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Anticoagulant Prophylaxis Markedly Reduces Thromboembolic Complications in Cushing’s Syndrome

Department of Internal Medicine (M.B.), Division of Endocrinology, University of Ancona, 60100 Ancona, Italy; and Department of Medical and Surgical Sciences, Division of Endocrinology (N.S., A.S., L.B., F.F.), and Second Chair of Medicine (M.T.S., G.M.P., A.G.), University of Padova, 35128 Padova, Italy

Address all correspondence and requests for reprints to: Marco Boscaro, M.D., Department of Internal Medicine, Division of Endocrinology, University of Ancona, 60100 Torrette, Ancona, Italy. E-mail: . m.boscaro{at}ao-umbertoprimo.marche.it

Abstract

A hypercoagulable state and an increased incidence of thromboembolic complications are reported in Cushing’s syndrome. The hypercoagulable state is related to an increase in plasma clotting factors, especially Factor VIII and von Willebrand factor complex, and to an impairment of fibrinolytic capacity. Retrospective analysis of postoperative thromboembolic events in a large group of patients with Cushing’s syndrome, including 75 patients (group 1) evaluated in the period from 1972–1981 not receiving anticoagulants, and 232 patients (group 2), evaluated in the period from 1982–2000. Patients of group 1 underwent routine hemostatic function, i.e. prothrombin time and activated partial thromboplastine time. Patients of group 2 underwent a thorough investigation as to hemostatic parameters and received prophylactic treatment with heparin and/or warfarin. Patients with Cushing’s syndrome showed various abnormalities of hemostatic parameters. A significant correlation between activated partial thromboplastine time and urinary free cortisol was observed. During follow-up, 15 patients (20%; mean follow-up, 9.4 ± 6.4 yr) of group 1 and 14 (6.0%; mean follow-up, 6.6 ± 4.2 yr) of group 2 showed thromboembolic complications. Of these patients, eight of group 1 and one of group 2 died. Survival analysis demonstrated a significantly higher morbidity and mortality due to thromboembolic events in group 1, not receiving anticoagulant prevention, than in group 2, treated with anticoagulants in the perioperative period until cure of the disease and normalization of clotting parameters. Cushing’s syndrome is associated with a hypercoagulable state. An adequate anticoagulant prophylaxis can reverse this prothrombotic state and avoid postoperative thromboembolic events.

INCREASED COAGULABILITY HAS been observed in both patients treated with glucocorticoids and in those showing endogenous glucocorticoid hypersecretion (1). High levels of circulating glucocorticoids increase plasma clotting factors, especially Factor VIII (FVIII) and von Willebrand factor (vWF) complex, and impair fibrinolytic capacity (2, 3, 4, 5). The hypercoagulable state is considered a crucial factor predisposing patients with Cushing’s syndrome to thromboembolic events, mostly after surgery (3). On the basis of our previous experience, we started at the beginning of 1982 to treat systematically all of our patients with Cushing’s syndrome with postoperative anticoagulant prophylaxis as long as they reached a normalization of clotting parameters. In the present study, we evaluated the occurrence of thromboembolic events in patients with Cushing’s syndrome, before and after the introduction of anticoagulant prevention.

Patients and Methods

Patients

During the last 28 yr, 313 consecutive patients with Cushing’s syndrome were evaluated at the Division of Endocrinology of Padova University. Mean age of patients was 38.4 ± 13.5 yr (range, 8–75 yr); 249 were females, and 64 were males. All patients showed the typical clinical features of Cushing’s syndrome, and the diagnosis was made according to standard criteria (6). Of 313 patients, 203 were diagnosed as having pituitary-dependent Cushing’s disease, 16 pituitary-dependent nodular adrenal hyperplasia, 18 ectopic ACTH production (17 from a lung carcinoid and 1 from a thymoma), 49 adrenal adenoma, 21 adrenal carcinoma, and 6 primary bilateral nodular adrenal hyperplasia.

