Hypercoagulability and Thrombotic Events in Cushing Syndrome

Abstract and Introduction

Abstract

Background: The risk of Cushing syndrome (CS) patients experiencing a thrombotic event (TE) is significantly higher (odds ratio; OR 18%) than that of the general population. However, there are currently no anticoagulation guidelines.

Methods: A retrospective, single-center, longitudinal study of patients undergoing all types of treatment—surgical (pituitary, unilateral, and bilateral adrenalectomy) and medical treatment—was undertaken. TEs were recorded at any point up until last patient follow-up; myocardial infarction (MI), deep venous thrombosis (DVT), and pulmonary embolism (PE) or stroke. Patients' doses and complications of anticoagulation were recorded.

Results: Included were 208 patients; a total of 165 (79.3%) were women, and mean age at presentation was 44 ± 14.7 years. Thirty-nine (18.2%) patients had a TE; extremity DVT (38%), cerebrovascular accident (27%), MI (21%), and PE (14%). Of 56 TEs, 27 (48%) were arterial and 29 (52%) were venous. Patients who underwent bilateral adrenalectomy (BLA) had an odds ratio of 3.74 (95% CI 1.69–8.27) of developing a TE. Of patients with TEs, 40.5% experienced the event within the first 60 days after surgery. Baseline 24-hour urinary free cortisol levels did not differ in patients with or without TE after BLA. Of 197 patients who underwent surgery, 50 (25.38%) received anticoagulation after surgery, with 2% having bleeding complications.

Conclusions: The risk of TEs in patients with CS was approximately 20%. Many patients had more than 1 event, with higher risk 30 to 60 days postoperatively. The optimal prophylactic anticoagulation duration is unknown, but most likely needs to continue up to 60 days postoperatively, particularly after BLA.

Introduction

Cushing syndrome (CS) is associated with a 2- to 4-fold higher mortality rate compared to the general population when not appropriately treated.^[1–4] largely because of an increase in cardiovascular disease and infection.^[1,5–7] Hypercoagulability has been described both in patients with CS and in patients on glucocorticoid (GC) treatment;^[8] however, an underlying mechanism has yet to be determined. Coagulation factors VIII, IX, and XI, and von Willebrand factor were shown to be increased indirectly in some studies that compared healthy controls to endogenous hypercortisolemic patients, representing activation of the coagulation pathway.^[9–13] Patients with CS also have a significant increase in fast-activating plasminogen activator inhibitor 1, impairing the fibrinolytic system and thereby increasing coagulation risk.^[10,14] The presence of inflammation in patients with CS, enhanced oxidative stress, and platelet activation may also have a pathogenic role.^[15,16] Increased inflammatory and procoagulant activity, and decreased fibrinolytic factors, lead to an elevated risk both of venous and arterial thromboembolism in patients with CS.

The risk of a thrombotic event (TE) in patients with CS has been reported to be up to 10 times higher than that of the general population.^[17,18] A systematic review found TE risk to be 1.9% to 2.5% in the absence of surgical intervention, corresponding to an incidence of 2.5 to 3.1 per 1000 person-years.^[18] In a recent meta-analysis, we reported that the calculated odds ratio (OR) of venous thromboembolism events (VTEs) in patients with CS was 17.82 compared to that of the general population.^[19] Furthermore, a multicenter cohort study reported that the risk of postoperative VTE was significantly higher in patients with Cushing disease (CD) compared to patients undergoing pituitary surgery for a nonfunctioning pituitary adenoma, suggesting that the high risk for postoperative VTE in patients with CS is cortisol mediated,^[17] with similarly reported results in smaller series.^[18,20–22]

A thromboprophylaxis protocol is well established for orthopedic surgeries, which are considered high VTE risk (TE up to 40% to 60% of patients if not on prophylaxis,^[23,24]), but there are currently no guidelines for hypercortisolemic patients undergoing transsphenoidal surgery (TSS), unilateral adrenalectomy (UA), or bilateral adrenalectomy (BLA).^[25] Thus, the outcomes for patients with CS, with or without perioperative anticoagulation treatment, remain unclear. Here we evaluate the risk both of arterial TEs and VTEs and thromboembolic events in patients with CS and postoperative complications associated with prophylactic anticoagulation after TSS or BLA.

