This study examined the current clinical practice for thromboprophylaxis management in patients with CS across Endo-ERN RCs. This study provides valuable insight into the large variety of thromboprophylaxis strategies for patients with CS, and the limited availability of protocols on thromboprophylaxis even in the reference centers of Endo-ERN that have been endorsed as expert centers for the diagnosis and treatment of CS.
CS is associated with hypercoagulability and an increased risk of VTE (i.e. PE or DVT) both during the active phase of the disease, in postoperative setting, and even after biochemical remission.2 There are currently no treatment studies on thromboprophylaxis of CS and no guidelines on the use of thromboprophylaxis for patients with CS, and therefore thromboprophylaxis management is committed to each center’s clinical practice.5
The in-depth assessment of thromboprophylaxis management showed that the majority of the RCs provided thromboprophylaxis routinely to all patients with CS or only in selected/severe cases (n=23/25), however, a thromboprophylaxis protocol for patients with CS was unavailable in the vast majority of them (n=22/23). Thromboprophylaxis was mostly started from diagnosis onwards, whereas the moment of stopping thromboprophylaxis was merely based on individual characteristics rather than standardized treatment duration. Because active CS is associated with a moderate to high risk on VTE there is a rationale to start with thromboprophylaxis at diagnosis. On the other hand, CS is also accompanied by an increased bleeding tendency due to capillary fragility. Future studies should assess additional risk factors to determine which patients are particularly at risk for VTE and would benefit from thromboprophylaxis. The individualized decision to abrogate depended mostly on the mobility status of the patient. Risk factors that influenced the initiation of thromboprophylaxis in patients with CS were most frequently reported to be ‘previous VTE’ and ‘severity of hypercortisolism’, and LMWH was selected as the first-choice anticoagulant drug by all RCs. Furthermore, the majority of RCs reported ‘severe immobilization’ as an indication to start postoperative thromboprophylaxis in patients with CS if not (routinely) provided preoperatively, and lastly, did not provide standardized testing for hemostatic parameters in the postoperative care of CS.
A thromboprophylaxis protocol for patients with CS was provided by only one center. This center referred to a recently published article by Barbot et al.6 In this article, perioperative multidisciplinary management of patients with sellar lesions submitted for transsphenoidal surgery was described and suggested. Specifically for patients with CD, the clinical practice included elastic compression stockings for every patient from the day of admission until full mobilization, treatment with enoxaparin 4000 U once daily, doubling the dose for patients with a body weight above 80 kg for 30 days, starting twenty-four hours after the surgical procedure. However, this protocol did not compromise the whole spectrum of CS.6
As no studies have been conducted on thromboprophylaxis management in patients with CS, we compared our findings with currently available reports on closely related topics. First, in our study, multiple factors were reported that were taken into account in the decision of thromboprophylaxis initiation in patients with CS. Currently available studies reported multiple risk factors that may be associated with the hypercoagulable state of CS and to our knowledge, no evidence- based VTE risk assessment model for patients with CS has been published thus far.3,7,8,9 In our study, the severity of hypercortisolism was one of the most frequently reported factors that influenced the initiation of thromboprophylaxis. One study found that patients with CS developing VTE had significantly higher plasma cortisol concentrations, compared with CS patients without VTE.7 However, this was a retrospective study with a very small sample size. Multiple studies found no correlations between the severity of hypercortisolism, and coagulation and fibrinolysis indexes, which was confirmed by Wagner et al. in their recently published systematic meta-analysis. 3,10,11
