Download PDF
Semin Thromb Hemost 2009; 35(7): 605-612
DOI: 10.1055/s-0029-1242714
© Thieme Medical Publishers

Hemostatic and Fibrinolytic Abnormalities in Endocrine Diseases: A Narrative Review

Giovanni Targher1 , Isabella Pichiri1 , Giacomo Zoppini1 , Enzo Bonora1 , Michel Chonchol2
  • 1Section of Endocrinology, Department of Biomedical and Surgical Sciences, University of Verona, Verona, Italy
  • 2Division of Renal Diseases and Hypertension, University of Colorado Denver Health Sciences Center, Denver, Colorado
Further Information

Publication History

Publication Date:
09 December 2009 (online)

    Permissions and Reprints

ABSTRACT

This review summarizes current knowledge of the effects of polycystic ovary syndrome, Cushing's syndrome, thyrotoxicosis, hypothyroidism, primary hyperparathyroidism, acromegaly, hypopituitarism, and growth hormone deficiency on coagulation and fibrinolysis. Several abnormalities of the coagulation-fibrinolytic system have been described among patients affected by these endocrine disorders. Although further larger studies are needed to provide more definitive information, clinically overt hypothyroidism appears to be associated with a bleeding tendency, whereas all other endocrine diseases appear to be associated with a thrombotic tendency. The disorders of coagulation and fibrinolysis observed in these endocrine pathologies usually range from mild to moderate and, rarely, to potentially severe laboratory abnormalities (e.g., bleeding diathesis in overt hypothyroidism mainly due to an acquired von Willebrand's syndrome type 1), are reversible after pharmacologic treatment of the hormonal dysfunction, and are usually of limited consequence in clinical practice. Nevertheless, the prompt recognition of potentially severe disorders of blood coagulation is mandatory for the correct management of these patients.

KEYWORDS

Endocrine diseases - coagulation - fibrinolysis - hemostatic disorders - coagulation disorders