As the first line treatment, of the 219 patients with pituitary-dependent forms, 166 underwent pituitary microsurgery, 28 underwent bilateral adrenalectomy, 19 had conventional pituitary irradiation, and 6 received medical therapy with serotonin antagonists (7). Patients with adrenocortical adenoma and carcinoma as well as those with ectopic ACTH production underwent surgical removal of the tumors. All patients with primary bilateral nodular adrenal hyperplasia underwent bilateral adrenalectomy. Patients with Cushing’s disease in whom pituitary surgery was not successful (n = 27) or with relapse after cure by pituitary surgery (n = 34) underwent repeat pituitary surgery, pituitary irradiation, bilateral adrenalectomy and/or pharmacological treatment. Similarly, patients in whom pituitary irradiation as the first treatment was not successful (n = 9) or with relapse (n = 7) were treated by bilateral adrenalectomy. Pituitary surgery by a transsphenoidal approach was performed by the same neurosurgeon, and adrenal surgery was performed by the same surgical team by the posterior-lateral approach in all cases. All patients treated by bilateral adrenalectomy received adequate replacement therapy with cortisone acetate or dexamethasone and 9-fluorohydrocortisone. Inhibitors of steroid biosynthesis, such as ketoconazole, aminoglutethimide, metyrapone, and mitotane were administered to 101 patients in an attempt to reduce hypercortisolism before surgery, during and after radiotherapy, or whenever a definitive treatment was delayed (6, 8).

Study design and data collection

Patients were divided into two groups according to the presence or absence of prophylactic treatment with anticoagulant drugs. Group 1 included 75 patients (mean age, 36.6 ± 2.1 yr; 59 females and 16 males), studied in the period from 1972–1981 who had routine coagulation parameters and were not treated with anticoagulants; group 2 included 232 patients (mean age, 38.9 ± 0.9 yr; 184 females and 48 males) evaluated in the period from 1982–2000, who underwent a thorough evaluation as to coagulation parameters by the methods available at the time of the study. At diagnosis, risk factors for thromboembolism, including known cancer, known thrombophilia, pregnancy, recent childbirth, and use of oral contraceptives were similar in the two groups. Patients of group 2 received postoperative antithrombotic prophylaxis with sc unfractionated heparin at doses of 15,000–22,500 U/d for at least 2 wk, based on the type of surgery, severity of the disease, and clotting abnormalities. Six patients evaluated in the period from 1982–2000, with mild hypercortisolism of hypothalamus-pituitary origin and successfully treated with antiserotoninergic drugs (7), did not receive anticoagulant treatment; therefore they were not included in group 2. The two groups were compared for epidemiological data, clinical severity, urinary cortisol levels, and routine coagulation tests (Table 1). Clinical condition was rated as severe or mild as a global judgment according to the number, extent, and clinical significance of the following features: fat distribution, skin lesions, muscle weakness, mood disorder, hypertension, diabetes, hypokalemia, and sex-related disturbances (9, 10).

Informed consent was obtained from all subjects, and the investigation was performed in accordance with the principles of the Declaration of Helsinki.

Laboratory methods

Urinary cortisol. During the first decade, urinary free cortisol was measured by RIA after extraction with dichloromethane, using a commercial kit from Sorin (Saluggia, Italy). Subsequently, a kit from Diagnostic Products Corp. (Los Angeles, CA) was employed. The normal range for both assays was 55–331 nmol/d. There was a good correlation between urinary cortisol results obtained with these assays.

Hemostatic parameters. Before 1982 only routine measurements of hemostatic parameters, i.e. PT and activated partial thromboplastin time (aPTT), were performed. All other coagulation parameter analyses, i.e. FVIII coagulant activity (FVIII:C), vWF antigen (vWF:Ag), vWF ristocetin cofactor activity (vWF:Rcof), euglobin clot lysis time (ELT), plasminogen activator inhibitor (PAI-1) activity, and fibrinogen, were added thereafter. PT was measured by conventional clotting methods using Simplastin General Diagnostic until 1987 and Tromborel S (Dade, Marburg, Germany) thereafter; aPTT was measured by a conventional clotting method using cephaloplastin (Dade). FVIII:C was measured using a one-stage method with cephaloplastin as activated cephalin (11); vWF:Ag was determined using an ELISA method (12); vWF:Rcof was assessed using normal washed, formalin-fixed platelets, and 1 mg/ml (final concentration) ristocetin (13); ELT was measured according to the method proposed by Cliffton and Cannamela (14) modified by our group (15); PAI-1 activity was carried out using chromogenic substrates (Stachrom PAI, Diagnostica Stago, Asnières, France) as described (16). Fibrinogen was measured in a kinetic method (Fibrinogen Kinetic, Roche Molecular Biochemicals Italy, Milan, Italy) (17).