Furthermore, in our study we found a limited role for the measurement of coagulation parameters in the thromboprophylaxis management of CS applied by the Endo-ERN expertise centers. Only one RC reported that the ending of thromboprophylaxis in patients with CS depended on the results of hemostatic variables, including XDP, PT, aPTT and fibrinogen. Additionally, only six RCs reported that hemostatic parameters were screened routinely during follow-up care after transsphenoidal surgery or adrenalectomy. Results of studies examining the hemostatic profiles in patients with CS and the effect of (successful) treatment on these profiles were diverse. A prospective study by Manetti et. al showed an improvement of coagulations indices after successful surgery including vWF, thrombin-antithrombin, antithrombin III, PAI-1, alpha 2-antiplasmin and aPTT.11 Kastelan et al. found extensive significant improvements of coagulation factors in patients with CS after remission and concluded that the risk of TE six months after successful treatment was not greater than the risk faced by healthy individuals.12 In contrast, a cohort study by Dekkers et al. reported high risks of VTE during the first 3 months following surgery in patients with CS.8 Furthermore, a study by van der Pas et al. showed no significant changes in aPTT and vWF:Ag in patients with CD after successful pharmaceutical treatment, and additionally showed persistent elevated levels of PAI-1 and alpha 2-antiplasmin.10 A reason for these contradicting findings may well be the differences in follow-up duration. A systematic meta-analysis by Wagner et al. confirmed the association between CS and VTE, and changes in coagulation parameters including vWF, protein C, protein S, aPTT, fibrinogen and factor VIII, but found no relationship between coagulation parameters and number of thrombotic events.3 However, more evidence is needed to show whether screening for hemostatic parameters and (changes in) laboratory coagulation metrics can define timing, duration and intensity of (extended) thromboprophylaxis before implementation in daily clinical practice.
In our study we found that four out of 23 centers reported to consider the subtype of CS in the decision of initiation of thromboprophylaxis. The subtypes of CS that were deemed to be associated with an increased risk of TE by these RCs were CD, ectopic ACTH/CRH syndrome and/or malignant adrenal CS. Previous studies showed a higher VTE rate in patients with CD compared to adrenal CS.4,13 The reason for the differences in VTE incidence in patients with different etiologies of CS is not clear. Tirosh et al. observed higher AT- III activity and vWF:Ag antigen in patients with CD compared to patients with primary adrenal CS, along with higher baseline mean cortisol levels, and proposed that higher cortisol levels could explain the differences in coagulation profile and increased risk for VTE.14 However, another study reported no significant differences in coagulation profile between ACTH- dependent and ACTH- independent CS.15 As to patients with adrenal carcinoma and ectopic ACTH source, the presence of malignancy per se is considered a VTE risk factor, and therefore, these subtypes of CS can be considered prothrombotic in clinical practice, as seen in our study.
The association between preoperative medical treatment and reduction of VTE risk in patients with CS remains controversial. In our detailed assessment of the use of preoperative medical treatment at the different centers, we found that only about half of the responding RCs (n=12/23) reported to take risk factors for VTE (e.g. older age, cancer and previous VTE) into account in the decision of starting treatment in patients with CS. In addition, about two-thirds (n=15/23) reported that reduction of the risk of VTE postoperatively was one of the goals of preoperative medical treatment. Preoperative medical treatment might have a role in reducing the likelihood of VTE by reducing the cortisol withdrawal syndrome (i.e. a rapid and large decrease in cortisol exposure after surgery) that can trigger a rebound inflammatory response by withdrawal of the anti-inflammatory effect of cortisol.3 Stuijver et al. reported a reduced risk ratio of VTE three months postoperatively in patients with CS who were medically pretreated before surgery, in comparison to patients who were not.4 In contrast, a study by Valassi et al., in which data on preoperative medical treatment from The European Registry on Cushing’s syndrome (ERCUSYN) was analyzed, reported no differences in postsurgical morbidities including thromboembolism within 180 days of surgery between patients who received preoperative medical treatment compared to patients who underwent surgery directly. Furthermore, there was little evidence that preoperative medical treatment affected postsurgical outcome.16
Important limitation of our study is that our findings may be biased due to non-responders and missing data. However, a minimum response rate of sixty percent was achieved, and the survey questions were mainly independent from each other. We tried to prevent ambiguity in our survey questions by making a clear distinction between start of thromboprophylaxis in an inpatient and/or ambulatory/out-patient setting, and by enquiring about the exact time of initiation of thromboprophylaxis. However, thromboprophylaxis management in general of patients who are not diagnosed with CS or of patients admitted to the RCs for surgery related to a condition other than CS was not surveyed.