REFERENCES

  • 1 Kannel W B. Overview of hemostatic factors involved in atherosclerotic cardiovascular disease.  Lipids. 2005;  40(12) 1215-1220
    CrossrefPubMedGoogle Scholar
  • 2 Davì G, Patrono C. Platelet activation and atherothrombosis.  N Engl J Med. 2007;  357(24) 2482-2494
    CrossrefPubMedGoogle Scholar
  • 3 Fay W P, Garg N, Sunkar M. Vascular functions of the plasminogen activation system.  Arterioscler Thromb Vasc Biol. 2007;  27(6) 1231-1237
    CrossrefPubMedGoogle Scholar
  • 4 Franchini M, Targher G, Montagnana M, Lippi G. The metabolic syndrome and the risk of arterial and venous thrombosis.  Thromb Res. 2008;  122(6) 727-735
    CrossrefPubMedGoogle Scholar
  • 5 Mina A, Favaloro E J, Koutts J. Hemostatic dysfunction associated with endocrine disorders as a major risk factor and cause of human morbidity and mortality: a comprehensive meta-review.  Semin Thromb Hemost. 2007;  33(8) 798-809
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Targher G, Chonchol M, Miele L, Zoppini G, Pichiri I, Muggeo M. Nonalcoholic fatty liver disease as a contributor to hypercoagulation and thrombophilia in the metabolic syndrome.  Semin Thromb Hemost. 2009;  35(3) 277-287
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Norman R J, Dewailly D, Legro R S, Hickey T E. Polycystic ovary syndrome.  Lancet. 2007;  370(9588) 685-697
    CrossrefPubMedGoogle Scholar
  • 8 Meyer C, McGrath B P, Teede H J. Overweight women with polycystic ovary syndrome have evidence of subclinical cardiovascular disease.  J Clin Endocrinol Metab. 2005;  90(10) 5711-5716
    CrossrefPubMedGoogle Scholar
  • 9 Wild S, Pierpoint T, McKeigue P, Jacobs H. Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: a retrospective cohort study.  Clin Endocrinol (Oxf). 2000;  52(5) 595-600
    Google Scholar
  • 10 Yildiz B O, Haznedaroğlu I C, Kirazli S, Bayraktar M. Global fibrinolytic capacity is decreased in polycystic ovary syndrome, suggesting a prothrombotic state.  J Clin Endocrinol Metab. 2002;  87(8) 3871-3875
    CrossrefPubMedGoogle Scholar
  • 11 Kelly C J, Lyall H, Petrie J R et al.. A specific elevation in tissue plasminogen activator antigen in women with polycystic ovarian syndrome.  J Clin Endocrinol Metab. 2002;  87(7) 3287-3290
    CrossrefPubMedGoogle Scholar
  • 12 Atiomo W U, Bates S A, Condon J E, Shaw S, West J H, Prentice A G. The plasminogen activator system in women with polycystic ovary syndrome.  Fertil Steril. 1998;  69(2) 236-241
    CrossrefPubMedGoogle Scholar
  • 13 Erdoğan M, Karadeniz M, Alper G E et al.. Thrombin-activatable fibrinolysis inhibitor and cardiovascular risk factors in polycystic ovary syndrome.  Exp Clin Endocrinol Diabetes. 2008;  116(3) 143-147
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Adali E, Yildizhan R, Kurdoglu M, Bugdayci G, Kolusari A, Sahin H G. Increased plasma thrombin-activatable fibrinolysis inhibitor levels in young obese women with polycystic ovary syndrome.  Fertil Steril. 2009;  , April 13 (Epub ahead of print)
    PubMedGoogle Scholar
  • 15 Mak W, Dokras A. Polycystic ovarian syndrome and the risk of cardiovascular disease and thrombosis.  Semin Thromb Hemost. 2009;  35 613-620
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Orme S M, McNally R J, Cartwright R A, Belchetz P E. United Kingdom Acromegaly Study Group . Mortality and cancer incidence in acromegaly: a retrospective cohort study.  J Clin Endocrinol Metab. 1998;  83(8) 2730-2734
    CrossrefPubMedGoogle Scholar
  • 17 Bates A S, Van't Hoff W, Jones J M, Clayton R N. An audit of outcome of treatment in acromegaly.  Q J Med. 1993;  86(5) 293-299
    PubMedGoogle Scholar
  • 18 Bogazzi F, Battolla L, Spinelli C et al.. Risk factors for development of coronary heart disease in patients with acromegaly: a five-year prospective study.  J Clin Endocrinol Metab. 2007;  92(11) 4271-4277
    CrossrefPubMedGoogle Scholar
  • 19 Landin-Wilhelmsen K, Tengborn L, Wilhelmsen L, Bengtsson B A. Elevated fibrinogen levels decrease following treatment of acromegaly.  Clin Endocrinol (Oxf). 1997;  46(1) 69-74
    CrossrefPubMedGoogle Scholar
  • 20 Erem C, Nuhoglu I, Kocak M et al.. Blood coagulation and fibrinolysis in patients with acromegaly: increased plasminogen activator inhibitor-1 (PAI-1), decreased tissue factor pathway inhibitor (TFPI), and an inverse correlation between growth hormone and TFPI.  Endocrine. 2008;  33(3) 270-276
