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Hormones, haemostasis, and the risk of thrombosis

van Zaane, B.

Publication date2010

Link to publication

Citation for published version (APA):van Zaane, B. (2010). Hormones, haemostasis, and the risk of thrombosis.

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Chapter 12Hypercoagulable state in Cushing’s syndrome: a systematic review

Bregje van Zaane, Erfan Nur, Alessandro Squizzato, Olaf M Dekkers, Marcel ThB Twickler, Eric Fliers, Victor EA Gerdes, Harry R Büller, Dees PM Brandjes

Journal of Clinical Endocrinology & Metabolism 2009;

94:2743-2750

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Hypercoagulable state in Cushing’s syndrome

IntroductionChronic glucocorticoid excess in patients with Cushing’s syndrome is associated with increased morbidity and mortality, mainly arising from cardiovascular complications due to persistent hypertension, obesity and glucose intolerance[1-3]. In addition, from the early 1970s onward, an increased risk of both unprovoked and postoperative venous thromboembolism (VTE) has been reported in patients with Cushing’s syndrome, further adding to the cardiovascular morbidity[4-6]. Nowadays, the presence of a glucocorticoid-induced hypercoagulable state, i.e. the propensity to develop thrombosis due to either an acquired or inherited increase in procoagulant elements or a decrease in anticoagulant elements, in patients with Cushing’s syndrome is a well-established notion that has prompted thromboprophylactic measures to be used in several centres[7-10]. Yet, recent guidelines on the treatment of Cushing’s syndrome or the prevention of thrombosis did not address this issue specifically[11;12]. This is not surprising, given the various designs and settings of the available studies. A large number of studies have methodological drawbacks, such as lack of a well-defined control group, small cohort/population sizes, and heterogeneity of both origin and severity of hypercortisolism, and therefore do not allow for definite conclusions.Knowing whether Cushing’s syndrome is associated with moderate or high risk of symptomatic venous thromboembolism is important because this may directly affect management in terms of choice, intensity, and duration of thromboprophylaxis. In this systematic review, we aimed to summarise published literature on the effects of glucocorticoid excess on coagulation and fibrinolysis, as well as on the clinical outcome of VTE. The review is confined to endogenous hypercortisolism.

Materials and MethodsSearch strategy and selection criteriaWe performed a computer-assisted search of the MEDLINE and EMBASE electronic databases in July 2008 for published studies investigating the effect of glucocorticoid excess on either haemostatic parameters or the occurrence of VTE in patients with endogenous Cushing’s syndrome of benign origin. The following search terms (free text, truncation and MeSH or EMTREE terms) were used: (“Cushing disease” OR “Cushing syndrome” OR “hypercortisolism” OR “hyper[adreno]corticism” OR “adrenocortical hyperplasia” OR “adrenocortical hyperfunction” OR “adrenocortical adenoma” OR “corticotroph adenoma” OR “ACTH secreting pituitary adenoma” OR “inappropriate ACTH secreting syndrome” OR “pituitary ACTH hypersecretion” OR “pituitary hyperplasia”) AND (“h[a]emostasis” OR “blood coagulation [tests/factors/inhibitors]” OR “hypercoagulability” OR “prothrombotic state” OR “[venous] thrombosis” OR “[thrombo]embolism” OR “deep[-]vein/venous thrombosis” OR “pulmonary embolism” OR “pulmonary infarction”). Reference lists of included studies were hand-searched to identify other potentially eligible studies. No restriction with respect to language was applied.For the effect of endogenous hypercortisolism on the coagulation and fibrinolytic system, studies reporting laboratory tests for evaluation of haemostatic parameters were eligible for inclusion. Included studies had to enroll patients with Cushing’s syndrome of benign

AbstractIntroduction: It has been debated whether an increased risk of venous

thromboembolism (VTE) exists in patients with Cushing’s syndrome. We aimed

to summarise published literature on the effects of endogenous hypercortisolism

on coagulation and fibrinolysis, as well as on the clinical outcome of VTE.

Methods: We searched the MEDLINE and EMBASE databases up to July 2008.

