Horm Metab Res 2017; 49(05): 365-371
DOI: 10.1055/s-0043-100113
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

Coagulation Profile in Patients with Different Etiologies for Cushing Syndrome: A Prospective Observational Study

Amit Tirosh
1   Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
,
Maya Lodish
1   Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
,
Charalampos Lyssikatos
1   Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
,
Elena Belyavskaya
1   Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
,
Richard A. Feelders
3   Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands
,
Constantine A. Stratakis
1   Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
› Author Affiliations
Further Information

Publication History

received 19 August 2016

accepted 13 December 2016

Publication Date:
22 February 2017 (online)

Abstract

Previous studies reported a higher prevalence of venous-thromboembolic events among patients with Cushing disease (CD) compared to those with ACTH-independent Cushing syndrome (CS) from adrenal sources. The objective of the current study was to evaluate the coagulation profile of patients with CS from different etiologies. A prospective observational study was conducted at a clinical research center. The study included adult patients admitted for evaluation of suspected CS (n=85), that were divided into 3 groups: CD (n=22), ACTH-independent CS from an adrenal tumor/hyperplasia (adrenal CS, n=21), and a control group consisting of subjects with negative screening for CS (rule-out CS, n=42). Coagulation profiles were drawn before and 8.5±4.3 months after surgery (trans-sphenoidal or adrenalectomy, n=18), and included fibrinogen, Factor VIII (FVIII), von Willebrand factor antigen (vWF:Ag), plasminogen activator inhibitor-1 (PAI-1), antithrombin III (ATIII), Protein C (PC), Protein S (PS), α2-antiplasmin (α2AP), and aPTT measurements. Patients with CD had higher baseline mean cortisol levels, ATIII activity and vWF:Ag levels compared with adrenal CS. Differences in ATIII activity and vWF:Ag levels remained even after controlling for BMI, and ATIII after also controlling for 24-h urinary free cortisol collections. Our study showed for the first time the differences in coagulation profiles between various etiologies of CS. We assume that the higher cortisol burden among CD patients may explain the differences found in the coagulation profile as well as the higher risk for VTE compared with primary adrenal CS patients.

