Thyroid Dysfunction and Fibrin Network Structure: A Mechanism for Increased Thrombotic Risk in Hyperthyroid Individuals
Abstract
CONTEXT: Hyperthyroidism is associated with increased thrombosis risk, and fibrin clot structure determines susceptibility to vascular thrombotic events. OBJECTIVE: Our objective was to investigate clot formation and lysis in hyperthyroidism using observational and interventional studies. DESIGN: Ex vivo fibrin clot structure/fibrinolysis and plasma levels of thrombotic/inflammatory markers were investigated in hyperthyroid individuals (n = 24) and matched controls (n = 19), using turbidimetric assays, ELISA, and confocal and electron microscopy. The effects of normalizing thyroid function were analyzed (n = 19) and the role of short-term exogenous hyperthyroidism in healthy volunteers studied (n = 16). RESULTS: Hyperthyroid subjects displayed higher clot maximum absorbance compared with controls (0.41 ± 0.03 and 0.27 ± 0.01 arbitrary units, respectively; P < 0.01), and longer clot lysis time (518 ± 23 and 461 ± 18 sec, respectively; P < 0.05), which correlated with free T(4) levels. Plasma levels of fibrinogen and plasminogen activator inhibitor-1 were significantly higher in patients compared with controls. Normalizing thyroid function in 19 subjects was associated with lower maximum absorbance and shorter lysis time, accompanied by reduction in fibrinogen, plasminogen activator inhibitor-1, and D-dimer levels. Complement C3, but not C-reactive protein, levels were higher in hyperthyroid subjects compared with controls (0.92 ± 0.05 and 0.64 ± 0.03 g/liter, respectively; P < 0.01), correlated with clot structure parameters, and decreased after intervention. Confocal and electron microscopy confirmed more compact clots and impaired fibrinolysis during hyperthyroidism. Exogenous hyperthyroidism in healthy volunteers had no effect on any of the clot structure parameters. CONCLUSIONS: Endogenous hyperthyroidism is associated with more compact clots and resistance to fibrinolysis ex vivo, related to the degree of hyperthyroidism and C3 plasma levels, and these changes are modulated by achieving euthyroidism. Altered clot structure/lysis may be one mechanism for increased thrombotic risk in hyperthyroidism.
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Thyrotoxicosis induced by administration of LT4 to healthy volunteers and those with thyroid nodules induces a procoagulant state, associated with increased levels of FVIII, FIX, FX, VWF, fibrinogen D-dimer, and PAI-1 with delayed fibrin clot lysis and a shortening of the APTT, but with an inconsistent impact on clot structure parameters.
“Thyrotoxicosis induced by administration of LT4 to healthy volunteers and those with thyroid nodules also induces a procoagulant state, associated with increased levels of FVIII, FIX, FX, VWF, fibrinogen D-dimer, and PAI-1 with delayed fibrin clot lysis and a shortening of the APTT, but with an inconsistent impact on clot structure parameters”
From Pharmacodynamic and Therapeutic Actions of Levothyroxine (2021) · cites this paper as [120]
Cites
Molecular Intercommunication between the Complement and Coagulation Systems
Amara, U., Flierl, M. A., Rittirsch, D., Klos, A., Chen, H., Acker, B., Brückner, U. B., Nilsson, B., Gebhard, F. T., Lambris, J. D., et al. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0903678 · Cited by 719 · see citing works
Inflammation and atherosclerosis: role of C-Reactive protein in risk assessment
Libby, P., & Ridker, P. M. (2004) · The American Journal of Medicine · doi:10.1016/j.amjmed.2004.02.006 · Cited by 596 · see citing works
Influence of Fibrin Network Conformation and Fibrin Fiber Diameter on Fibrinolysis Speed
Collet, J. ‐., Park, D., Lesty, C., Soria, J., Soria, C., Montalescot, G., & Weisel, J. W. (2000) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.20.5.1354 · Cited by 492 · see citing works
Jp, C., Allali, Y., Lesty, C., Tanguy, M., Silvain, J., Ankri, A., Blanchet, B., Dumaine, R. L., Gianetti, J., Payot, L., et al. (2006) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000241589.52950.4c · Cited by 348 · see citing works
Autoimmune thyroid disease: propagation and progression
Weetman, A. (2003) · European Journal of Endocrinology · doi:10.1530/eje.0.1480001 · Cited by 223 · see citing works
Thyroid Dysfunction and Effects on Coagulation and Fibrinolysis: A Systematic Review
Squizzato, A., Romualdi, E., Buller, H. R., & Gerdes, V. E. A. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-0199 · Cited by 222 · see citing works
