Hypercoagulability in Cushing's syndrome: prevalence, pathogenesis and treatment

Authors


Correspondence: R. van der Pas, Erasmus Medical Center, room Ee 569, Dr. Molewaterplein 50, 3015 GE Rotterdam, the Netherlands.

Tel.: +31 10 7034394; Fax: +31 10 7035430;

E-mail: r.vanderpas@erasmusmc.nl

Summary

Cushing's syndrome is not only accompanied by an increased prevalence of cardiovascular disease but also by a hypercoagulable state that is reflected by an increased incidence of venous thromboembolism. Overall, patients with CS have been reported to have a more than 10-fold increased risk of developing venous thromboembolism. Moreover, the incidence of postoperative thrombosis has been shown to be comparable to the risk after major orthopaedic surgery. Hypercoagulability in CS is due to both increased production of procoagulant factors with activation of the coagulation cascade and an impaired fibrinolytic capacity, resulting in a shortened activated partial thromboplastin time and an increased clot lysis time respectively.

Although these abnormalities seem to improve 1 year following successful surgery, they do not yet normalize. Therefore, sustained biochemical remission might be required to fully resolve the hypercoagulable state in CS.

Considering the risk of venous thromboembolism in uncontrolled CS there may be a rationale to give patients with active CS thromboprophylaxis. So far this seems warranted following surgical interventions. However, further studies are needed to determine the optimal dosage and duration of thromboprophylaxis.

Introduction

Cushing's syndrome (CS) is caused by chronic glucocorticoid excess that leads to considerable morbidity and mortality.[1-3] Hypertension, insulin resistance, obesity and hyperlipidaemia are important hallmarks of CS and give rise to an increased risk of cardiovascular disease.[4-6] Furthermore, CS is accompanied by psychiatric and cognitive disorders, osteoporosis and muscle weakness.[5, 7, 8] The multitude of symptoms that occur in patients with CS leads to a severely impaired quality of life.[9-11]

The causes of CS are divided into those dependent and those independent on adrenocorticotrophin (ACTH). Pituitary-dependent CS or Cushing's disease (CD), which is caused by an ACTH-secreting adenoma, is the most frequently observed cause of CS, representing approximately 70% of all cases.[5] The ectopic ACTH syndrome causes approximately 10% of all cases of CS, whereas 20% of all cases of CS are due to ACTH-independent pathology like ACTH-independent macronodular adrenal hyperplasia (AIMAH), cortisol-producing adrenocortical adenomas or carcinomas.[5] Surgery is the primary treatment option for all forms of CS, but radiotherapy or medical therapy can be applied in case of surgical failure or ineligibility to undergo surgery.[12, 13]

As already mentioned, CS is accompanied by an increased risk on arterial thrombosis.[5] However, when compared with the general population, patients with CS have also been reported to have an increased prevalence of venous thromboembolism (VTE).[14-16] Rarely, CS can even present with VTE.[17] In recent years, an increasing amount of evidence has become available that elucidates the mechanism underlying this hypercoagulable state. In addition, some studies showed the effects of successful treatment of CS on the coagulation and fibrinolysis pathways. Although to date no guidelines are available on type and duration of thromboprophylaxis, some authors have proposed routine administration of thromboprophylactic drugs to patients with CS.[18-20] In this review, the prevalence, pathogenesis and treatment of the hypercoagulability in CS are discussed.

Incidence of venous thromboembolism in CS

Several studies reported an increased incidence of VTE in patients with CS, not only during active disease but especially following surgery. In their systematic review, Van Zaane et al. concluded that VTE not related to surgery occurs in 1·9–2·5% of the patients with CS, corresponding to an incidence rate of 2·5–3·1 per 1000 person years[15]. This incidence rate is considerably higher than that in the normal population, in which an incidence rate of 0.27 per 1000 person years has been described among 40-year-old women, the population that represents most of the patients with CS.[21] Van Zaane and co-workers also reported that the risk of postoperative VTE in patients with CS varies between 0 and 5.6%, a percentage that is comparable to the risk of VTE after total hip or knee replacement under routine thromboprophylaxis.[15]

