Hypercoagulability in Cushing Syndrome, Prevalence of Thrombotic Events

A Large, Single-Center, Retrospective Study

Maria Gabriela Suarez; Madeleine Stack; Jose Miguel Hinojosa-Amaya; Michael D. Mitchell; Elena V. Varlamov; Chris G. Yedinak; Justin S. Cetas; Brett Sheppard; Maria Fleseriu


J Endo Soc. 2020;4(2) 

In This Article


Demographics of Patients With Cushing Syndrome by Etiology

Of 208 patients included, 165 (79.3%) were women, with a mean age at presentation of 44 (± 14.7) years. All patients were overweight or obese with a mean body mass index (BMI) of 33.9 kg/m2 (± 8.4), 147 (70.7%) had hypertension and 87 (41.8%) had diabetes mellitus (Table 1).

Type of Treatment for Cushing Syndrome

The majority of individuals with CD were treated with TSS only. However, after failed TSS, BLA was more common than UA. Five patients underwent only a UA and 4 patients only a BLA. Pituitary radiation was used as adjunctive treatment for tumor growth, treatment failure, or Nelson syndrome. Medical therapy was used when the patient was a poor surgical candidate or refused surgery. Of the 14 patients diagnosed with ACS, 3 underwent BLA, 4 underwent UA, 4 underwent TSS followed by UA, and 3 were treated medically. Of the 8 patients with ECS, 3 had initial surgery for the ectopic source and then other therapies, 3 were treated with medical therapy, 1 underwent UA, 3 underwent BLA, and 1 opted for no therapy (Table 1).

Types of Thrombotic Events

Thirty-nine (18.2%) patients had a TE; however, there were a total of 56 TEs because 12 patients had more than 1 TE. The most common events were extremity DVT (32%), cerebrovascular accident (27%), followed by MI (21%) and PE (14%). The extremity TEs found in this study were 3 (5%) bilateral lower extremity (LE) DVTs, 11 (20%) unilateral LE DVTs, 1 (2%) bilateral upper extremity (UE) DVT, and 6 (11%) unilateral UE DVTs. Of the 56 TEs found in our study, 27 (48%) cases were arterial and 29 (52%) cases were venous.

Sex, age, BMI, smoking status, estrogen/testosterone supplementation, diabetes mellitus, and hypertension were not found to significantly increase the risk of developing a TE (Table 2). However, all 23 patients who had a UE DVT had a peripherally inserted central catheter (PICC); therefore, patients with a PICC line are 46% more likely to develop a UE DVT.

From the patients who had a TE, the majority underwent only TSS. However, one-third of patients who underwent BLA alone or TSS + BLA had a TE. We found that 14 (38.8%) of 36 patients who underwent a BLA had a TE, with a calculated OR of 3.74 (95% CI 1.69–8.27). We did not find an increased risk of TE in patients who underwent TSS + UA, UA alone, medical therapy, or those that did not want to pursue therapy (Table 3).

Timing of Thrombotic Events

Of all patients evaluated in this study, 39 had a TE. As previously indicated, 2 patients were excluded from this particular analysis because the date of their TE was unknown. We found that 15 (40.5%) patients had a TE within the first 60 days after surgery, 5 (13.51%) patients between the first 61 days and 3 years after surgery, and 5 (13.51%) more than 3 years after surgery. We also found that 12 (32.43%) patients had a TE before surgery (Figure 1). When analyzed within each surgical therapy, almost the same number of patients had a TE before undergoing TSS as within the first 60 days after surgery.

Figure 1.

Interval from surgery to thrombotic event (TE). Incidence of TEs subdivided into groups based on the time period when patients experienced a TE.

This highest incidence of TE within the first 60 days after surgery prevailed when we examined a subgroup of patients depending on whether they underwent TSS only, TSS and BLA, or BLA only. There was a clear trend that the highest TE incidence occurred during the first 60 days after TSS and BLA, and BLA alone.

For patients who had a BLA, there was no statistically significant difference in the mean 3 × 24-hour UFC levels (expressed as the ratio UFC:ULN) prior to BLA between patients with and without TE (5.3 vs 1.3, respectively, P = .129), albeit with possible limitations related to different UFC methods. Concomitantly, there was no significant correlation between mean 24-hour UFC levels and the timing of TE after 1 patient, with a 24-hour UFC of 1900 μg/day, was removed from the analysis as an outlier.

There was no significant relationship between mean 24-hour UFC at the time of TE in patients who underwent BLA (Figure 2) or in the timing of TE with respect to BLA surgery.

Figure 2.

Mean 24-hour urinary free cortisol (UFC) in relation to timing of thrombotic events (TEs) in patients undergoing bilateral adrenalectomy (BLA). The distribution analysis of mean 24-h UFC (μg/d) in patients who did not have a TE and those who did have a TE in different time periods in relation to the date of BLA. ◊ = data mean, ○ = data outliers, Prob > F = P value for the effect of the classification variable on the response. Small F, with a big P value indicates not significantly different.

Length of Stay for Surgery

The overall longer length of stay (LOS) in patients who underwent TSS and had a TE in the immediate postoperative period was 5.8 ± 3.1 days compared to patients who did not have a TE of 4.4 ± 3.3 days. Additionally, patients who underwent a BLA who had a TE in the immediate postoperative period had a longer LOS (7.5 ± 0.5 days) when compared to those who did not have a TE (3.9 ± 2.0 days). However, it is important to note that there were only 4 patients with a TE in the immediate postoperative period in the TSS group and only 2 patients with a TE in the BLA group, thus limiting data interpretation.

Anticoagulation Risks

A total of 197 patients underwent surgery, either TSS or BLA, of whom 50 (25.3%) received anticoagulation after surgery and only 1 (2%) developed complications. Per hospital protocol, all our patients are placed on compression stockings and undergo mobilization the day of surgery. There were 19 (9.6%) patients who received prophylactic anticoagulation before surgery with no reported complications during surgery or after. Nine (4.6%) patients were started on anticoagulation with a therapeutic dose of warfarin during the first 2 days after surgery; 8 of the patients taking warfarin underwent TSS and 1 underwent BLA. Concomitantly, in the immediate postoperative period, 5 (2.5%) patients received a therapeutic dose of enoxaparin and 42 (24.3%) were on prophylactic doses. Of all the patients anticoagulated with enoxaparin, 17 (36.1%) underwent adrenalectomy and 30 (63.8%) TSS; only 1 patient developed a complication after being treated with dual warfarin and enoxaparin therapy for bilateral LE DVTs after TSS. This patient sustained an intraventricular hemorrhage and developed hemoptysis. Anticoagulation was held temporarily and the patient did not develop any further complications. No other patients developed bleeding or complications at the site or surgery associated with anticoagulation. At the time of the TE event, 5 patients (12.8% of those who had a TE) were prophylactically anticoagulated with enoxaparin.