Table 1. Demographic and Baseline Characteristics Data
Characteristic	All Patients (n = 208)
Age at presentation, y ± SD	44.4 ± 14.7
Female, n, %	165, 79.3
Male, n, %	43, 20.7
Body mass index ± SD	33.9 ± 8.4
Smoker, n, %	69, 33.5
Hypertension, n, %	147, 70.7
Diabetes mellitus, n, %	87, 41.8
On estrogen, n, %	42, 25.4 of women
On testosterone replacement, n, %	23, 51.1 of men
Cushing disease, n, %	168, 89.4
Adrenal Cushing syndrome, n, %	14, 6.73
Ectopic Cushing, n, %	8, 3.85
Transsphenoidal surgery	152 (73%)
Transsphenoidal surgery + bilateral adrenalectomy	32 (15.38%)
Transsphenoidal surgery + unilateral adrenalectomy	4 (1.92%)
Unilateral adrenalectomy	5 (2.4%)
Bilateral adrenalectomy	4 (1.9%)
Medication only	8 (3.85%)
No therapy	3 (1.44%)

Table 2. Risk Factors for Thrombosis: Demographic, Clinical Data, and Treatment Modalities of Adult Patients With Cushing Syndrome Subdivided by Patients With TEs and Without TEs
Characteristic	Patients With TE (n = 39)	Patients Without TE (n = 167)	P	OR	95%CI
Age at time of event, y ± SD	49 ± 13.5	43 ± 13.5
Female, n, %	30, 81	133, 78.7	.69	0.83	0.34–2.05
Male, n, %	7, 19	36, 21	.69	0.83	0.34–2.05
Body mass index ± SD	33.3 ± 7.5	34 ± 8.6	.69	0.99	0.95–1.03
Smoker, n, %	14, 37.8	55, 32.5	.57	1.35	0.65–2.79
Hypertension, n, %	28, 75.6	117, 69.2	.38	1.43	0.63–3.24
Diabetes mellitus, n, %	15, 40.5	71, 42	.77	0.90	0.44–1.85
Estrogen^a, n, %	3, 7.14	39, 92.86	.62	^b	^b
Testosterone^a, n, %	3, 13.1	17, 73.9	.59	^b	^b
Cushing disease, n, %	35, 18.8	151, 81.2	.005	1.04	0.33–3.27
Adrenal Cushing syndrome, n, %	2, 14.3	12, 85.7	.19	^b	^b
Ectopic Cushing, n, %	2, 25	6, 75	.21	^b	^b
TSS, n, %	36, 19.15	152, 80.85	.35	2.01	0.44–9.10
BLA, n, %	14, 38.88	22, 61.11	.001	3.74	1.69–8.27
Pituitary radiation, n, %	5, 21.74	18, 78.26	.65	1.27	0.44–3.67

Table 2. Risk Factors for Thrombosis: Demographic, Clinical Data, and Treatment Modalities of Adult Patients With Cushing Syndrome Subdivided by Patients With TEs and Without TEs

Characteristic

Patients With TE (n = 39)

Patients Without TE (n = 167)