Boscaro and co-workers compared two cohorts of patients with CS and found a firm decrease in the incidence of VTE in patients that were treated with postoperative thrombopro-phylaxis. In the group of patients that did not receive thromboprophylaxis, 15/75 patients (20%) developed VTE (i.e. pulmonary embolism or deep vein thrombosis) during the course of their disease, as opposed to 14/232 patients (6%) that were treated with unfractionated heparin (15·000–22·500 units daily for at least 2 weeks postoperatively).[18] Remarkably, although the distribution of aetiology in these patients (ACTH-dependent vs ACTH-independent CS) was as expected based on the literature, 27/29 patients (93%) that developed VTE in this study had CD and only two had an adrenocortical adenoma. Eighteen of the cases of VTE occurred postoperatively, mostly within 3 months following either pituitary or adrenal surgery.[18]

Stuijver et al. conducted a retrospective multicentre cohort study among 473 Dutch patients with CS.[14] In this series, the overall incidence rate of VTE was 14.6 per 1000 person years and this number did not differ between ACTH dependent and ACTH independent CS (Table 1). The authors concluded that untreated CS is accompanied by a more than 10-fold increased risk for VTE compared with the general population, in which the incidence rate is approximately 0.3 per 1000 person years.[14] The risk for postoperative VTE in patients with CD was 3.4% (12/350 cases) vs 0% after trans-sphenoidal surgery for nonfunctioning pituitary adenomas (Fig. 1), again comparable to the postoperative VTE risk after total hip or knee replacement. An important observation is that VTE after trans-sphenoidal adenomectomy for CD not only occurred in the first week but also up to 2 months postoperatively.[14] Remarkably, none of the 113 patients with ACTH-independent CS developed VTE following adrenal surgery. This raises the question whether ACTH itself might also play a role in the hypercoagulable state in CD,[14] although no (in vitro) data are available that support this.

Table 1. Incidence of venous thromboembolism (VTE) in Cushing's syndrome
 Cushing patients, nPerson-yearsVTE, nIncidence rate per 1000Person-years95% CI
  1. DVT: deep venous thrombosis; PE: pulmonary embolism. Reproduced with permission from Stuijver et al.[14]

Overall incidence
VTE47325263714·610.3–20.1
DVTand/or PE47325373313·09.0–18.2
First-ever VTE46324773413·79.5–19.1
First-ever DVT and/or PE46424903012·08.1–17.2
Prior to treatment
VTE47313441914.18.5–22.0
DVT/PE47313451712.67.4–20.2
First-ever VTE46313151712.97.5–12.6
First-ever DVT and/or PE46413181511.46.4–18.7
Figure 1.

Cumulative incidence of postoperative VTE. *, from log-rank test. Reproduced with permission from Stuijver et al.[14]

A recent Italian study showed eight cases of VTE in a series of 58 consecutive CS patients. Five of these cases (5/58; 8.6%) were unrelated to surgery, whereas the remaining three (5.2%) occurred mainly within 2 weeks postoperatively when patients were on routine anticoagulant prophylaxis (nadroparin 3800 U or enoxaparin 4000 U).[16] Compared with patients that developed VTE, the 50 patients who did not had better glycaemic control and needed less antihypertensive drugs. Therefore, the authors postulated that the presence of (components of) the metabolic syndrome might have contributed to the development of VTE.[16]

Other series also reported the occurrence of VTE following surgery. Three of 54 (6%) and 4/105 patients (3·8%), respectively, presented with VTE within 1 month following trans-sphenoidal surgery for CD in two different studies.[20, 22] On the other hand, an incidence of only 0.7% was found among more than 3500 inpatients following trans-sphenoidal surgery for CD in a nationwide analysis in the US. Importantly, the median length of stay among these patients was only 4 days and therefore, many cases of VTE that developed later on might have been missed in the analysis.[23]

Similar to pituitary surgery, Pezzulich and Mannix reported an increased risk for VTE after adrenal surgery for CS already in 1970. In their series, pulmonary embolism occurred following 5/108 procedures in CS patients, as opposed to 0/102 after adrenal surgery for indications other than CS, a difference that was statistically significant.[24]

No data are available on the incidence of VTE in patients with ACC and EAS. However, because malignancy itself is associated with an increased thromboembolic risk, it can be anticipated that the incidence of VTE among these patients will be at least as high, if not higher than among patients with CS of other origin.[25, 26]