Review of reference lists further identified candidate studies. Two investigators

independently performed study selection and data extraction. Eligible studies

had to include patients with Cushing’s syndrome and evaluate either haemostatic

parameters in comparison with control persons or post-treatment levels, or

describe the occurrence of VTE. The Newcastle-Ottawa Scale was used to assess

study quality. A scoring system divided studies into categories of low, medium

and high quality.

Results: Of 441 identified publications, 15 reports were included. They contained

information on 8 cross-sectionals, 2 intervention- and 8 cohort studies. No high

quality studies were identified. Hypercoagulability was suggested by high levels

of factor VIII, IX and von Willebrand factor, and evidence of enhanced thrombin

generation. A risk of 1.9% and 2.5% was reported for VTE not provoked by surgery,

whereas risk of postoperative VTE varied between 0 and 5.6%, with one outlier of

20%. VTE was reported as cause of death in 0-1.9% of Cushing patients.

Conclusions: Available studies suggest a high risk of venous thrombosis in

patients with Cushing’s syndrome. Glucocorticoid-induced hypercoagulability

as well as surgery and obesity almost certainly contribute to this thrombotic

tendency.

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deviation, range). For haemostatic parameters, mean differences were calculated and further descriptive analysis was performed using notations of statistical significant increase, statistical significant decrease, or no statistical significant difference. The occurrence of venous thromboembolic events was described as risk.

ResultsSearch results and included studiesWe identified a total of 441 citations from the database and reference searches (Figure 1). Seventy-seven publications were considered potentially relevant, of which 46 were retrieved in full copy for further scrutiny. After review of the full text, another 31 publications were excluded for containing either insufficient (n=26) or duplicate data (n=1), or an inclusion date prior to 1980 (n=4). In total, 15 papers were included for the final analysis. Characteristics of included studies are summarised in Table 1. Six reports investigated coagulation and fibrinolytic parameters in patients with Cushing’s syndrome and 1 in subclinical Cushing’s syndrome[18-24]. Together, they included data on 8 cross-sectional and 2 intervention studies because 3 reports incorporated multiple designs or comparisons; 1 was designed as both cross-sectional and intervention study, also re-evaluating patients with Cushing’s syndrome after treatment, whereas 2 others contained additional comparison

Figure 1. Flow chart of the search strategy and selection.

origin and include either a normocortisolaemic control group or a pre- and post-treatment assessment. For evaluation of clinical outcomes, cohort studies describing the occurrence of symptomatic VTE in patients with Cushing’s syndrome, irrespective of whether they were preceded by surgical intervention, were included[13]. For either purpose, case reports, case series, reviews, editorials, in vitro and non-human studies were excluded. Furthermore, in light of the well-recognised association between cancer and VTE, studies on patients with adrenal carcinoma as well as patients with ectopic Cushing’s syndrome due to a malignant tumour, were not eligible for the present review. If a study included patients with Cushing’s syndrome of both malignant and benign origin, and subgroup analysis for the latter could be performed, we extracted only data for this subgroup. Finally, considering that non-invasive diagnostic methods for venous thrombosis came into routine use only after the introduction of impedance plethysmography in 1972 and its subsequent validation to “gold standard” in the following years, we have solely included papers that evaluated patients with cushing’s syndrome from 1980 onwards[14;15].

Data extractionTwo investigators reviewed search results and independently performed study selection and data extraction. Full articles were retrieved for further assessment if the information in the abstract suggested that the aforementioned inclusion criteria were satisfied. No attempt was made to translate papers written in a language unknown to the reviewers (other than English, French, Spanish, German, Dutch, and Italian). Decisions regarding inclusion or data extraction were made separately and any disagreement was resolved by consensus or the opinion of a third reviewer, if necessary. The following characteristics were collected, if applicable: (i) underlying cause of Cushing’s syndrome; (ii) type of treatment; (iii) total number of Cushing patients and controls; (iv) mean time of follow-up; (v) performed coagulation/fibrinolytic tests and statistical difference of each coagulation test of either cases vs controls, or pre- vs post-treatment levels; (vi) number and type of VTE, time from treatment, and cortisol status around the time of VTE (hyper- or eucortisolism).

