The haemostatic system in acromegaly: a single-centre case–control study

Abstract

Purpose

Although the mortality from acromegaly is due in most cases to an increased cardiovascular risk, no study has globally evaluated the haemostatic balance in acromegaly to ascertain the presence of hypercoagulability. We endeavoured to assess the overall coagulation profile in patients with acromegaly using both traditional and global coagulation assays.

Methods

Consecutive outpatients with a diagnosis of acromegaly were enrolled and matched with healthy subjects. Whole blood thromboelastometry and impedance aggregometry, procoagulant, anticoagulant and fibrinolytic factors, as well as thrombin-generation assay and circulating endothelium-derived microvesicles were measured.

Results

Forty patients (M/F 14/26, median age 59 years) with either new diagnosis (naïve, 14 cases) or treated acromegaly (26 cases) were enrolled in this study. Median time from diagnosis was 11 years. Levels of factor VIII and fibrinogen were significantly higher in acromegalic patients vs. controls (p = 0.029 and < 0.003, respectively). Overall, thromboelastometry parameters showed a faster coagulation formation with a more stable clot. Acromegaly patients showed significantly higher endogenous thrombin potential [ETP] and thrombin peak compared to controls (p = 0.016 and p < 0.001, respectively). ETP remained significantly higher (p < 0.001) when thrombomodulin was added. Endothelial-derived microvesicles were significantly higher in acromegaly patients than controls (52 [40.5–67] MVs/µL and 30 [18–80] MVs/µL, p = 0.03). Patients with untreated (naïve) acromegaly showed significantly reduced ETP with and without thrombomodulin vs. patients with treated acromegaly (p = 0.01).

Conclusion

Hypercoagulability in acromegaly is mainly due to higher levels of fibrinogen, factor VIII and thrombin generation, and appears to be more linked to the chronic phase of the disease.

This is a preview of subscription content, log in to check access.

References

  1. 1.

    Melmed S (2006) Medical progress: acromegaly. N Engl J Med 355:2558–2573

    CAS  Article  Google Scholar 

  2. 2.

    Vilar L, Naves LA, Costa SS, Abdalla LF, Coelho CE, Casulari LA (2007) Increase of classic and non-classic cardiovascular risk factors in patients with acromegaly. Endocr Pract 13:363–372

    Article  Google Scholar 

  3. 3.

    Rajasoorya C, Holdaway IM, Wrightson P, Scott DJ, Ibbertson HK (1994) Determinants of clinical outcome and survival in acromegaly. Clin Endocrinol (Oxf) 41:95–102

    CAS  Article  Google Scholar 

  4. 4.

    Erem C, Nuhoglu I, Kocak M, Yilmaz M, Sipahi ST, Ucuncu O, Ersoz HO (2008) Blood coagulation and fibrinolysis in patients with acromegaly: increate plasminogen activator inhibitor-1 (PAI-1), decreased tissue factor pathway inhibitor (TFPI) and an inverse correlation between growth hormone and TFPI. Endocrine 33:270–276

    CAS  Article  Google Scholar 

  5. 5.

    Landin-Whilelmsen K, Tengborn L, Wilhelmsen B-Å (1997) Elevated fibrinogen levels decrease following treatment of acromegaly. Clin Endocrinol 46:69–74

    Article  Google Scholar 

  6. 6.

    Delaroudis SP, Efstathiadou ZA, Koukoulis GN, Kita MD, Farmakiotis D, Dara OG, Goulis DG, Makedou A, Makris P, Slavakis A, Avramides AI (2008) Amelioration of cardiovascular risk factors with partial biochemical control of acromegaly. Clin Endocrinol (Oxf) 69:279–284

    CAS  Article  Google Scholar 

  7. 7.

    Sartorio A, Cattaneo M, Bucciarelli P, Bottasso B, Porretti S, Epaminonda P, Faglia G, Arosio M (2000) Alterations of haemostatic and fibrinolytic markers in adult patients with growth hormone deficiency and with acromegaly. Exp Clin Endocrinol Diabetes 108:486–492

    CAS  Article  Google Scholar 

  8. 8.

    Colak A, Yılmaz H, Temel Y, Demirpence M, Simsek N, Karademirci İ, Bozkurt U, Yasar E (2016) Coagulation parameters and platelet function analysis in patients with acromegaly. J Endocrinol Investig 39:97–101

    CAS  Article  Google Scholar 

  9. 9.