Pathogenesis of hypercoagulability in CS

A simplified schematic representation of the coagulation and fibrinolysis pathways are depicted in Fig. 2. CD is associated with increased production of procoagulant factors and activation of the coagulation cascade, as reflected by shortening of activated partial thromboplastin time (aPTT), but also with impaired fibrinolytic capacity, indicated by an increased clot lysis time (CLT).[15, 27-33] An overview of changes in coagulation and fibrinolysis parameters in CS is provided in Table 2. Although the mechanism behind the altered production of these proteins is not fully understood, some studies have shown direct effects of glucocorticoids on the expression levels of factors that inhibit fibrinolysis (as discussed below). Plasminogen activator inhibitor type 1 (PAI-1) impairs tissue type plasminogen activator (tPA)-induced plasmin formation, whereas thrombin-activatable fibrinolysis inhibitor (TAFI) is a carboxypeptidase that attenuates fibrinolysis by reducing binding of tPA and plasminogen to fibrin by cleavage of arginine and lysine residues from partially degraded fibrin.[34]

Table 2. Overview of studies that evaluated key parameters of coagulation and fibrinolysis in patients with CS
StudyaPTTFactor VIIIvWFvWF:ristocetin cofactorFibrinogenFibrinolytic capacityPAI-1TAFIα2-antiplasmin
  1. ↑ indicates statistically significant elevation compared with control; ↓ indicates statistically significant decrease compared with control; = indicated no significant difference between patients and controls; ND: not determined. Besides its important role in primary haemostasis, where Von Willebrand Factor (vWF) facilitates platelet adhesion to the subendothelium and platelet aggregation, VWF is also a carrier protein of Factor VIII and thereby prevents FVIII from proteolytic degradation by activated protein C. VWF ristocetin cofactor (VWF:RCo) activity is a functional measurement of VWF. VWF:RCo activity measures the ability of a patient's plasma to agglutinate platelets in the presence of the antibiotic ristocetin. The rate of ristocetin-induced agglutination is related to the functional activity of the plasma VWF. aPTT: activated partial thromboplastin time; PAI-1: plasminogen activator inhibitor type 1; TAFI: thrombin-activatable fibrinolysis inhibitor.

Ikkala et al.[42]NDNDNDNDNDNDND
Patrassi et al.[33]ND=NDND
Casonato et al.[30]NDNDNDNDND
Ambrosi et al.[49]NDND=NDND=NDND
Boscaro et al.[18]NDND
Kastelan et al.[31]NDND=NDNDND
Erem et al.[32]==NDND=ND
Manetti et al.[28]=NDNDND
Van der Pas et al.[27]=ND
Figure 2.

The coagulation and fibrinolysis pathways depicted in a simplified manner. Factors involved in coagulation (either stimulatory or inhibitory) are depicted in red; factors involved in fibrinolysis (either stimulatory or inhibitory) are depicted in blue. Upon tissue damage, tissue factor (TF) binds Factor VII. The TF–Factor VII complex activates both Factor IX to Factor IXa and X to Xa. The Factor IXa–VIIIa complex also activates Factor X to Xa. The Factor Xa–Va complex activates Factor II to IIa (thrombin). Thrombin facilitates the conversion of fibrinogen into fibrin. Besides its important role in primary haemostasis, Von Willebrand Factor (vWF) is a carrier protein of Factor VIII and thereby prevents FVIII from proteolytic degradation by activated protein C. Factors that inhibit fibrin formation include antithrombin, Protein C and Protein S. Antithrombin binds and inactivates thrombin and, to a lesser extent, inhibits TF-bound Factor VIIa and Factors Xa and IXa. Protein S is a cofactor to protein C. Activated protein C inactivates Factors Va and VIIIa. Fibrinolysis is initiated by Tissue Plasminogen Activator (tPA), which stimulates the formation of plasmin out of plasminogen. Plasmin in turn dissolves the fibrin complex. Proteins that inhibit fibrinolysis include Plasminogen activator inhibitor type 1 (PAI-1), thrombin-activatable fibrinolysis inhibitor (TAFI) and α2-antiplasmin. PAI-1 inhibits tPA-induced plasmin formation. TAFI is a carboxypeptidase that inhibits fibrinolysis by reducing tPA and plasminogen binding to fibrin. Α2-antiplasmin inhibits plasmin-induced fibrin breakdown. Black arrows indicate activation of a next step in the pathway. Dashed lines indicate inhibitory actions. Reproduced with permission from Van der Pas et al.[27]