Quality assessmentThe Newcastle-Ottawa Scale (NOS scale) for assessing quality of non-randomised studies in meta-analysis was used as a guide to assess study quality[16]. This scale assesses three broad areas: (i) selection; (ii) comparability; (iii) outcome or exposure. For summarising study validity, we adopted a simple Cochrane Collaboration approach for interventional studies[17]. Three categories were therefore identified: high quality (low risk of bias), medium quality (moderate risk of bias), or low quality (high risk of bias). Quality of the included studies was assessed independently by the same two reviewers and any differences were resolved by consensus or the opinion of the third reviewer, if necessary. No attempts to mask for authorship, journal name or institution were made. Appendix 1 details the quality assessment and scoring system.

Statistical analysisCategorical data were presented as number (n) and percent (%). Continuous variables were summarised using measures of central tendency (mean, median) and dispersion (standard

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Tab

le 1

. Ch

arac

teri

stic

s o

f in

clu

ded

stu

die

s.

Sou

rce

Stu

dy

des

ign

Tota

l n

o.

of

pat

ien

ts

Un

der

lyin

g ca

use

of

cort

iso

l ex

cess

(n)

Qu

alit

y H

aem

ost

atic

par

amet

ers

VT

E

Dal

Bo

Zan

on

et a

l 198

2[18]

Inte

rven

tion

15Pi

tuit

ary

aden

oma

(8)

Ad

ren

al a

den

oma

(6)

Bila

tera

l adr

enal

an

d pi

tuit

ary

aden

omas

(1

)

Low

PT, a

PTT,

FV

III:

Ag/

C, V

WF:

C,

fibr

inog

en, F

DP,

fibr

inol

ytic

act

ivit

y,

ATI

II, p

late

let

aggr

egat

ion

(ris

toce

tin

)

Smal

l et

al

1983

[29]

Coh

ort

10A

dre

nal

ad

enom

a (6

)Pi

tuit

ary

dri

ven

ad

ren

al h

yper

pla

sia

(4)

Med

ium

Post

oper

ativ

e

Ikk

ala

et a

l 19

85[2

0]

Cro

ss-s

ecti

onal

10Pi

tuit

ary

aden

oma

(7)

Ad

ren

al a

den

oma

(3)

Low

Ble

edin

g ti

me,

pla

tele

t ag

greg

atio

n

(AD

P, a

dre

nal

ine,

col

lage

n)

Patr

assi

et

al

1985

[21]

Cro

ss-s

ecti

onal

9

Pitu

itar

y ad

enom

a (6

)A

dre

nal

ad

enom

a (1

)Bi

late

ral a

dren

al a

nd

pitu

itar

y ad

enom

as

(2)

Low

FVII

I:A

g/C

, FIX

:C, F

XI:

C, F

XII

:C,

VW

F:C

, pla

smin

ogen

:C, α

2-an

tip

lasm

in:C

, kal

likr

ein

:C, p

re-

kal

likr

ein

:C

Patr

assi

et

al

1992

[22]

Cro

ss-s

ecti

onal

30

Pitu

itar

y ad

enom

a (1

9)A

dre

nal

ad

enom

a (8

)B

oth

ad

ren

al a

nd

pit

uit

ary

aden

oma

(3)

Low

aPTT

, FV

III:

C, V

WF:

Ag,

fibr

inog

en,

pla

smin

ogen

:C, E

LT, t

-PA

, PA

, PA

I-1

Sem

ple

et

al

1999

[27]

Coh

ort

105

Pitu

itar

y ad

enom

aLo

wPo

stop

erat

ive

Fatt

i et

al

2000

[19]

Cro

ss-s

ecti

onal

C

ross

-sec

tion

ala

17Pi

tuit

ary

aden

oma

(15)

Ad

ren

al a

den

oma

(2)

Low

Low

Ble

edin

g ti

me,

PT,

aPT

T, F

VII

:Ag/

C,

FXII

:C, V

WF:

Ag,

F1+

2, T

AT,

d-d

imer

, PA

I-1, P

AP

Sire

n e

t al

20

00[2

8]

Coh

ort

3Pi

tuit

ary

aden

oma

(1)

Ad

ren

al a

den

oma

(2)

Low

Post

oper

ativ

e

Ch

ee e

t al

20

01[2

5]

Coh

ort

61Pi

tuit

ary

aden

oma

Med

ium

Lon

g-te

rm

foll

ow-u

pb

Bos

caro

et

al

2002

[7]