    CrossrefPubMedGoogle Scholar
  • 21 Wildbrett J, Hanefeld M, Fücker K et al.. Anomalies of lipoprotein pattern and fibrinolysis in acromegalic patients: relation to growth hormone levels and insulin-like growth factor I.  Exp Clin Endocrinol Diabetes. 1997;  105(6) 331-335
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Tomlinson J W, Holden N, Hills R K West Midlands Prospective Hypopituitary Study Group et al. Association between premature mortality and hypopituitarism.  Lancet. 2001;  357(9254) 425-431
    CrossrefPubMedGoogle Scholar
  • 23 Elhadd T A, Abdu T A, Clayton R. Hypopituitarism and atherosclerosis.  Ann Med. 2001;  33(7) 477-485
    CrossrefPubMedGoogle Scholar
  • 24 Johansson J O, Landin K, Tengborn L, Rosén T, Bengtsson B A. High fibrinogen and plasminogen activator inhibitor activity in growth hormone-deficient adults.  Arterioscler Thromb. 1994;  14(3) 434-437
    PubMedGoogle Scholar
  • 25 Johansson J O, Landin K, Johannsson G, Tengborn L, Bengtsson B A. Long-term treatment with growth hormone decreases plasminogen activator inhibitor-1 and tissue plasminogen activator in growth hormone-deficient adults.  Thromb Haemost. 1996;  76(3) 422-428
    PubMedGoogle Scholar
  • 26 Kvasnicka J, Marek J, Kvasnicka T et al.. Increase of adhesion molecules, fibrinogen, type-1 plasminogen activator inhibitor and orosomucoid in growth hormone (GH) deficient adults and their modulation by recombinant human GH replacement.  Clin Endocrinol (Oxf). 2000;  52(5) 543-548
    CrossrefPubMedGoogle Scholar
  • 27 Elhadd T A, Abdu T A, Oxtoby J et al.. Biochemical and biophysical markers of endothelial dysfunction in adults with hypopituitarism and severe GH deficiency.  J Clin Endocrinol Metab. 2001;  86(9) 4223-4232
    CrossrefPubMedGoogle Scholar
  • 28 Sesmilo G, Biller B M, Llevadot J et al.. Effects of growth hormone administration on inflammatory and other cardiovascular risk markers in men with growth hormone deficiency. A randomized, controlled clinical trial.  Ann Intern Med. 2000;  133(2) 111-122
    PubMedGoogle Scholar
  • 29 Devin J K, Blevins Jr L S, Verity D K et al.. Markedly impaired fibrinolytic balance contributes to cardiovascular risk in adults with growth hormone deficiency.  J Clin Endocrinol Metab. 2007;  92(9) 3633-3639
    CrossrefPubMedGoogle Scholar
  • 30 Serri O, St-Jacques P, Sartippour M, Renier G. Alterations of monocyte function in patients with growth hormone (GH) deficiency: effect of substitutive GH therapy.  J Clin Endocrinol Metab. 1999;  84(1) 58-63
    CrossrefPubMedGoogle Scholar
  • 31 Sartorio A, Cattaneo M, Bucciarelli P et al.. Alterations of haemostatic and fibrinolytic markers in adult patients with growth hormone deficiency and with acromegaly.  Exp Clin Endocrinol Diabetes. 2000;  108(7) 486-492
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Sesmilo G, Miller K K, Hayden D, Klibanski A. Inflammatory cardiovascular risk markers in women with hypopituitarism.  J Clin Endocrinol Metab. 2001;  86(12) 5774-5781
    CrossrefPubMedGoogle Scholar
  • 33 Abdu T A, Elhadd T A, Buch H, Barton D, Neary R, Clayton R N. Recombinant GH replacement in hypopituitary adults improves endothelial cell function and reduces calculated absolute and relative coronary risk.  Clin Endocrinol (Oxf). 2004;  61(3) 387-393
    CrossrefPubMedGoogle Scholar
  • 34 Völzke H, Schwahn C, Wallaschofski H, Dörr M. Review: The association of thyroid dysfunction with all-cause and circulatory mortality: is there a causal relationship?.  J Clin Endocrinol Metab. 2007;  92(7) 2421-2429
    CrossrefPubMedGoogle Scholar
  • 35 Ochs N, Auer R, Bauer D C et al.. Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality.  Ann Intern Med. 2008;  148(11) 832-845
    CrossrefPubMedGoogle Scholar
  • 36 Squizzato A, Romualdi E, Büller H R, Gerdes V EA. Clinical review: thyroid dysfunction and effects on coagulation and fibrinolysis: a systematic review.  J Clin Endocrinol Metab. 2007;  92(7) 2415-2420
    CrossrefPubMedGoogle Scholar
  • 37 Franchini M, Montagnana M, Manzato F, Vescovi P P. Thyroid dysfunction and hemostasis: an issue still unresolved.  Semin Thromb Hemost. 2009;  35(3) 288-294