    Wildbrett J, Hanefeld M, Fucker K, Pinzer T, Bergmann S, Siegert G, Breidert M (1997) Anomalies of lipoprotein pattern and fibrinolysis in acromegalic patients: relation to growth hormone levels and insulin-like growth factor I. Exp Clin Endocrinol Diabetes 301:331–335

    Google Scholar 

  10. 10.

    Koutroumpi S, Spiezia L, Albiger N, Barbot M, Bon M, Maggiolo S, Gavasso S, Simioni P, Frigo A, Mantero F, Scaroni C (2014) Thrombin generation in Cushing's Syndrome: do the conventional clotting indices tell the whole truth? Pituitary 17:68–75

    CAS  Article  Google Scholar 

  11. 11.

    Ceccato F, Lizzul L, Zilio M, Barbot M, Denaro L, Emanuelli E, Alessio L, Rolma G, Manara R, Saller A, Boscaro M, Scaroni C (2016) Medical treatment for acromegaly does not increase the risk of central adrenal insufficiency: a long-term follow-up study. Horm Metab Res 48:514–519

    CAS  Article  Google Scholar 

  12. 12.

    Campello E, Spiezia L, Radu CM, Bulato C, Gavasso S, Tormene D, Woodhams B, Dalla Valle F, Simioni P (2016) Circulating microparticles and the risk of thrombosis in inherited deficiencies of antithrombin, protein C and protein S. Thromb Haemost 115:81–88

    Article  Google Scholar 

  13. 13.

    Bulato C, Radu CM, Campello E, Gavasso S, Spiezia L, Tormene D, Simioni P (2016) New prothrombin mutation (Arg596Trp, prothrombin Padua 2) associated with venous thromboembolism. Arterioscler Thromb Vasc Biol 36:1022–1029

    CAS  Article  Google Scholar 

  14. 14.

    Campello E, Spiezia L, Zabeo E, Maggiolo S, Vettor R, Simioni P (2015) Hypercoagulability detected by whole blood thromboelastometry (ROTEM) and impedance aggregometry (MULTIPLATE) in obese patients. Thromb Res 135:548–553

    CAS  Article  Google Scholar 

  15. 15.

    Hemker HC, Giesen P, AlDieri R, Regnault V, de Smed E, Wagenvoord R, Lecompte T, Béguin S (2002) The calibrated automated thrombogram (CAT): a universal routine test for hyper-and hypocoagulability. Pathophysiol Haemost Thromb 32:249–253

    CAS  Article  Google Scholar 

  16. 16.

    Russo FP, Zanetto A, Campello E, Bulato C, Shalaby S, Spiezia L, Gavasso S, Franceschet E, Radu C, Senzolo M, Burra P, Lisman T, Simioni P (2018) Reversal of hypercoagulability in patients with HCV-related cirrhosis after treatment with direct-acting antivirals. Liver Int 38:2210–2218

    CAS  Article  Google Scholar 

  17. 17.

    Campello E, Radu CM, Duner E, Lombardi AM, Spiezia L, Bendo R, Ferrari S, Simioni P, Fabris F (2018) Activated platelet-derived and leukocyte-derived circulating microparticles and the risk of thrombosis in heparin-induced thrombocytopenia: a role for PF4-bearing microparticles? Cytom Part B Clin Cytom 94:334–341

    CAS  Article  Google Scholar 

  18. 18.

    Kim EH, Oh MC, Lee EJ, Kim SH (2012) Predicting long-term remission by measuring immediate postoperative growth hormone levels and oral glucose tolerance test in acromegaly. Neurosurgery 70:1106–1113

    Article  Google Scholar 

  19. 19.

    Vitale G, Pivonello R, Galderisi M, D’Errico A, Spinelli L, Lupoli G, Lombardi G, Colao A (2001) Cardiovascular complications in acromegaly: methods of assessment. Pituitary 4:251–257

    CAS  Article  Google Scholar 

  20. 20.

    Negrev N, Nyagolov Y, Stanchewa E (1995) Somatotropin and somatostatin effects on vitamin K-dependent plasma coagulation factors. Eur J Pharmacol 277:145–149

    CAS  Article  Google Scholar 

  21. 21.