In vitro, glucocorticoid responsive elements have been identified in the promoter regions of the PAI-1 and TAFI genes in rat hepatoma cells. Moreover, glucocorticoid treatment enhanced the promoter activity of these genes and increased the production of PAI-1 in cultured human adipocytes.[35-38] High concentrations of dexamethasone have also been reported to increase the mRNA expression levels of Von Willebrand Factor (vWF) in human umbilical vein endothelial cells.[39] In addition, Huang and colleagues showed an increase of the endothelial release of vWF and PAI-1 after in vitro treatment with dexamethasone.[40] In vivo, it has been shown that dexamethasone increased plasma concentrations of Factor VIII, Factor IX and fibrinogen in healthy volunteers, also suggesting a direct stimulatory effect on blood coagulation.[41]

Multiple studies have shown that patients with CS have an increased production of procoagulant proteins. It was reported by Ikkala and co-workers that patients with CD have elevated activity of Factor VIII and vWF:ristocetin cofactor.[42] Besides its important role in primary haemostasis, where vWF facilitates platelet adhesion to the subendothelium and platelet aggregation, vWF is also a carrier protein of Factor VIII and thereby prevents Factor VIII from proteolytic degradation by activated protein C. vWF ristocetin cofactor (vWF:RCo) activity is a functional measurement of vWF. vWF:RCo activity measures the ability of a patient's plasma to agglutinate platelets in the presence of the antibiotic ristocetin. The rate of ristocetin-induced agglutination is related to the functional activity of the plasma VWF.

A later study by Patrassi et al. showed no differences in fibrinogen levels between 30 patients with CS (of which 19 had CD) and 30 controls, but patients had increased levels of PAI-1. They also reported increased plasma concentrations of vWF, and due to increased levels of FVIII, a shortened aPTT. Moreover, the increase in plasminogen activators following a venous occlusion test was impaired in patients compared with controls, suggesting impaired fibrinolytic capacity in CS.[33] This is an important observation, as hypofibrinolysis has been shown to contribute to both arterial and venous thrombosis.[43, 44]

In another study, 20 patients with CS (11 with CD, 7 with an adrenal tumour and 2 with ectopic ACTH production) were shown to have increased Factor VIII activity, vWF antigen and vWF ristocetin cofactor activity, which resulted in a shortening of the aPTT.[30] This group also reported the presence of unusually large vWF multimers in their patients, a finding that is associated with increased haemostatic capacity.[45] An interesting study by Daidone suggested that the glucocorticoid-induced increase in vWF concentrations in patients with CS might be dependent on the presence of certain single nucleotide polymorphisms in the promoter region of the vWF gene. It was shown that compared with CS patients with normal vWF concentrations, patients with elevated vWF concentrations had a higher prevalence of haplotype 1 as compared with haplotype 2 in the promoter region of the vWF gene.[46]

Boscaro et al. compared 232 patients with CS to 80 healthy controls and observed some major differences.[18] Patients had significantly shorter aPTT compared with controls, which was explained by higher levels of procoagulant factors like fibrinogen, Factor VIII, vWF:Ag and vWF:ristocetin cofactor. Moreover, the euglobin clot lysis time, a global test for fibrinolytic capacity, was significantly increased in patients, pointing towards an impaired fibrinolytic potential. This observation was also supported by higher levels of PAI-1 compared with controls.[18]

Kastelan et al. showed some significant differences between 33 patients with CS and 31 controls. Twenty-five of these patients had CD, while eight had an adrenal adenoma. One of the patients encountered deep vein thrombosis and two presented with pulmonary embolism during the course of their disease. On average, the activity of Factors II, V, VIII, IX and XI, Protein C and S and concentrations of antithrombin, PAI-1 and plasminogen were significantly higher in the patient group. In particular, PAI-1 concentrations and Factor VIII activity were far above the upper limit of normal.[31] These abnormalities resulted in a shortening of aPTT. Plasma concentrations of fibrinogen were higher in the patient group, but this difference was not statistically significant. It should be noted that patients had significantly higher BMI than controls and that this difference was not corrected for when comparing haemostatic parameters between both groups.[31]