95%CI

Age at time of event, y ± SD

49 ± 13.5

43 ± 13.5

Female, n, %

30, 81

133, 78.7

.69

0.83

0.34–2.05

Male, n, %

7, 19

36, 21

.69

0.83

0.34–2.05

Body mass index ± SD

33.3 ± 7.5

34 ± 8.6

.69

0.99

0.95–1.03

Smoker, n, %

14, 37.8

55, 32.5

.57

1.35

0.65–2.79

Hypertension, n, %

28, 75.6

117, 69.2

.38

1.43

0.63–3.24

Diabetes mellitus, n, %

15, 40.5

71, 42

.77

0.90

0.44–1.85

Estrogen^a, n, %

3, 7.14

39, 92.86

.62

Testosterone^a, n, %

3, 13.1

17, 73.9

.59

Cushing disease, n, %

35, 18.8

151, 81.2

.005

1.04

0.33–3.27

Adrenal Cushing syndrome, n, %

2, 14.3

12, 85.7

.19

Ectopic Cushing, n, %

2, 25

6, 75

.21

TSS, n, %

36, 19.15

152, 80.85

.35

2.01

0.44–9.10

BLA, n, %

14, 38.88

22, 61.11

.001

3.74

1.69–8.27

Pituitary radiation, n, %

5, 21.74

18, 78.26

.65

1.27

0.44–3.67

Table 3. Thrombotic Events in Different Therapeutic Groups
Therapy	Thromboembolic Events
No	Yes	Total
BLA only, n	1	3	4
% of all patients	0.48	1.44	1.92
% of patient with BLA	25	75	100
% of patients w/wo TE	0.59	7.69
Medication only, n	8	0	8
% of all patients	3.86	0	3.85
% of patients with medication only	100	0	100
% of all patients w/wo TE	4.73	0
No therapy, n	3	0	3
% of all patients	1.44	0	1.44
% of patient with no therapy	100	0	100
% of all patients w/wo TE	1.78	0
TSS + BLA, n	21	11	32
% of all patients	10.1	5.29	15.38
% of patients with TSS + BLA	65.63	34.38	100
% of all patients w/wo TE	12.43	28.21
TSS + UA, n	4	0	4
% of all patients	1.92	0	1.92
% of patients with TSS + UA	100	0	100
% of all patients w/wo TE	2.37	0
TSS only, n	127	25	152
% of all patients	61.06	12.02	73.08
% of patients with TSS only	83.55	16.45	100
% of all patients w/wo TE	75.15	65.1
UA only, n	5	0	5
% of all patients	2.4	0	2.4
% of patients with UA only	100	0	100
% of all patients w/wo TE	2.96	0
Total, n	169	39	207
% of all patients	81.25	18.75	100
% of all patients w/wo TE	100	100

Table 3. Thrombotic Events in Different Therapeutic Groups

Therapy

Thromboembolic Events

Yes

Total

BLA only, n

% of all patients

0.48

1.44

1.92

% of patient with BLA

100

% of patients w/wo TE

0.59

7.69

Medication only, n

% of all patients

3.86

3.85

% of patients with medication only

100

% of all patients w/wo TE

4.73

No therapy, n

% of all patients

1.44

% of patient with no therapy

100

% of all patients w/wo TE

1.78

TSS + BLA, n

% of all patients

10.1

5.29

15.38

% of patients with TSS + BLA

65.63

34.38

100

% of all patients w/wo TE

12.43

28.21

TSS + UA, n

% of all patients

1.92

% of patients with TSS + UA

100

% of all patients w/wo TE

2.37

TSS only, n

127

152

% of all patients

61.06

12.02

73.08

% of patients with TSS only

83.55

16.45

100

% of all patients w/wo TE

75.15

65.1

UA only, n

% of all patients

2.4

% of patients with UA only

100

% of all patients w/wo TE

2.96

Total, n

169

207

% of all patients

81.25

18.75

100

% of all patients w/wo TE

100

Hypercoagulability in Cushing Syndrome, Prevalence of Thrombotic Events

A Large, Single-Center, Retrospective Study

Abstract and Introduction

Abstract

Introduction

Hypercoagulability in Cushing Syndrome, Prevalence of Thrombotic Events

A Large, Single-Center, Retrospective Study

Abstract and Introduction

Abstract

Introduction

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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