Self-citationFatah, K., Silveira, A. M. V., Tornvall, P., Karpe, F., Blombäck, M., & Hamsten, A. (1996) · Thrombosis and Haemostasis · doi:10.1055/s-0038-1650618 · Cited by 221 · see citing works
Undas, A., Szuldrzynski, K. S., Stępień, E. Ł., Zalewski, J., Godlewski, J., Tracz, W., Pasowicz, M., & Zmudka, K. F. (2007) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2007.05.028 · Cited by 191 · see citing works
Mills, J. D., Ariëns, R. A. S., Mansfield, M. W., et al. (2002) · Circulation · doi:10.1161/01.cir.0000033221.73082.06 · Cited by 186 · see citing works
Heritability of Clot Formation, Morphology, and Lysis
Carter, A. M., Cymbalista, C. M., Spector, T. D., et al. (2007) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.107.153221 · Cited by 180 · see citing works
Blood coagulation and fibrinolysis in patients with hyperthyroidism
Erem, C., Ersöz, H. Ö., Karti, S. S., Ükinç, K., Hacıhasanoğlu, A., Değer, O., & Telatar, M. (2002) · Journal of Endocrinological Investigation · doi:10.1007/bf03344016 · Cited by 142 · see citing works
Arterial Embolism in Thyrotoxicosis With Atrial Fibrillation
Bar-Sela, S. (1981) · Archives of Internal Medicine · doi:10.1001/archinte.1981.00340090087019 · Cited by 138 · see citing works
Erem, C. (2006) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2006.02464.x · Cited by 136 · see citing works
Altered Fibrin Clot Structure/Function in Patients With Cryptogenic Ischemic Stroke
Undas, A., Podolec, P. S., Zawilska, K., Pieculewicz, M., Jedliński, I. M., Stępień, E. Ł., Konarska-Kuszewska, E., Węglarz, P., Duszyńska, M., Hanschke, E., et al. (2009) · Stroke · doi:10.1161/strokeaha.108.532812 · Cited by 133 · see citing works
Distelmaier, K., Adlbrecht, C., Jakowitsch, J., Winkler, S., Dunkler, D., Gerner, C., Wagner, O. F., Lang, I. M., & Kubicek, M. (2009) · Thrombosis and Haemostasis · doi:10.1160/th09-02-0103 · Cited by 120 · see citing works
Burggraaf, J., Lalezari, S., EMEIS, J. J., Vischer, U. M., Meyer, P., Pijl, H., & Cohen, A. F. (2001) · Thyroid · doi:10.1089/105072501300042820 · Cited by 108 · see citing works
A novel mechanism for hypofibrinolysis in diabetes: the role of complement C3
Hess, K., ALZAHRANI, S. H., Mathai, M., Schroeder, V., Carter, A. M., Howell, G. J., Koko, T., Strachan, M. W. J., Price, J. F., Smith, K. A., et al. (2011) · Diabetologia · doi:10.1007/s00125-011-2301-7 · Cited by 104 · see citing works
Self-citationThyrotoxicosis, atrial fibrillation, and embolism, revisited
Presti, C. F., & Hart, R. G. (1989) · American Heart Journal · doi:10.1016/0002-8703(89)90642-x · Cited by 103 · see citing works
Factor VIII Activity and Thyroid Function
Rogers, J., SHANE, S. R., & JENCKS, F. S. (1982) · Annals of Internal Medicine · doi:10.7326/0003-4819-97-5-713 · Cited by 103 · see citing works
Coagulation disorders in thyroid diseases
Hofbauer, L. C., & Heufelder, A. E. (1997) · European Journal of Endocrinology · doi:10.1530/eje.0.1360001 · Cited by 95 · see citing works
Complement-endothelial cell interactions: pathophysiological implications
Tedesco, F. (1999) · Molecular Immunology · doi:10.1016/s0161-5890(99)90054-8 · Cited by 84 · see citing works
Ajjan, R., Lim, B. C. B., Standeven, K. F., et al. (2007) · Blood · doi:10.1182/blood-2007-05-091231 · Cited by 79 · see citing works
Self-citationUndas, A., Kolarz, M., Kopeć, G., et al. (2007) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfm884 · Cited by 76 · see citing works
Low serum thyrotropin is associated with high plasma fibrinogen
Dörr, M., Robinson, D. M., Wallaschofski, H., Schwahn, C., John, U., Felix, S. B., & Völzke, H. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-1786 · Cited by 73 · see citing works
Franchini, M., Lippi, G., & Targher, G. (2011) · Clinical and Applied Thrombosis/Hemostasis · doi:10.1177/1076029610364521 · Cited by 71 · see citing works
Yu, H., Yang, Y., Zhang, M., Lü, H., Zhang, J., Wang, H., & Cianflone, K. (2006) · Nutrition & Metabolism · doi:10.1186/1743-7075-3-13 · Cited by 66 · see citing works
Complement C3 and C-reactive protein levels in patients with stable coronary artery disease
Ajjan, R., Futers, T. S., Brown, J., Cymbalista, C. M., Boothby, M., Carter, A., & Grant, P. J. (2005) · Thrombosis and Haemostasis · doi:10.1160/th05-06-0384 · Cited by 65 · see citing works
Self-citationThyroid Dysfunction and Hemostasis: An Issue Still Unresolved
Franchini, M., Montagnana, M., Manzato, F., & Vescovi, P. P. (2009) · Seminars in Thrombosis and Hemostasis · doi:10.1055/s-0029-1222607 · Cited by 64 · see citing works
Hormonal regulation of mannan-binding lectin synthesis in hepatocytes