 
  • References

  • 1 Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet (London, England) 2015; 386: 913-927
  • 2 Colao A, Pivonello R, Spiezia S, Faggiano A, Ferone D, Filippella M, Marzullo P, Cerbone G, Siciliani M, Lombardi G. Persistence of increased cardiovascular risk in patients with Cushing’s disease after five years of successful cure. J Clin Endocrinol Metab 1999; 84: 2664-2672
  • 3 Stuijver DJF, van Zaane B, Feelders RA, Debeij J, Cannegieter SC, Hermus AR, van den Berg G, Pereira AM, de Herder WW, Wagenmakers MAEM, Kerstens MN, Zelissen PMJ, Fliers E, Schaper N, Drent ML, Dekkers OM, Gerdes VEA. Incidence of venous thromboembolism in patients with Cushing’s syndrome: a multicenter cohort study. J Clin Endocrinol Metab 2011; 96: 3525-3532
  • 4 Van Zaane B, Nur E, Squizzato A, Dekkers OM, Twickler MTB, Fliers E, Gerdes VEA, Büller HR, Brandjes DPM. Hypercoagulable state in Cushing’s syndrome: a systematic review. J Clin Endocrinol Metab 2009; 94: 2743-2750
  • 5 Johannesdottir Sa, Horváth-Puhó E, Dekkers OM, Cannegieter SC, Jørgensen JOL, Ehrenstein V, Vandenbroucke JP, Pedersen L, Sørensen HT. Use of Glucocorticoids and Risk of Venous Thromboembolism: A Nationwide Population-Based Case-Control Study. JAMA Intern Med 2013; 173: 1-10
  • 6 Stuijver DJF, Majoor CJ, van Zaane B, Souverein PC, de Boer A, Dekkers OM, Büller HR, Gerdes VEA. Use of oral glucocorticoids and the risk of pulmonary embolism. CHEST J 2013; 143: 1337
  • 7 Van Der Pas R, Leebeek FWG, Hofland LJ, De Herder WW, Feelders RA. Hypercoagulability in Cushing’s syndrome: Prevalence, pathogenesis and treatment. Clin Endocrinol (Oxf) 2013; 78: 481-488
  • 8 Manetti L, Bogazzi F, Giovannetti C, Raffaelli V, Genovesi M, Pellegrini G, Ruocco L, Iannelli A, Martino E. Changes in coagulation indexes and occurrence of venous thromboembolism in patients with Cushing’s syndrome: results from a prospective study before and after surgery. Eur J Endocrinol 2010; 163: 783-791
  • 9 Barbot M, Daidone V, Zilio M, Albiger N, Mazzai L, Sartori MT, Frigo AC, Scanarini M, Denaro L, Boscaro M, Casonato S, Ceccato F, Scaroni C. Perioperative thromboprophylaxis in Cushing’s disease: What we did and what we are doing?. Pituitary 2015; 18: 487-493
  • 10 Kastelan D, Dusek T, Kraljevic I, Polasek O, Giljevic Z, Solak M, Salek SZ, Jelcic J, Aganovic I, Korsic M. Hypercoagulability in Cushing’s syndrome: the role of specific haemostatic and fibrinolytic markers. Endocrine 2009; 36: 70-74
  • 11 Boscaro M, Sonino N, Scarda A, Barzon L, Fallo F, Sartori MT, Patrassi GM, Girolami A. Anticoagulant prophylaxis markedly reduces thromboembolic complications in Cushing’s syndrome. J Clin Endocrinol Metab 2002; 87: 3662-3666
  • 12 Isidori AM, Minnetti M, Sbardella E, Graziadio C, Grossman A. Mechanisms in endocrinology: The spectrum of haemostatic abnormalities in glucocorticoid excess and defect. Eur J Endocrinol 2015; 3: EJE-15-0308
  • 13 Coelho MCA, Santos CV, Vieira Neto L, Gadelha MR. Adverse effects of glucocorticoids: coagulopathy. Eur J Endocrinol 2015; 173: M11-M21
  • 14 Zeiger MA, Thompson GB, Duh Q-Y, Hamrahian AH, Angelos P, Elaraj D, Fishman E, Kharlip J. American association of clinical endocrinologists and american association of endocrine surgeons medical guidelines for the management of adrenal incidentalomas: executive summary of recommendations. Endocr Pract 15: 450-453
  • 15 Correa R, Salpea P, Stratakis C. a. Carney complex: an update. Eur J Endocrinol 2015; 173: M85-M97
  • 16 Patrassi GM, Sartori MT, Viero ML, 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: 789-793
  • 17 Patrassi GM, 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: 518-520
  • 18 Dal Bo Zanon, Fornasiero R, Boscaro L, Cappellato M, Fabris G, Girolami F. A. Increased factor VIII associated activities in Cushing’s syndrome: a probable hypercoagulable state. Thromb Haemost 1982; 47: 116-117
  • 19 Van Der Pas R, De Bruin C, Leebeek FWG, De Maat MPM, Rijken DC, Pereira AM, Romijn JA, Netea-Maier RT, Hermus AR, Zelissen PMJ, De Jong FH, Van Der Lely AJ, De Herder WW, Lamberts SWJ, Hofland LJ, Feelders RA. The hypercoagulable state in Cushing’s disease is associated with increased levels of procoagulant factors and impaired fibrinolysis, but is not reversible after short-term biochemical remission induced by medical therapy. J Clin Endocrinol Metab 2012; 97: 1303-1310
  • 20 Fatti LM, Bottasso B, Invitti C, Coppola R, Cavagnini F, Mannucci PM. Markers of activation of coagulation and fibrinolysis in patients with Cushing’s syndrome. J Endocrinol Invest 2000; 23: 145-150
  • 21 Casonato A, Pontara E, Boscaro M, Sonino N, Sartorello F, Ferasin S, Girolami A. Abnormalities of von Willebrand factor are also part of the prothrombotic state of Cushing’s syndrome. Blood Coagul Fibrinolysis 1999; 10: 145-151
  • 22 Tauchmanovà L, Rossi R, Biondi B, Pulcrano M, Nuzzo V, Palmieri E-A, Fazio S, Lombardi G. Patients with subclinical Cushing’s syndrome due to adrenal adenoma have increased cardiovascular risk. J Clin Endocrinol Metab 2002; 87: 4872-4878
  • 23 Erem C, Nuhoglu I, Yilmaz M, Kocak M, Demirel A, Ucuncu O, Onder Ersoz H. 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: 169-174
  • 24 Allen KS, Sawheny E, Kinasewitz GT. Anticoagulant modulation of inflammation in severe sepsis. World J. Crit care Med 2015; 4: 105-115
  • 25 Mertens I, Considine RV, Van der Planken M, Van Gaal LF. Hemostasis and fibrinolysis in non-diabetic overweight and obese men and women. Is there still a role for leptin? Eur J Endocrinol 2006; 155: 477-484
  • 26 Heijnen CJ, Zijlstra J, Kavelaars A, Croiset G, Ballieux RE. Modulation of the immune response by POMC-derived peptides. I. Influence on proliferation of human lymphocytes. Brain Behav Immun 1987; 1: 284-291
  • 27 Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med 2010; 38: S26-S34