Statistical analysis

Results are given as mean ± SD or median and range. Correlations were examined by linear regression analysis. Comparisons between variables were tested with Pearson’s ² test and t test, as appropriate. Survival analysis was carried out by the Kaplan-Meier method and compared with the log-rank test. For determination of factors related to overall survival, a Cox proportional hazards model was used. P value less than 0.05 was considered statistically significant.

Results

No statistically significant differences in clinical, biochemical, and hormonal data, or etiology of Cushing’s syndrome were observed between group 1, not receiving anticoagulant therapy, and group 2, treated with anticoagulant prophylaxis (Table 1). Urinary free cortisol levels were similar in group 1 and group 2 (1520.5 ± 131.4 nmol/d and 1653.8 ± 146.0 nmol/d, respectively). Mean PT and aPTT values were similar between the two groups (PT, 94.8 ± 8.2% in group 1 and 96.4 ± 9.9% in group 2; aPTT, 29.9 ± 0.6 sec in group 1 and 28.2 ± 0.4 sec in group 2). A significant inverse correlation between aPTT values and urinary cortisol levels was observed (r = -0.34; P < 0.001). Patients of group 2 compared with controls, disclosed significantly different values of clotting and fibrinolytic parameters all compatible with a prothrombotic state (Table 2).

Thromboembolic complications in group 1

During follow-up, 15 patients (20%; 13 females and 2 males; median age, 51 yr; range, 39–68 yr) of group 1 showed thromboembolic complications (deep vein thrombosis or pulmonary thromboembolism), and 8 of these (10.7%; all females; median age, 48.5 yr; range, 39–55 yr) died (Table 3). Of these patients, 14 had pituitary-dependent Cushing’s syndrome, and 1 had an adrenal adenoma. Median urinary cortisol levels were 949.4 nmol/d (range, 441.6–1512.4); median PT and aPTT values were 90% (range, 82–100%) and 26 sec (range, 24–29 sec), respectively. Thromboembolic events occurred in the postoperative period (range, 8 d to 3 months from surgery) in nine patients (pituitary surgery in one case, unilateral adrenalectomy in two, bilateral adrenalectomy in six). The remaining six patients with thromboembolic complications had persistent hypercortisolism despite medical therapy with mitotane.

In group 2, 14 patients (6.0%; 11 females and 3 males; median age, 57 yr; range, 42–72 yr) had thromboembolic complications, and only 1 (0.4%; 72-yr-old female) died (Table 3). Median baseline urinary cortisol levels were 1015.6 nmol/d (range, 883.2–1242.0 nmol/d); median PT and aPTT values were 100% (range, 94–108%) and 24 sec (range, 23–27 sec), respectively. The patient who died underwent bilateral adrenalectomy as the last therapeutic approach for a severe form of pituitary-dependent Cushing’s syndrome. The other 13 patients, who showed nonfatal thromboembolic events, had pituitary-dependent Cushing’s syndrome in 12 cases and adrenal adenoma in 1. Of 14 patients, 9 patients, including the one who died, showed thromboembolic complications within 3 months from operation (pituitary surgery in 4, unilateral adrenalectomy in 1, bilateral adrenalectomy in 4; postoperative period range, 12 d to 3 months). All 8 patients who underwent pituitary surgery had slight to moderate hypercortisolism at the time of thromboembolic event, despite medical therapy (mitotane in 2 patients and ketoconazole in 6). One patient (patient 12) showed thromboembolic complications during treatment with heparin, whereas the remaining 13 patients were on warfarin at the time of thromboembolic event. No bleeding events were observed in any patients during anticoagulant treatment.