Sørensen, C. M., Hansen, T. K., Steffensen, R., Jensenius, J. C., & Thiel, S. (2006) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2006.03101.x · Cited by 63 · see citing works
Immunological and hematological changes in patients with hyperthyroidism or hypothyroidism
Jafarzadeh, A., Poorgholami, M., Izadi, N., et al. (2010) · Clinical and investigative medicine · doi:10.25011/cim.v33i5.14352 · Cited by 61 · see citing works
Skellern, G., Knight, B., Low, C., et al. (1980) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.1980.tb05823.x · Cited by 60 · see citing works
Venous Thromboembolism in Patients Hospitalized With Thyroid Dysfunction
Danescu, L. G., Badshah, A., Danescu, S. C., Janjua, M. S. T., Marandici, A. M., Matta, F., Yaekoub, A. Y., Malloy, D. J., & Stein, P. D. (2009) · Clinical and Applied Thrombosis/Hemostasis · doi:10.1177/1076029609336856 · Cited by 52 · see citing works
VAN ZAANE, B., SQUIZZATO, A., DEBEIJ, J., DEKKERS, O. M., MEIJERS, J. C. M., VAN ZANTEN, A. P., BÜLLER, H. R., GERDES, V. E. A., CANNEGIETER, S. C., & BRANDJES, D. P. M. (2011) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2011.04430.x · Cited by 46 · see citing works
Self-citationFibrinogen and fibrinolytic activity in hyperthyroidism before and after antithyroid treatment
Marongiu, F., Conti, M. V., Mameli, G., et al. (1988) · Journal of Endocrinological Investigation · doi:10.1007/bf03350928 · Cited by 34 · see citing works
The Spectrum of Coagulation Abnormalities in Thyroid Disorders
Vescovi, P. P., Favaloro, E. J., Lippi, G., et al. (2011) · Seminars in Thrombosis and Hemostasis · doi:10.1055/s-0030-1270065 · Cited by 31 · see citing works
Activation of Blood Coagulation and Fibrinolysis in Graves' Disease
Marongiu, F., Conti, M., Murtas, M. L., et al. (1991) · Hormone and Metabolic Research · doi:10.1055/s-2007-1003766 · Cited by 28 · see citing works
Humar, M., Dohrmann, H., Stein, P., et al. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.132407 · Cited by 25 · see citing works
Potluková, E., Jiskra, J., Freiberger, T., Limanova, Z., Zivorova, D., Malíčková, K., Springer, D., Grodecká, L., Antošová, M., Telička, Z., et al. (2010) · Clinical Immunology · doi:10.1016/j.clim.2010.02.015 · Cited by 23 · see citing works
Effects of exogenous thyroxine on C-2 and C-16a hydroxylations of estradiol in humans
Michnovicz, J. J. (1990) · Steroids · doi:10.1016/0039-128x(90)90069-n · Cited by 23 · see citing works
Levels of plasma fibrinogen and D-dimer in subjects with subclinical hyperthyroidism.
Çoban, E., & Aydemir, M. (2008) · PubMed · Cited by 22 · see citing works
Zhang, B., Jiang, Y., Yang, Y., et al. (2008) · PubMed · Cited by 20 · see citing works
Ea, S.-T., Nair, C. H., & Dp, D. (1994) · PubMed · Cited by 14 · see citing works
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Bano, A., Chaker, L., de Maat, M. P. M., Atiq, F., Kavousi, M., Franco, O. H., Mattace-Raso, F. U. S., Leebeek, F. W. G., & Peeters, R. P. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2019-00072 · Cited by 25 · see citing works
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- Authors
- Hooper, J. M. W., Stuijver, D. J. F., Orme, S. M., van Zaane, B., Hess, K., Gerdes, V. E., Phoenix, F., Rice, P., Smith, K. A., Alzahrani, S. H., Standeven, K. F., & Ajjan, R. A.
- Affiliations
- University of Leeds (GB)
- Slotervaartziekenhuis (NL)
- Leeds Teaching Hospitals NHS Trust (GB)
- Universitätsklinikum Aachen (DE)
- Corresponding author
- Ajjan, R. A.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2012-05
- Volume
- 97
- Issue
- 5
- Pages
- 1463-1473
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W1964705259
- Cited by
- 54
- References
- 42
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 5 · 2020: 4 · 2019: 5 · 2018: 6 · 2017: 4 · 2016: 2 · 2015: 7 · 2014: 3 · 2013: 6 · 2012: 3
- FWCI
- 4.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- British Thyroid Foundation
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Blood properties and coagulation
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Keywords
- thrombosis risk, fibrin clot structure, fibrinolysis, clot lysis time, fibrinogen, plasminogen activator inhibitor-1, D-dimer, complement C3, thyroid function normalization, free thyroxine
- MeSH terms
- Adult, Blood Coagulation, Cross-Sectional Studies, Female, Fibrin, Fibrin Fibrinogen Degradation Products, Fibrinogen, Humans, Hyperthyroidism, Male, Risk, Thrombosis, Thyroid Function Tests, Thyroid Gland, Plasminogen Activator Inhibitor 1
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