Coh

ort

203

Pitu

itar

y ad

enom

a (1

51)

Ad

ren

al a

den

oma

(35)

AC

TH-d

epen

den

t ad

ren

al h

yper

plas

ia (1

2)A

CTH

-inde

pen

den

t ad

ren

al h

yper

plas

ia (5

)

Med

ium

Post

oper

ativ

eLo

ng-

term

fo

llow

-up

Ree

s et

al

2002

[26]

Coh

ort

54Pi

tuit

ary

aden

oma

Med

ium

Post

oper

ativ

eLo

ng-

term

fo

llow

-up

b

Tau

chm

anov

a et

al 2

002[2

3]

Cro

ss-s

ecti

onal

Inte

rven

tion

28 8

Ad

ren

al m

ass

(in

cid

enta

lom

a)M

ediu

mLo

wPT

c , aP

TTc ,

fibr

inog

en

Sud

hak

ar e

t al

200

4[30]

Coh

ort

22Pi

tuit

ary

aden

oma

Low

Post

oper

ativ

e

Terz

olo

et a

l 20

04[2

4]

Cro

ss-s

ecti

onal

Cro

ss-

sect

ion

ala

41Pi

tuit

ary

aden

oma

(25)

Ad

ren

al a

den

oma

(5)

AC

TH-in

dep

ende

nt

adre

nal

hyp

erp

lasi

a (5

)N

on-in

vasi

ve e

ctop

ic A

CTH

(ben

ign

) (6)

Med

ium

Med

ium

PT, a

PTT,

fibr

inog

en

Zog

rafo

s et

al

2006

[31]

Coh

ort

18Pi

tuit

ary

aden

oma

(4)

Ad

ren

al a

den

oma

(14)

Low

Post

oper

ativ

e

N i

nd

icat

es n

um

ber;

VTE

, ven

ous

thro

mbo

embo

lism

; PT,

pro

thro

mbi

n t

ime;

aPT

T, a

ctiv

ated

par

tial

th

rom

bop

last

in t

ime;

F, f

acto

r; A

g, a

nti

gen

; C, a

ctiv

ity;

VW

F, v

on

Wil

leb

ran

d f

acto

r; F

DP,

fib

rin

deg

rad

atio

n p

rod

uct

; A

TIII

, an

tith

rom

bin

-III;

AD

P, a

den

osin

e 5’

-dip

hos

ph

ate;

ELT

, eu

glob

uli

n l

ysis

tes

t; t

-PA

, tis

sue-

typ

e p

lasm

inog

en

acti

vato

r; P

A,

pla

smin

ogen

act

ivat

ors;

PA

I-1,

pla

smin

ogen

act

ivat

or i

nh

ibit

or-1

; F1

+2,

pro

thro

mb

in f

ragm

ent

1+2;

TA

T, t

hro

mb

in-a

nti

thro

mb

in c

omp

lex;

an

d P

AP,

p

lasm

in-a

nti

pla

smin

com

ple

x.a P

atie

nts

wit

h C

ush

ing’

s sy

nd

rom

e vs

pat

ien

ts i

n r

emis

sion

of

Cu

shin

g’s

syn

dro

me.

b VTE

-rel

ated

mor

tali

ty.

c Not

tes

ted

in

in

terv

enti

on s

tud

y.

168

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12

169


with patients in remission of Cushing’s syndrome[19;23;24]. Eight papers reported on the occurrence of VTE in patients with Cushing’s syndrome[7;25-31]. Five described this complication within three months after pituitary or adrenal surgery (postoperative VTE), 1 contained information on venous thromboembolic disease during long-term follow-up, and 2 were concerned with both postoperative and long-term incidence of VTE.

Methodological quality of included studiesNo high quality studies were identified. Three cross-sectional and 4 cohort studies were of medium quality[7;23-26;29] (Appendix 2). For cross-sectional and intervention studies, items with a low score included the definition of patients, the definition of post-intervention cortisol concentration, and the definition of a normocortisolaemic control group. This was mainly due to negligence to report the timing of the coagulation tests in relation to the cortisol measurement and failure to report cortisol measurement at inclusion. For cohort studies, main items yielding a low score included the demonstration that the outcome of interest was not present prior to study onset, the assessment of exposure, and adequacy of follow-up (i.e. failure to describe history of VTE, cortisol status at the time of thrombosis, and the number of patients lost to follow-up).

