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


TEs contribute to high mortality rates in CS,[26,27,4] with PE accounting for 11%, ischemic cardiac disease for 19%, and stroke for 17% of deaths.[26] Standardized mortality ratio decreases in patients with CS who are successfully treated but does not return to that of the normal population.[1,2,4,5]

Our study is to date the largest single-center study to analyze both arterial and venous TE. Despite inherent retrospective study limitations, we were able to determine a high (~18%) prevalence of all TE in patients with CS. Notably, 12.8% of these patients were prophylactically anticoagulated with enoxaparin at the time of the event, confirming the high risk of hypercoagulability.

Interestingly, we did not find any statistically significant correlation between TE and UFC levels, sex, age, BMI, smoking, diabetes mellitus, hypertension, or estrogen/testosterone replacement. However, there was a slightly higher trend of TE in patients with hypertension and those who smoked. Similar to data from a recent meta-analysis,[19] patients with CS in our center were more often women with a mean age of 44 years. Other studies have also demonstrated a lack of correlation between UFC levels and severity of CS comorbidities.[28] Studies examining the relationship between metabolic syndrome and the risk of VTE remain controversial.[29,30] Kastelan et al found no significant association between UFC and increased procoagulant factors in CS.[31] However, Koutroumpi and colleagues demonstrated a negative correlation between UFC levels and partial thromboplastin time, suggesting that severe hypercortisolism may result in elevated factor VIII.[20] However, the clinical manifestations of CS do not always correlate with hypercortisolism severity,[32] which could explain why we did not find a correlation between degree of biochemical hypercortisolism and TE. In a large, multicenter European study, preoperative medical treatment of hypercortisolism also did not decrease VTE risks.[33]

Data on arterial TE are scarce. A population study found that patients with CS were at increased risk of acute MI (hazard ratio; HR 3.7, 95% CI 2.4–5.5) and stroke (HR 2.0, 95% CI 1.3–3.2) compared with the general population.[4]

Our study found an overall TE rate of 18%, of which 52% were VTE. Without VTE prophylaxis, VTE incidence in medical and general surgical hospitalized patients is 10% to 40%.[23] Coelho et al reviewed 13 studies with 1356 patients with CS (1080 with CD) and observed a VTE incidence rate close to what we report here, 8.9%, 53% of which were related to surgery.[34] Furthermore, Dekkers and colleagues found, when compared to the general population, an HR of 2.6 (95% CI 1.5–4.7) of VTE in CS.[4] Use of a PICC line clearly increased risk of UE DVT in our group, and use has been discontinued in patients with CS over the last decade.

Timelines of TE from CS diagnosis and/or in relation to surgery are also intriguing.[4,35] We found that there is an increased overall risk of TE 3 years before diagnosis and is highest during the 2 months following BLA or TSS. This risk was significantly higher in patients undergoing BLA (OR 3.47l; CI 1.55–7.78). Babic et al found that adrenalectomy for CS significantly increases risk of VTE vs patients having adrenalectomy for other etiologies (2.6% [n = 8/310] vs 0.9% [n = 37/3907]; P = .007).[36] We cannot exclude postoperative iatrogenic hypercortisolemia as a contributor to VTE in our study; however, the majority of patients were tapered down to a physiologic replacement dose with hydrocortisone by 1 month.

Based on these results, we suggest that patients undergoing BLA for CS be anticoagulated up to 30 to 60 days postoperatively if there are no contraindications.

Although it is well recognized that patients with CS are at increased risk of VTE events, especially in the postoperative setting, use of thromboprophylaxis is neither routine nor standardized.[34,37] Few studies have examined the risk of VTE in CS in patients receiving thromboprophylaxis for surgery. In our study, prophylactic anticoagulation 1 week preoperatively and up to 28 days postoperatively was reserved for high-risk patients (as deemed by our multidisciplinary team based on previous history of TE, significantly elevated UFC, and other known risks factors for TE not related to CS). Of all the patients in this study, 10% were anticoagulated preoperatively and 25.3% postoperatively. Only 1 patient (2%) developed an intraventricular hemorrhage after being started on warfarin and enoxaparin for bilateral LE DVT. However, no patients who had prophylactic anticoagulation developed any complications, demonstrating the relative safety of anticoagulation in these patients.