    Sesmilo G, Fairfield WP, Katznelson L, Pulaski K, Freda PU, Bonert V, Dimaraki E, Stavrou S, Vance ML, Hayden D, Klibanski A (2002) Cardiovascular risk factors in acromegaly before and after normalization of serum IGF-I levels with the GH antagonist pegvisomant. J Clin Endocrinol Metab 87:1692–1699

    CAS  Article  Google Scholar 

  22. 22.

    Verhelst J, Velkeniers B, Maiter D, Haentjens P, T'Sjoen G, Rietzschel E, Corvilain B, Abrams P, Nobels F, Abs R, Bex M (2013) Active acromegaly is associated with decreased hs-CRP and NT-proBNP serum levels: insights from the Belgian registry of acromegaly. Eur J Endocrinol 168:177–184

    CAS  Article  Google Scholar 

  23. 23.

    Caicedo D, Díaz O, Devesa P, Devesa J (2018) Growth hormone (GH) and cardiovascular system. Int J Mol Sci 19:E290

    Article  Google Scholar 

  24. 24.

    Colao A, Di Somma C, Savanelli MC, De Leo M, Lombardi G (2006) Beginning to end: cardiovascular implications of growth hormone (GH) deficiency and GH therapy. Growth Horm IGF Res 16:S41–S48

    CAS  Article  Google Scholar 

  25. 25.

    Olarescu NC, Ueland T, Godang K, Lindberg-Larsen R, Jørgensen JO, Bollerslev J (2013) Inflammatory adipokines contribute to insulin resistance in active acromegaly and respond differently to different treatment modalities. Eur J Endocrinol 170:39–48

    Article  Google Scholar 

  26. 26.

    Ronchi CL, Varca V, Beck-Peccoz P, Orsi E, Donadio F, Baccarelli A, Giavoli C, Ferrante E, Lania A, Spada A, Arosio M (2006) Comparison between 6-year therapy with long-acting somatostatin analogs and successful surgery in acromegaly: effects on cardiovascular risk factors. J Clin Endocrinol Metab 91:121–128

    CAS  Article  Google Scholar 

  27. 27.

    van Thiel SW, Romijn JA, Biermasz NR, Ballieux BE, Frölich M, Smit JW, Corssmit EP, Roelfsema F, Pereira AM (2004) Octreotide long-acting repeatable and lanreotide Autogel are equally effective in controlling growth hormone secretion in acromegalic patients. Eur J Endocrinol 150:489–495

    Article  Google Scholar 

  28. 28.

    Campello E, Spiezia L, Radu CM, Simioni P (2016) Microparticles as biomarkers of venous thromboembolic events. Biomark Med 10:743–755

    CAS  Article  Google Scholar 

  29. 29.

    Yuana Y, Sturk A, Nieuwland R (2013) Extracellular vesicles in physiological and pathological conditions. Blood Rev 27:31–39

    CAS  Article  Google Scholar 

Download references

Acknowledgements

The authors would like to thank M. Fadin, G. Saggiorato, P. Zerbinati, and F. Sartorello for coagulation and fibrinolytic factors analyses. The authors are indebted to F. Nde for English grammar revision.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Author information

Affiliations

Authors

Contributions

EC, MB, CS and PS contributed to the study concept and design; MM, MB, GV and FC contributed to patients enrolment and clinical data collection; CMR, LS and SG contributed to the laboratory analyses; EC and MB contributed to the statistical analysis and drafted the manuscript; FC, CS and PS critically reviewed the manuscript. All authors contributed to the interpretation of the results and approved the final version of the manuscript.

Corresponding author

Correspondence to P. Simioni.

Ethics declarations

Conflict of interest

The authors disclose no potential conflicts of interest.

Ethical approval

The research conforms to the principles of the Declaration of Helsinki, revised in 2000. Padua University Hospital’s Ethics Committee approved the protocol.

Informed consent

Written informed consent was obtained from all patients.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 13 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Campello, E., Marobin, M., Barbot, M. et al. The haemostatic system in acromegaly: a single-centre case–control study. J Endocrinol Invest 43, 1009–1018 (2020). https://doi.org/10.1007/s40618-020-01186-9

Download citation

Keywords

  • Endocrine disorders
  • Hypercoagulability
  • Inflammation
  • Microvesicles
  • Thrombin generation