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Franchini M, Lippi G, Manzato F, Vescovi P P. Thyroid-associated autoimmune coagulation disorders.  J Thromb Thrombolysis. 2009;  , March 10 (Epub ahead of print)
    PubMedGoogle Scholar
  • 39 Homoncik M, Gessl A, Ferlitsch A, Jilma B, Vierhapper H. Altered platelet plug formation in hyperthyroidism and hypothyroidism.  J Clin Endocrinol Metab. 2007;  92(8) 3006-3012
    CrossrefPubMedGoogle Scholar
  • 40 Burggraaf J, Lalezari S, Emeis J J et al.. Endothelial function in patients with hyperthyroidism before and after treatment with propranolol and thiamazol.  Thyroid. 2001;  11(2) 153-160
    CrossrefPubMedGoogle Scholar
  • 41 Horne III M K, Singh K K, Rosenfeld K G et al.. Is thyroid hormone suppression therapy prothrombotic?.  J Clin Endocrinol Metab. 2004;  89(9) 4469-4473
    CrossrefPubMedGoogle Scholar
  • 42 Demir T, Akinci B, Comlekci A et al.. Levothyroxine suppression treatment for benign thyroid nodules alters coagulation.  Clin Endocrinol (Oxf). 2009;  71(3) 446-450
    CrossrefPubMedGoogle Scholar
  • 43 Erem C, Ersoz H O, Karti S S et al.. Blood coagulation and fibrinolysis in patients with hyperthyroidism.  J Endocrinol Invest. 2002;  25(4) 345-350
    CrossrefPubMedGoogle Scholar
  • 44 Akinci B, Comlekci A, Yener S et al.. Thrombin activatable fibrinolysis inhibitor antigen levels are inversely correlated with plasminogen activator inhibitor-1 antigen levels in hyperthyroid patients.  Endocr J. 2007;  54(4) 593-599
    CrossrefPubMedGoogle Scholar
  • 45 Erem C. Blood coagulation, fibrinolytic activity and lipid profile in subclinical thyroid disease: subclinical hyperthyroidism increases plasma factor X activity.  Clin Endocrinol (Oxf). 2006;  64(3) 323-329
    CrossrefPubMedGoogle Scholar
  • 46 Lippi G, Franchini M, Targher G et al.. Hyperthyroidism is associated with shortened APTT and increased fibrinogen values in a general population of unselected outpatients.  J Thromb Thrombolysis. 2009;  28(3) 362-365
    CrossrefPubMedGoogle Scholar
  • 47 Müller B, Tsakiris D A, Roth C B, Guglielmetti M, Staub J J, Marbet G A. Haemostatic profile in hypothyroidism as potential risk factor for vascular or thrombotic disease.  Eur J Clin Invest. 2001;  31(2) 131-137
    CrossrefPubMedGoogle Scholar
  • 48 Coban E, Yazicioglu G, Ozdogan M. Platelet activation in subjects with subclinical hypothyroidism.  Med Sci Monit. 2007;  13 CR211-214
    PubMedGoogle Scholar
  • 49 Gullu S, Sav H, Kamel N. Effects of levothyroxine treatment on biochemical and hemostasis parameters in patients with hypothyroidism.  Eur J Endocrinol. 2005;  152(3) 355-361
    CrossrefPubMedGoogle Scholar
  • 50 Erikci A A, Karagoz B, Ozturk A et al.. The effect of subclinical hypothyroidism on platelet parameters.  Hematology. 2009;  14(2) 115-117
    CrossrefPubMedGoogle Scholar
  • 51 Franchini M, Zugni C, Veneri D et al.. High prevalence of acquired von Willebrand's syndrome in patients with thyroid diseases undergoing thyroid surgery.  Haematologica. 2004;  89(11) 1341-1346
    PubMedGoogle Scholar
  • 52 Manfredi E, van Zaane B, Gerdes V EA, Brandjes D P, Squizzato A. Hypothyroidism and acquired von Willebrand's syndrome: a systematic review.  Haemophilia. 2008;  14(3) 423-433
    CrossrefPubMedGoogle Scholar
  • 53 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
    CrossrefPubMedGoogle Scholar
  • 54 Michiels J J, Schroyens W, Berneman Z, van der Planken M. Acquired von Willebrand syndrome type 1 in hypothyroidism: reversal after treatment with thyroxine.  Clin Appl Thromb Hemost. 2001;  7(2) 113-115
    CrossrefPubMedGoogle Scholar
  • 55 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
    PubMedGoogle Scholar
  • 56 Erem C. Coagulation and fibrinolysis in thyroid dysfunction.  Endocrine. 2009;  36(1) 110-118
    CrossrefPubMedGoogle Scholar
  • 57 Lundgren E, Lind L, Palmér M, Jakobsson S, Ljunghall S, Rastad J. Increased cardiovascular mortality and normalized serum calcium in patients with mild hypercalcemia followed up for 25 years.  Surgery. 2001;  130(6) 978-985
    CrossrefPubMedGoogle Scholar
  • 58 Söreide J A, van Heerden J A, Grant C S, Yau Lo C, Schleck C, Ilstrup D M. Survival after surgical treatment for primary hyperparathyroidism.  Surgery. 1997;  122(6) 1117-1123
    CrossrefPubMedGoogle Scholar