Coagulation and fibrinolytic parametersData on coagulation and fibrinolytic tests in medium (n=3) and low (n=7) quality studies are summarised in Tables 2 and 3, respectively. Activated partial thromboplastin time (aPTT), prothrombin time (PT), and fibrinogen were the only parameters reported in the three medium-quality studies[23;24]. A shortening of the aPTT was found in the majority of studies, whereas PT, bleeding time, and platelet aggregation were mostly unchanged in patients with Cushing’s syndrome. All tests of coagulation factors were slightly increased during glucocorticoid excess, but statistical significance was only reached for FVIII, FIX, and VWF. For (anti)fibrinolytic tests, a statistical increase in plasmin-antiplasmin complex (PAP), plasminogen activity, tissue-type plasminogen activator antigen (t-PA:Ag) and α2-antiplasmin activity was observed, as well as a trend of increased levels of D-dimer and plasminogen activator inhibitor-1 activity (PAI-1:C). Impaired fibrinolytic activity, as well as increased levels of factor XII activity and kallikrein, was reported once. Except for the increase in FVIII, FIX and VWF, no univocal statistical significant differences were observed between patients with active Cushing’s syndrome and those in remission[18;19;24]. In addition, no clear difference was observed for subclinical Cushing’s syndrome[23].

Clinical outcome of VTETable 4 summarises the data on clinical outcomes of VTE. In 8 studies, a total of 476 patients with Cushing’s syndrome were described: 78 cases of adrenal hypercortisolism, 398 cases of Cushing’s disease. VTE not provoked by surgery was reported in 2 studies, with cumulative incidences of 1/54 (1.9%) and 5/203 (2.5%)[7;26]. Five of these 6 events occurred during persistent hypercortisolism or relapse. The reported risk of postoperative VTE was less than 6% in 7 studies, but it was reported to be 20% in one study[29]. VTE, i.e. pulmonary embolism, was reported as cause of death in 0-1.9% of patients with Cushing’s syndrome, and mostly occurred within 3 months after surgery. T

able

2. O

vera

ll c

oag

ula

tio

n a

nd

fib

rin

oly

tic

chan

ges

in m

ediu

m q

ual

ity

stu

die

s.

CS

com

par

ed t

o h

ealt

hy

con

tro

lsC

S co

mp

ared

to

CS

in r

emis

sio

n

Firs

t au

tho

rPa

tien

ts(n

)C

on

tro

ls(n

)St

atis

tica

l d

iffe

ren

ceM

ean

D

iffe

ren

ce

(%)

Co

ntr

ols

(n)

Stat

isti

cal

dif

fere

nce

Mea

n

Dif

fere

nce

(%

)

aPTT

Tau

chm

anov

a[23]

-a28

100

=4.

4

Terz

olo[2

4]41

105

-1

0.0

16=

-8.3

PTTa

uch

man

ova[2

3]-a

2810

0=

5.5

Terz

olo[2

4]41

105

9.

416

=6.

6

Fibr

inog

enTa

uch

man

ova[2

3]-a

2810

0

21.7

Terz

olo[2

4]41

105

=4.

916

=1.

7

Mea

n d

iffe

ren

ce is

pre

sen

ted

in p

erce

nta

ge c

han

ge a

s op

pos

ed t

o va

lues

in h

ealt

hy

con

trol

s or

pat

ien

ts in

rem

issi

on o

f C

ush

ing’

s sy

nd

rom

e. P

osit

ive

resu

lts

corr

esp

ond

w

ith

in

crea

sed

val

ues

, an

d n

egat

ive

resu

lts

wit

h d

ecre

ased

val

ues

in

pat

ien

ts w

ith

Cu

shin

g’s

syn

dro

me

com

par

ed t

o h

ealt

hy

con

trol

s or

pat

ien

ts i

n r

emis

sion

of

Cu

shin

g’s

syn

dro

me.