Twenty-four patients with CS (13 with CD, 10 with adrenal adenoma and 1 with an adrenocortical carcinoma) were compared to age- and sex-matched controls in a study by Erem and co-workers.[32] Although there appeared to be some differences between both groups, no significant differences were found in the activity of Factors V, VII, VIII, IX and X, nor in activity of vWF and Protein C and S and concentrations of TAFI. In contrast, patients did have significantly shortened aPTT and higher levels of fibrinogen, antithrombin III (AT-III) and PAI-1. The increase in AT-III, an important anticoagulant molecule that mainly binds and inactivates thrombin (Factor II; see Fig. 2), was speculated to be a compensatory mechanism for the hypercoagulable state in these patients.[32] Interestingly, midnight serum cortisol levels were significantly correlated with PAI-1 concentrations. Moreover, an inverse correlation was found between aPTT and morning serum cortisol concentrations. Finally, patients had lower levels of tissue factor pathway inhibitor (TFPI) compared with controls, pointing towards increased tendency of thrombosis as low TFPI concentrations have been associated with both venous and arterial thrombosis.[47, 48]

In contrast to virtually all other studies discussed above, Ambrosi et al. did not find any differences in plasma concentrations of PAI-1, tPA and vWF between 11 patients with CS and 40 control subjects matched for age and gender. The authors speculated that this discrepancy might have been due to a difference in length or severity of the disease.[49] In contrast, fibrinogen levels were significantly elevated in patients compared with controls.[49]

More recently, 40 patients with CS (36 with CD) were shown to have shortened aPTT compared with controls in a study by Manetti and colleagues.[28] This was accompanied by increased levels of thrombin–antithrombin complexes, which are markers for thrombin formation, fibrinogen, Factor IX activity, vWF antigen, PAI-1 and α2-antiplasmin. No differences were found between both groups in the activity of Factors II, V, VII and VIII and Protein C and S.[28] In this study, no correlations were found between cortisol levels and haemostatic parameters.

We recently reported that compared with healthy control subjects, 17 patients with CD had increased levels of fibrinogen and Factor VIII and a shortened aPTT.[27] Antithrombin and vWF antigen concentrations did not differ significantly from controls in patients with CD. With respect to fibrinolysis, patients had higher levels of TAFI (in contrast to what was reported by Erem et al.[32]), PAI-1 and α2-antiplasmin, which resulted in a significant decrease of fibrinolytic potential as determined by prolongation of the plasma CLT.[27] A statistically significant difference in BMI between patients and controls has been observed in several studies, including ours.[27, 28, 31, 32] Abdominal obesity, an important hallmark of CS, is associated with increased plasma levels of fibrinogen, Factor VII, vWF and PAI-I.[50, 51] In agreement with this, but in contrast to Manetti et al.,[28] significant correlations were found in our study between BMI and several coagulation and fibrinolytic parameters, including aPTT, CLT, Factor VIII, vWF, PAI-1, α2-antiplasmin and TAFI.[27] This suggests that the disturbances in coagulation and fibrinolytic parameters might partially be explained by an increased abdominal fat mass. However, aPTT and CLT significantly differed between patients and controls also after adjustment for BMI in our study, indicating that the increased BMI in CD patients is not the only explanation for their hypercoagulable state. Accordingly, a relative risk of 2·5 for VTE has been reported among the obese population,[52] whereas compared with the general population, patients with CS may have a more than 10-fold increased risk for VTE.[14]

It was described above that the incidence of VTE in CS is especially increased following surgery. Stuijver et al. reported an incidence of 3.4% after trans-sphenoidal surgery for CD and it was hypothesized that the development of VTE following a rapid decrease in cortisol levels might partially be due to a rebound inflammatory response, as glucocorticoids have a strong anti-inflammatory effect.[14, 27] This is supported by the observed increase in plasma levels of interleukin-6, and to a lesser extent of interleukin-1 and tumour necrosis factor α, during hypocortisolism in the first week postoperatively in patients who underwent pituitary surgery for CD.[53] Inflammation induces activation of the coagulation cascade by various mechanisms.[54] Proinflammatory cytokines stimulate mononuclear cells to express tissue factor, which in turn leads to activation of the coagulation cascade.[54] Furthermore, inflammation is associated with a blunted Protein C system and decreased plasma levels of antithrombin, resulting in a malfunctioning anticoagulant pathway.[54] In addition, interleukins 2 and 6 increase the mRNA expression of PAI-1 by cultured human hepatoma cells.[55] In patients with CS due to ACC or EAS, the underlying malignancy might also contribute to the development of VTE, as malignant tumours are well known to be associated with VTE,[25, 26, 56] for example by expressing procoagulant proteins or stimulating other cells, for example monocytes, to increase their procoagulant activity.[57]