Survival analysis showed a significantly higher rate of thromboembolic events in group 1 than in group 2 (log-rank, 13.7; P < 0.001) and a significantly higher mortality rate due to thromboembolic events in group 1, not receiving anticoagulant prevention, than in group 2 (log-rank, 28; P < 0.00001). At variance, survival rate was not influenced by sex, age, etiology of Cushing’s syndrome, or severity of disease, as assessed by log-rank analysis.

Excluding the six patients of group 2 with persistent thrombophilia in whom anticoagulant prophylaxis was maintained after successful treatment of hypercortisolism, all patients in whom cure of the disease was achieved showed a concomitant normalization of PT and aPTT levels.

Discussion

Cushing’s syndrome is an uncommon syndrome. Because of its rarity, it is difficult to carry out prognostic studies and identify factors influencing patients’ outcome. In our specialized center, we had the possibility to evaluate retrospectively in a large population of patients with endogenous hypercortisolism the efficacy of an accurate assessment of hemostatic parameters and of a standard anticoagulant treatment in preventing thromboembolic complications of the disease. The results of our study confirm that patients with Cushing’s syndrome have a prothrombotic state related to abnormalities in FVIII and vWF, associated with higher levels of PAI-1 and reduced fibrinolytic capacity (1, 2, 3, 4, 5, 18, 19). Interestingly, aPTT values showed an inverse correlation with urinary cortisol levels, suggesting the use of aPTT as a convenient routine hemostatic parameter.

Before any prophylactic treatment with anticoagulant drugs, 10% of our patients with Cushing’s syndrome died because of thromboembolism, and 10% had vascular morbidity. After the introduction of the screening of hemostatic parameters and postoperative antithrombotic prophylaxis, morbidity and mortality due to thromboembolic events dropped to 6% and 0.4%, respectively. Because age, sex, etiology of Cushing’s syndrome, urinary cortisol levels at the time of complications, and risk factors for thromboembolism were similar in the two groups of patients, it is conceivable that the different morbidity and mortality rates rely in the thrombophilic state of patients not receiving anticoagulant prophylaxis.

Of 29 thromboembolic events (including patients of group 1 and group 2), 18 (62%) occurred within 3 months after surgery. Indeed, patients with Cushing’s syndrome show a period of increased thrombotic risk early after surgery due to worsening of clotting profile (19). A higher mortality rate during the first year after the initial admission than during the following years has been reported by Lindholm et al. (20) in a large group of patients with Cushing’s syndrome, but the causes of death were not indicated.

Sixteen (8 of group 1 and 8 of group 2) of 29 patients with thromboembolic events (55%) had persistent hypercortisolism after surgery that was not completely controlled by treatment or showed relapse after years of apparent cure. An influence of pharmacotherapy on thrombotic events is unlikely, because mitotane increases bleeding time acting on platelet function (21), and ketoconazole does not affect platelet aggregation (22). As to patients with adrenal carcinoma and ectopic ACTH source, malignancy itself may induce a thromboembolic state (23) and influence mortality. However, none of our patients who died for thromboembolic events had malignancy. Surgical techniques and perioperative management of patients were similar in the two groups of patients. However, we cannot exclude that an improvement in surgical practice as well as general measures to reduce venous thromboembolism contributed to the better outcome of group 2.

In conclusion, the evidence of a severe prothrombotic state in Cushing’s syndrome and the dramatic reduction of mortality in patients with an adequate anticoagulant treatment strongly suggest the use of anticoagulant prophylaxis to avoid thromboembolic events. In case confirmatory studies allow to incorporate the anticoagulant prophylaxis for Cushing’s syndrome into general practice, further prospective investigations will optimize anticoagulant protocols in this condition.

Acknowledgments

Footnotes

This work was supported by in part by Grant 9906153187 from Ministero Istruzione Università Ricerca, Rome, Italy.

Abbreviations: aPTT, Activated partial thromboplastin time; ELT, euglobin clot lysis time; FVIII, factor VIII; FVIII:C, FVIII coagulant activity; PAI-1, plasminogen activator inhibitor; PT, prothrombin time; vWF, von Willebrand factor; vWF:Ag, vWF antigen; vWF:Rcof, vWF ristocetin cofactor activity.

Received February 8, 2002.

Accepted April 16, 2002.

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