CS

ind

icat

es C

ush

ing’

s sy

nd

rom

e; n

, nu

mbe

r; a

PTT,

act

ivat

ed p

arti

al t

hro

mbo

pla

stin

tim

e; P

T, p

roth

rom

bin

tim

e;

, sta

tist

ical

sig

nifi

can

t in

crea

se;

, sta

tist

ical

sig

nifi

can

t d

ecre

ase;

an

d =

, no

stat

isti

cal

sign

ifica

nt

dif

fere

nce

.a S

ubc

lin

ical

Cu

shin

g’s

syn

dro

me.

170

Cha

pter

12

171


Coag

ulat

ion

test

s

F1+2

Fatt

i[19]

1720

=1.

412

=0.

7

TAT

Fatt

i[19]

1720

82

.712

=59

.3

Fact

or V

II:A

gFa

tti[1

9]17

20=

20.2

12=

9.2

Fact

or V

II:C

Fatt

i[19]

1720

=7.

512

=14

.9

Fact

or V

III:

Ag

Patr

assi

[21]

920

70

.2

Dal

Bo

Zan

on[1

8]15

15b

N

R

Fact

or V

III:

CPa

tras

si[2

1]9

20

90.3

Dal

Bo

Zan

on[1

8]15

15b

N

R

Patr

assi

[22]

3030

60

.6

VW

F:A

gFa

tti[1

9]17

20

64.5

12

40.3

Patr

assi

[22]

3030

71

.5

VW

F:C

Patr

assi

[22]

920

69

.5

Dal

Bo

Zan

on[1

8]15

15b

N

R

Fact

or I

X:C

Patr

assi

[21]

920

45

.1

Fact

or X

I:C

Patr

assi

[21]

920

=14

.4

Tab

le 3

. Ove

rall

co

agu

lati

on

an

d fi

bri

no

lyti

c ch

ange

s in

lo

w q

ual

ity

stu

die

s.

CS

com

par

ed t

o h

ealt

hy

con

tro

lsC

S co

mp

ared

to

CS

in r

emis

sio

n

Firs

t au

tho

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172

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173


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DiscussionThe presence of haemostatic abnormalities and the risk of venous thrombosis in patients with Cushing’s syndrome have been the subject of investigation for several decades. In the present systematic review that delineated whether a haemostatic imbalance exists in endogenous hypercortisolism, chronic glucocorticoid excess is suggested to induce hypercoagulability of the blood, resulting in a substantial risk of venous thromboembolic events in patients with Cushing’s syndrome.

In this review, the risk of postoperative venous thrombosis varied between 0% and 5.6%, and this was observed in all but one study. The risk of postoperative VTE in that particular study was considerably higher (20%). In a nationwide inpatient sample database on trends, complications and outcomes following transsphenoidal surgery for Cushing’s disease, venous thrombosis was reported in 0.7% of identified cases[32]. It is, however, important to recognise that the observed risk only applied for in-hospital complications (mean length of stay 5.5 days), whereas symptomatic VTE most commonly presents after discharge[33;34]. Moreover, the transsphenoidal approach in pituitary surgery is associated with a short hospital stay compared to patients treated by transcranial approach.Given variation in the reported numbers of events, it is impossible to classify this risk of VTE as low, moderate, or high. In general, the rates of symptomatic VTE following transsphenoidal surgery or laparoscopic adrenal procedures for a mixture of endocrine disorders, sometimes even including Cushing’s syndrome, vary between 0 and 1.5% (transsphenoidal surgery) and from 0.8-3% (laparoscopic adrenal surgery)[28;30;31;35-42]. These results possibly suggest an enhanced risk of postoperative VTE that is inherent to endogenous glucocorticoid excess. When compared to VTE rates following major orthopaedic surgery (1.3-4.4% after total hip or knee replacement under routine use of thromboprophylaxis), neurosurgery (0.5-2.3%), gastrointestinal surgery (0.2-1.6%) or urologic surgery (0.3-1.0%), the risk reported in patients with Cushing’s syndrome is striking[12;43-46]. Of note, in the majority of these surgeries patients likely received some form of thromboprophylaxis, but this also holds for the series included in our review. In fact, the 4.4% risk observed by Boscaro and colleagues under extended postoperative prophylaxis with heparin and warfarin is still in range with that reported under thromboprophylaxis following total knee or hip replacement, which is a procedure considered at high risk for VTE[7;43;44].

