Abstract
Patients with active Cushing’s syndrome have an increased thrombotic tendency. We chose to reassess the mechanism underlying the thrombophilic state associated with this clinical condition using sensitive markers of coagulation and fibrinolysis activation in 17 patients with active disease. The results were compared with those obtained in 12 Cushing’s patients successfully treated by surgery and in 20 normal individuals. The general pattern of results in patients with active disease was the finding of increased levels of von Willebrand factor (VWF: Ag), a marker of enhanced metabolic function of endothelial cells (VWF:Ag 181±42 vs 110±43, p<0.001 in normal subjects), accompanied by signs of heightened thrombin and plasmin generation, expressed by high levels of thrombin-antithrombin (TAT 5.59±3.6 vs 3.06±0.92 ng/ml in controls, p<0.01) and plasmin-antiplasmin complexes (PAP 407±176 vs 245±67 ng/ml in controls, p<0.01). VWF:Ag and TAT values were significantly higher in hypertensive than in normotensive patients with active disease (205±40 vs 155±26 U/dl, p<0.05 and 7.49±3.7 vs 3.45±1.8, p<0.01, respectively). Plasma levels of plasminogen activator inhibitor type 1 were higher, though not to a statistically significant extent, in patients with active disease compared to controls (12.8±12.3 vs 5.6±7.4 IU/ml, NS) and positively correlated with body mass index (r=0.66, p<0.01). After surgical control of Cushing’s syndrome, there was a partial or complete reversal of the abnormalities to values similar to those found in normal individuals. Our data suggest that the thrombophilic state present in patients with active Cushing’s syndrome is related to an enhanced metabolic function of endothelial cells; this in turn may be caused by an heightened production of thrombin with secondary hyperfibrinolysis. Primary prophylaxis with anticoagulants is recommended in these patients when they are exposed to a thrombophilic condition such as surgery.
Similar content being viewed by others
References
Pezzulich R.A., Mannix H. Immediate complications of adrenal surgery. Ann. Surg. 1970, 172: 125–130.
Blichert-Toft M., Bargerskov A., Lockwood K., Hasner E. Operative treatment, surgical approach and related complication in 195 operations upon the adrenal glands. Surg. Gynecol. Obstet. 1972, 135: 261–266.
Sjoberg H.E., Blombäck M., Granberg P.O. Thromboembolic complications, heparin treatment and increase in coagulation factors in Cushing’s syndrome. Acta Med. Scand. 1976, 199: 95–98.
La Brocca A., Terzolo M., Pia A., Paccotti P., De Giuli P., Angeli A. Recurrent thromboembolism as a hallmark of Cushing’s syndrome. J. Endocrinol. Invest. 1997, 20: 211–214.
Diez J.J., Iglesias P. Pulmonary thromboembolism after inferior petrosal sinus sampling in Cushing’s syndrome. Clin. Endocrinol. 1997, 46: 775–777.
Mizokami T., Okamura K., Sato K., Kuroda T., Sadoshima S., Fujishima M. Risk factors for brain infarction in patients with Cushing’s disease. Case reports. Angiology 1996, 47: 1011–1017.
Jackson J.A., Trowbridge A., Smigiel M. Fatal pulmonary thromboembolism after successful transsphenoidal hypophysectomy for Cushing’s disease. South Med. J. 1990, 83: 960–996.
Nichols R. Concurrent illness and complications associated with canine hyperadrenocorticism. Probl. Vet. Med. 1990, 2: 565–572.
Isacson S. Effect of prednisolone on the coagulation and fibrinolytic system. Scand. J. Haematol. 1970, 7: 212–221.
Dal Bo Zanon R., Fornasiero L., Boscaro M., Cappellato G., Fabris F., Girolami A. Increased factor VIII associated activities in Cushing’s syndrome: a probable hypercoagulable state. Thromb. Haemost. 1982, 47: 116–117.
Dal Bo Zanon R., Fornasiero L., Boscaro M., Ruffato G., Luzzato G., Fabris F., Girolami A. Clotting changes in Cushing’s syndrome: elevated factor VIII activity. Folia Haematologica 1983, 110: 268–277.
Ikkala E., Myllyla G., Pelkonen R., Rasi V., Viinikka L., Yliokorkala O. Haemostatic parameters in Cushing’s syndrome. Acta Med. Scand. 1985, 217: 507–511.