  • 59 Hedbäck G, Odén A. Persistent disease after surgery for primary hyperparathyroidism: the long-term outcome.  Eur J Endocrinol. 2004;  150(1) 19-25
    CrossrefPubMedGoogle Scholar
  • 60 Lind L, Jacobsson S, Palmér M, Lithell H, Wengle B, Ljunghall S. Cardiovascular risk factors in primary hyperparathyroidism: a 15-year follow-up of operated and unoperated cases.  J Intern Med. 1991;  230(1) 29-35
    CrossrefPubMedGoogle Scholar
  • 61 Erem C, Kocak M, Nuhoglu I, Yilmaz M, Ucuncu O. Increased plasminogen activator inhibitor-1, decreased tissue factor pathway inhibitor, and unchanged thrombin-activatable fibrinolysis inhibitor levels in patients with primary hyperparathyroidism.  Eur J Endocrinol. 2009;  160(5) 863-868
    CrossrefPubMedGoogle Scholar
  • 62 Erem C, Kocak M, Hacihasanoglu A, Yilmaz M, Saglam F, Ersoz H O. Blood coagulation, fibrinolysis and lipid profile in patients with primary hyperparathyroidism: increased plasma factor VII and X activities and D-Dimer levels.  Exp Clin Endocrinol Diabetes. 2008;  116(10) 619-624
    Article in Thieme ConnectPubMedGoogle Scholar
  • 63 Chertok-Shacham E, Ishay A, Lavi I, Luboshitzky R. Biomarkers of hypercoagulability and inflammation in primary hyperparathyroidism.  Med Sci Monit. 2008;  14 CR628-632
    PubMedGoogle Scholar
  • 64 Etxabe J, Vazquez J A. Morbidity and mortality in Cushing's disease: an epidemiological approach.  Clin Endocrinol (Oxf). 1994;  40(4) 479-484
    CrossrefPubMedGoogle Scholar
  • 65 Mancini T, Kola B, Mantero F, Boscaro M, Arnaldi G. High cardiovascular risk in patients with Cushing's syndrome according to 1999 WHO/ISH guidelines.  Clin Endocrinol (Oxf). 2004;  61(6) 768-777
    CrossrefPubMedGoogle Scholar
  • 66 Boscaro M, Sonino N, Scarda A et al.. Anticoagulant prophylaxis markedly reduces thromboembolic complications in Cushing's syndrome.  J Clin Endocrinol Metab. 2002;  87(8) 3662-3666
    CrossrefPubMedGoogle Scholar
  • 67 Patrassi G M, Dal Bo Zanon R, Boscaro M, Martinelli S, Girolami A. Further studies on the hypercoagulable state of patients with Cushing's syndrome.  Thromb Haemost. 1985;  54(2) 518-520
    PubMedGoogle Scholar
  • 68 Patrassi G M, Sartori M T, Viero M L, Scarano L, Boscaro M, Girolami A. The fibrinolytic potential in patients with Cushing's disease: a clue to their hypercoagulable state.  Blood Coagul Fibrinolysis. 1992;  3(6) 789-793
    CrossrefPubMedGoogle Scholar
  • 69 Fatti L M, Bottasso B, Invitti C, Coppola R, Cavagnini F, Mannucci P M. Markers of activation of coagulation and fibrinolysis in patients with Cushing's syndrome.  J Endocrinol Invest. 2000;  23(3) 145-150
    CrossrefPubMedGoogle Scholar
  • 70 Terzolo M, Allasino B, Bosio S et al.. Hyperhomocysteinemia in patients with Cushing's syndrome.  J Clin Endocrinol Metab. 2004;  89 3745-3751
    CrossrefPubMedGoogle Scholar
  • 71 Erem C, Nuhoglu I, Yilmaz M et al.. Blood coagulation and fibrinolysis in patients with Cushing's syndrome: increased plasminogen activator inhibitor-1, decreased tissue factor pathway inhibitor, and unchanged thrombin-activatable fibrinolysis inhibitor levels.  J Endocrinol Invest. 2009;  32(2) 169-174
    CrossrefPubMedGoogle Scholar
  • 72 Ambrosi B, Sartorio A, Pizzocaro A, Passini E, Bottasso B, Federici A. Evaluation of haemostatic and fibrinolytic markers in patients with Cushing's syndrome and in patients with adrenal incidentaloma.  Exp Clin Endocrinol Diabetes. 2000;  108(4) 294-298
    Article in Thieme ConnectPubMedGoogle Scholar
  • 73 Van Zaane B, Nur E, Squizzato A et al.. Hypercoagulable state in Cushing's syndrome: a systematic review.  J Clin Endocrinol Metab. 2009;  94(8) 2743-2750
    CrossrefPubMedGoogle Scholar
  • 74 Tauchmanovà L, Rossi R, Biondi B et al.. Patients with subclinical Cushing's syndrome due to adrenal adenoma have increased cardiovascular risk.  J Clin Endocrinol Metab. 2002;  87(11) 4872-4878
    CrossrefPubMedGoogle Scholar
  • 75 Arnaldi G, Angeli A, Atkinson A B et al.. Diagnosis and complications of Cushing's syndrome: a consensus statement.  J Clin Endocrinol Metab. 2003;  88(12) 5593-5602
    CrossrefPubMedGoogle Scholar

Giovanni TargherM.D. 

Section of Endocrinology, Department of Biomedical and Surgical Sciences, University of Verona

Ospedale Civile Maggiore, Piazzale Stefani, 1, 37126 Verona, Italy

Email: giovanni.targher@univr.it

      >