. Bajzar, R. Manuel, M.E. Nesheim, Purification and characterization of TAFI, a thrombin-activable fibrinolysis inhibitor. J. Biol. Chem. 270, 14477–14484 (1995)
I. Juhan-Vague, P.E. Morange, H. Aubert, M. Henry, M.F. Aillaud, M.C. Alessi, A. Samnegård, E. Hawe, J. Yudkin, M. Margaglione, G. Di Minno, A. Hamsten, S.E. Humphries, HIFMECH Study Group. Plasma thrombin-activatable fibrinolysis inhibitor antigen concentration and genotype in relation to myocardial infarction in the north and south of Europe. Arterioscler. Thromb. Vasc. Biol. 22, 867–873 (2002)
A. Silveira, K. Schatteman, F. Goossens, E. Moor, S. Scharpé, M. Strömqvist, D. Hendriks, A. Hamsten, Plasma procarboxypeptidase U in men with symptomatic coronary artery disease. Thromb. Haemost. 84, 364–368 (2000)
V. Schroeder, T. Chatterjee, H. Mehta, S. Windecker, T. Pham, N. Devantay, B. Meier, H.P. Kohler, Thrombin activatable fibrinolysis inhibitor (TAFI) levels in patients with coronary artery disease investigated by angiography. Thromb. Haemost. 88, 1020–1025 (2002)
H.K. Lau, A. Segev, R.A. Hegele, J.D. Sparkes, J.M. Teitel, R.J. Chisholm, B.H. Strauss, Thrombin-activatable fibrinolysis inhibitor (TAFI): a novel predictor of angiographic coronary restenosis. Thromb. Haemost. 90, 1187–1191 (2003)
A. Santamaría, A. Martínez-Rubio, M. Borrell, J. Mateo, R. Ortín, J. Fontcuberta, Risk of acute coronary artery disease associated with functional thrombin activatable fibrinolysis inhibitor plasma level. Haematologica 89, 880–881 (2004)
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This study was supported by a research grant from the Karadeniz Technical University (Project No. 2005.114.003.2).
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Erem, C., Ucuncu, O., Yilmaz, M. et al. Increased thrombin-activatable fibrinolysis inhibitor and decreased tissue factor pathway inhibitor in patients with hypothyroidism. Endocr 35, 75–80 (2009). https://doi.org/10.1007/s12020-008-9116-4
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DOI: https://doi.org/10.1007/s12020-008-9116-4