Boscaro and colleagues retrospectively examined 307 patients with CS (66% with CD) in 2 groups. The first group did not receive postoperative thromboprophylaxis (75 patients) and the second (232 patients) received unfractionated heparin for at least 2 weeks and warfarin for at least 4 months after surgery. Twenty percent of patients in the first group developed VTE, as compared to only 6% in the second group who received thromboprophylaxis. Sixty-two percent of events occurred in the first 3 months after surgery.[38] In a recent retrospective study focused on patients with CD, 78 patients who underwent TSS were analyzed in 2 groups. The first group received fractionated heparin for a maximum of 14 days after surgery, and the second group was treated with subcutaneous enoxaparin for 30 days plus graduated elastic stockings until mobilization. Three VTE events were reported in the nonanticoagulated group, all within 30 days of surgery, compared to no VTE in the group that was anticoagulated.[39] However, in our study 5 (12%) patients developed a TE event while on prophylactic anticoagulation with enoxaparin. Smith et al discussed the possible use of aspirin to decrease risk of TE[40] and suggested that possible DVT risk reduction in their center was due to use of aspirin from day 1 postoperatively for 6 weeks, as implemented by the senior surgeon. The role of aspirin has not been directly studied in patients with CS; however, serum- and GC-regulated kinase 1 (SGK1) is a powerful regulator of a key mediator of the store-operated Ca2+ entry required for platelet activity.[41] Also, oxidative stress–induced platelet activation via the thromboxane pathway is significantly higher in CS and demonstrated by increased thromboxane B2 levels.[6,15]

The risk of VTE may remain elevated for many years after surgery,[4] even after remission from CS. Casonato and colleagues demonstrated that in 20 patients with CS, factor VIII and von Willebrand factor levels decreased, starting at 3 months postoperatively and normalized 1 year after surgical cure.[42] Likewise, Manetti et al demonstrated significant improvements in procoagulant markers 1 year following successful surgery.[43] Kastelan et al also reported that 6 months after surgical remission, some but not all procoagulant markers declined to levels comparable with that in the control population. Although factor VIII and plasminogen activator inhibitor 1 tended to normalize, there was no significant difference in these levels compared to the ones before surgery.[31] Together, these data suggest that a minimal period of sustained remission may be required to reverse the hypercoagulable state in CS, and that despite normalization of cortisol levels, persistence of other factors may play a role in residual VTE risk,[4,37] which could explain why 27% of our patients developed a TE years after their BLA. Although we did not find a correlation between TE and degree of UFC elevation preoperatively, in patients with adrenal insufficiency after CS remission, supraphysiological GC replacement could theoretically also be a culprit as described in patients without CS.[8]

A survey of Pituitary Society members[44] showed that awareness regarding hypercoagulability in CD increased 4-fold in 2 years, and routine VTE prophylaxis increased from 50% to 75% perioperatively. However, prophylactic treatment for hypercoagulability was not universally administered in many centers despite published data on possible benefits. Low-molecular-weight heparin was the preferred agent used for VTE prophylaxis in this survey,[44] and most of the responders used it for just approximately 2 weeks postoperatively. Zilio et al identified in a small study 6 VTE independent risk factors: age 69 years or older, reduced mobility, acute severe infections, previous cardiovascular events, midnight plasma cortisol level greater than 3.15 ULN, and decreased activated partial thromboplastin time.[45] However, we were not able to identify any clear-cut risk factors, nor were any identified in a large meta-analysis.[19]

Thromboprophylaxis in patients with CS appears to be safe. Similar to previously reported results, the overall risk of bleeding in our study was low.[38,39] Data suggest that thromboprophylaxis be used routinely in patients undergoing surgery for CS, but there is presently no consensus on the choice and duration of thromboprophylaxis administration.[25,34,37] In patients with gliomas (which have an even higher risk of VTE), recent guidelines suggest VTE prophylaxis with low-molecular-weight heparin be started within 24 hours postoperatively to decrease risk of hemorrhage.[46] A similar approach could be considered in patients with CS. Though not used in our patients, a role for aspirin postoperatively remains to be studied.

Our results suggest that thromboprophylaxis needs to be extended up to 60 days after surgery for most patients, especially after BLA. However, the exact duration and patient selection is yet to be established and requires further research.[17,37,39]

Study limitations include the retrospective design, relatively small sample size, and reporting of symptomatic events because not all patients with the exception of those who underwent BLA were screened for TE. Establishing a relationship between etiology of hypercortisolism and TE was not possible given the small number of patients with ACS and ECS. We were unable to determine whether there was a higher risk of TE in patients on estrogen or testosterone supplementation because the sample size was too small. Concomitantly, when subdividing patients into different treatment options, there was a lack of power analysis. Several patients had 24-hour UFC performed in different laboratories before their referral to our center. Throughout the time period during which this study took place, the methods used to measure free cortisol have changed, but we have attempted to correct for this by using UFC UNL standardization. Strengths included a large number of patients for a single-center study, all being managed uniformly in a tertiary referral, multidisciplinary pituitary center.