To summarize, the most consistent findings in the various studies on haemostasis in CS are shortened aPTT and increased levels of Factor VIII, fibrinogen, vWF and PAI-1. Discrepant results between studies may in part be explained by differences in patient characteristics, timing of sampling and used laboratory techniques.

Treatment of CS and effects on hypercoagulability

Only a limited number of studies have been published that evaluated the effect of treatment of CS on parameters of coagulation and fibrinolysis.

A study by Dal Bo Zanon et al. showed that Factor VIII activity, that was elevated before treatment, normalized within 4 months after successful surgery.[58] As described above, Casonato et al. reported that 20 patients with CS were shown to have increased levels of Factor VIII activity, vWF antigen concentrations and vWF ristocetin cofactor activity, which consequently resulted in a decrease in aPTT.[30] Irrespective of the outcome of surgery, Factor VIII and vWF ristocetin cofactor activity and vWF concentrations had increased further when evaluated again after 1 month. From the 3rd month postoperatively, these levels began to decrease in successfully operated patients and ultimately normalized 1 year following surgical cure. In addition, the vWF multimer pattern improved, although unusually large multimers were still present in plasma of some of these patients after 1 year.[30]

One year following successful surgery, Manetti and colleagues found significant improvements in the hypercoagulable state in patients with CS.[28] The aPTT significantly increased and levels of vWF antigen and thrombin–antithrombin complexes decreased in 27 patients after surgical cure. At baseline, Factor IX activity and fibrinogen concentrations were elevated compared with controls, but these parameters did not decrease postoperatively. Fibrinolysis also improved in patients who were cured, as suggested by significant decreases in plasma levels of PAI-1 and α2-antiplasmin.[28] In contrast, none of these ameliorations occurred in the group of 13 patients with persistent hypercortisolism after surgery. It is important to note that despite the observation that several parameters improved in patients with successfully treated CS, haemostasis had not fully normalized after 1 year.[28]

We described the effects of medical therapy of CD on coagulation and fibrinolysis.[27] In this study, 17 patients with CD were prospectively treated with the universal somatostatin analogue pasireotide. After 1 month of pasireotide monotherapy, the dopamine receptor type 2 agonist cabergoline was added in case of persistent hypercortisolism. UFC excretion was evaluated again after another month and ketoconazole, an imidazole derivative that directly inhibits steroidogenesis, was added to pasireotide and cabergoline in patients that did not have normalized UFC excretion. After 80 days of treatment, 15/17 patients (88%) reached normal UFC excretion levels using this stepwise approach.[59] As already mentioned above, these patients had elevated levels of procoagulant factors and impaired fibrinolysis compared with healthy control subjects. However, this haemostatic profile did not improve after 12 weeks despite biochemical remission.[27] Thus, procoagulant factors remained elevated and hypofibrinolysis persisted, which was reflected by prolonged CLT and elevated levels of inhibitors of fibrinolysis like PAI-1, α2-antiplasmin and TAFI.[27]

The lack of improvement in our study clearly contrasts with the results obtained in the studies by Manetti and Casonato.[28, 30] An explanation for the different outcomes after biochemical remission between our studies and theirs could be the different follow-up period (12 months vs less than 3 months respectively). This suggests that a minimal period of sustained biochemical remission is required to reverse the hypercoagulable state in patients with CD. The observation that despite normalization of cortisol levels, the hypercoagulable state persists in both our study and the study by Manetti et al. indicates that the increased risk for thrombosis in patients with CD might in part be due to the persistence of abdominal obesity rather than to the presence of hypercortisolism.[51] This would explain why apparently it takes a long time to reverse the hypercoagulable state in patients cured from CS. The long-term effects of medical therapy of CS on coagulation and fibrinolysis have not been investigated thus far.

Thromboprophylaxis: what to do?