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: 518–520.
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 Coag. Fibrinol. 1999, 10: 145–151.
Uddhammar A., Rantapaa-Dahlovist S., Nilsson T.K. Plasminogen activator inhibitor and von Willebrand factor in polymyalgia rheumatica. Clin. Rheumatol. 1992, 11: 211–215.
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 Coag. Fibrinol. 1992, 3: 789–793.
Huges A., McVerry B.A., Wilkinson L., Goldstone A.H., Lewis D., Bloom A. Diabetes, a hypercoagulable state? Haemostatic variables in newly diagnosed type 2 diabetic patients. Acta Haematol. 1983, 69: 254–259.
Boneu B., Durand D., Connillon F., Charlet J.P., Bierme R., Sue G.M. Increased level in factor VIII complex in severe arterial hypertension. Haemostasis 1978, 7: 332–338.
Oikarinen A., Hoythya M., Jarvinen M. Dexamethasone-induced plasminogen activator inhibitor: characterization, purification and preparation of monoclonal anti-bodies. Arch. Dermatol. Res. 1990, 282: 153–158.
Laug W.E. Glucocorticoids inhibit plasminogen activator production by endothelial cells. Thromb. Haemost. 1983, 50: 888–892.
Barouski-Miller P.A., Gelehrter T.D. Paradoxical effects of glucocorticoids on regulation of plasminogen activator activity of rat hepatoma cells. Cell. Biol. 1982, 79: 2319–232.
Merlini P.A., Bauer K., Mannucci P.M. Laboratory detection of the prethrombotic state. In: Verstraete M., Fuster V., Topol E. J. (Eds.), Cardiovascular Thrombosis. Lippincott-Raven Publisher, Philadelphia, 1998, p. 103.
Invitti C., Pecori Giraldi F., De Martin M., Cavagnini F., Study Group of the Italian Society of Endocrinology on the Pathophysiology of the Hypothalamic-Pituitary-Adrenal Axis. Diagnosis and management of Cushing’s syndrome: results of an Italian multicentre study. J. Clin. Endocrinol. Metab. 1999, 84: 440–448.
Mannucci P.M., Coppola R. Von Willebrand factor. In: Jespersen J., Bertina R.M., Haverkate F. (Eds.), ECAT Assay Procedures. A Manual of Laboratory Techniques. Kluwer Academic Publisher, Lancaster (UK), 1992, p. 71.
Coppola R., Tombesi S., Valentini F., Albertini A., Mannucci P.M. Enzyme linked immunosorbent assay of human factor VII based upon a monoclonal antibody that recognizes the native conformation of the protein. Thromb. Res. 1992, 68: 283–293.
Widgoose P., Nemerson Y., Hansen L.L., Nielsen F.E., Glazer S., Hender U. Measurement of basal levels of factor VIIa in haemophilia A and B patients. Blood 1992, 80: 25–28.
Invitti C., De Martin M., Delitala G., Veldhuis J.D., Cavagnini F. Altered morning and nighttime pulsatile ACTH and cortisol release in polycystic ovary syndrome. Metabolism 1998, 47: 143–148.
Mannucci P.M. Von Willebrand factor: a marker of endothelial damage? Arterioscler. Thromb. Vasc. Biol. 1998, 18: 1359–1362.
Blann A.C., Nagvi T., Waite M., McCollum C.N. Von Willebrand factor and endothelial damage in essential hypertension. J. Hum. Hypertens. 1993, 7: 107–111.
Pedrinelli R., Giampietro O., Carmassi F., Melillo E., Dell’Omo G., Catapano G., Matteucci E., Talarco L., Morale M., De Negri F., Di Bello V. Microalbuminuria and endothelial dysfunction in essential hypertension. Lancet 1994, 344: 14–18.
Lundgren C.H., Brown S.L., Nordt T.K., Sobel B.E., Fujii S. Elaboration of type-1 plasminogen activator inhibitor from adipocytes: A potential pathogenetic link between obesity and cardiovascular disease. Circulation 1996, 93: 106–110.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Fatti, L.M., Bottasso, B., Invitti, C. et al. Markers of activation of coagulation and fibrinolysis in patients with Cushing’s syndrome. J Endocrinol Invest 23, 145–150 (2000). https://doi.org/10.1007/BF03343697
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF03343697