Currently, there are no guidelines on type, dosage and duration of thromboprophylaxis for patients with CS before and after (surgical) treatment.[12] As described earlier, Boscaro et al. reported that the incidence of VTE among patients with CS decreased significantly in those who received thromboprophylaxis.[18] In the group of patients that did not receive thromboprophylaxis, 15/75 patients (20%) developed pulmonary embolism or deep vein thrombosis during the course of their disease, as opposed to 14/232 patients (6%) who were treated with unfractionated heparin (15.000–22.500 units daily for at least 2 weeks) postoperatively.[18] Thrombosis did also occur under routine low molecular weight heparin (LMWH) prophylaxis, for instance using 3800 U nadroparin.[16]

The reported postoperative period in which VTE occurs in patients with CS varies among different studies. However, all the cases of postoperative VTE are discovered within 3 months following surgery,[14, 16, 18, 20, 22] as has also been reported for other types of high-risk surgery.[60] We have been able to find 20 cases of postoperative VTE in which the exact interval between surgery and VTE has been described.[14, 20, 22, 61] Of these 20 patients, 16 developed VTE within 4 weeks following surgery, eight of which already presented with VTE in the first 2 weeks postoperatively. As described earlier, there is also an increased incidence of VTE in active CS before surgery. Therefore, it should be considered to administer thromboprophylaxis to patients with CS from the time of diagnosis, while awaiting surgery, until at least 4 weeks postoperatively. Similarly, thromboprophylaxis is recommended to be continued until maximally 4 weeks after discharge in patients who have undergone major surgery for cancer.[60]

So far, no prospective placebo-controlled trials have been reported that evaluated the effects of thromboprophylaxis in patients with CD. We would recommend a randomized controlled trial in which patients with CD would be randomized between LMWH in a high prophylactic dose (i.e. nadroparin 5700 U or enoxaparin 40 mg once daily), starting 24 h after surgery, for the duration of immobilization or duration of hospital stay, as is the current standard of care in many centres, and prolonged prophylaxis with LMWH for a period of 4 weeks postoperatively. The percentage of patients with VTE and bleeding complications should be compared between the two groups. Importantly, as the prevalence of CD is very low, this study should be carried out in a multicentre setting. Until a prospective study has yielded an optimal regimen for thromboprophylaxis, we would suggest giving LMWH in a high prophylactic dose (nadroparin 5700 U, dalteparin 5000 U or enoxaparin 40 mg sc once daily). Because some patients may have an increased risk of thrombosis until 3 months after surgery, prophylaxis should be tailored for the individual patients not only considering the additional risk factors of thrombosis (age, obesity etc.), but also the risk of bleeding. Thus, the benefit of prophylaxis should be carefully weighed against the risk of bleeding. Importantly, if LMWH is started preoperatively, it should be temporarily stopped at the time of surgery because of peroperative bleeding risk.

Conclusions

Cushing's syndrome is associated with an increased risk for venous thromboembolism. The incidence of VTE in CS has been reported to be more than 10-fold increased compared with the normal population, and postoperatively, the risk of VTE in patients with pituitary-dependent CS appears to be similar to the risk following major orthopaedic surgery. This hypercoagulable state is caused by both an increased production of procoagulant factors like fibrinogen, Factor VIII and vWF and an impaired fibrinolytic capacity, which is reflected by elevated plasma concentrations of PAI-1, TAFI and α2-antiplasmin. Ultimately, these changes result in a shortened aPTT and a decreased fibrinolytic potential.

Although some of these abnormalities have been shown to improve after surgical cure, the hypercoagulable state does not seem to fully disappear, at least after 1 year of biochemical remission from CS. This suggests that a minimal period of sustained biochemical remission is required to reverse the hypercoagulable state in patients with CD. Moreover, the persistence of haemostatic abnormalities despite biochemical cure might indicate that the increased risk for thrombosis in CS might in part be due to the persistence of abdominal obesity rather than to the presence of hypercortisolism. Thus, further studies are needed to evaluate the long-term effects of successful therapy of CS on parameters of coagulation and fibrinolysis.

Finally, thromboprophylaxis should be considered in patients with active CS and extended postoperative thromboprophylaxis in patients with CD after trans-sphenoidal adenomectomy. Randomized controlled trials are, however, needed to establish the optimal dosage and duration of thromboprophylaxis.

Disclosures

Nothing to declare.

Ancillary