VTE not provoked by surgical intervention was observed in 1.9% (1/54) and 2.5% (5/203) of patients with Cushing’s syndrome. Given the mean follow-up of 6.0 and 9.7 years in these studies, this corresponds with an incidence of VTE of 3.1 and 2.5 per 1000 persons-years, respectively[7;26]. In the normal population, the estimated incidence rates for VTE vary between 1 and 2 per 1000 person-years[47;48]. However, the incidence of thrombosis increases exponentially with age, and is slightly higher in women than in men. In both studies on Cushing’s syndrome, the majority of the patients were women with a mean age of 40 years, among whom an incidence rate of 0.27 per 1000 person-years is reported[49]. This further indicates that patients with Cushing’s syndrome are at high risk for VTE. T

able

4. C

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ou

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of

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t p

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by

surg

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n (%

)

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-o

per

ativ

e V

TE

n

(%)

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n (%

)

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(%)

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l[29]

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5]-a

1980

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1 (1

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.6)

PE

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s[26]

1980

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dal

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1 (1

.9)a

3

(5.6

)1

(1.9

)D

VT,

PE

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caro

[7]-c

1982

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0Su

rger

y, i

rrad

iati

on,

or m

edic

al t

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apy

203

5 (2

.5)

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.4)

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T, P

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cava

th

rom

bosi

s

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ple

[27]

1992

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(3.8

)0

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VT

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n[2

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95-1

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cop

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dre

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ecto

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30

(0.0

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0 (0

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96-2

001

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(4.5

)0

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0 (0

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s[31]

1997

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701

(1.4

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9(0

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N i

nd

icat

es n

um

ber;

VTE

, ven

ous

thro

mbo

embo

lism

; PE,

pu

lmon

ary

embo

lism

; an

d D

VT,

dee

p v

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bosi

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bu

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ith

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at

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mon

ths.

176

Cha

pter

12

177


number of the coagulation tests performed, and the observed alterations have rarely been confirmed in larger experiments. Because of its rarity, prospective studies on haemostatic abnormalities in Cushing’s syndrome are difficult to carry out. Nonetheless, high quality prospective studies are needed to confirm the observed alterations in coagulation and fibrinolytic parameters, and the presence of a hypercoagulable state in patients with Cushing’s syndrome.

In summary, this review showed that ample literature exists on haemostatic (im)balance in Cushing’s syndrome. The available studies suggest a high risk of venous thrombosis in patients with Cushing’s syndrome. Glucocorticoid-induced hypercoagulability as well as surgery and obesity, all conditions that patients with Cushing’s syndrome are subject to, almost certainly contribute to this thrombotic tendency. We therefore recommend that thromboprophylaxis with low-molecular weight heparin (LMWH), low-dose unfractionated heparin (LDUH), or fondaparinux be used routinely in patients with Cushing’s syndrome undergoing transsphenoidal or adrenal surgery (open or laparoscopic). However, well-designed studies are needed in the future to provide more definitive data. They should primarily focus on both the incidence of VTE during the overall course of Cushing’s syndrome and VTE risk after surgery. Only then can the choice, intensity, and duration of thromboprophylaxis, either peri- or postoperative or during active Cushing’s syndrome in general, be addressed further.

References1. Dekkers OM, Biermasz NR, Pereira AM, Roelfsema F, van Aken MO, Voormolen JH, Romijn JA. Mortality in

patients treated for Cushing’s disease is increased, compared with patients treated for nonfunctioning pituitary macroadenoma. J Clin Endocrinol Metab 2007; 92:976-81.

2. Etxabe J, Vazquez JA. Morbidity and mortality in Cushing’s disease: an epidemiological approach. Clin Endocrinol (Oxf) 1994; 40:479-84.

3. Lindholm J, Juul S, Jorgensen JO, Astrup J, Bjerre P, Feldt-Rasmussen U, Hagen C, Jorgensen J, Kosteljanetz M, Kristensen L, Laurberg P, Schmidt K, Weeke J. Incidence and late prognosis of cushing’s syndrome: a population-based study. J Clin Endocrinol Metab 2001; 86:117-23.

4. Blichert-Toft M, Bagerskov A, Lockwood K, Hasner E. Operative treatment, surgical approach, and related complications in 195 operations upon the adrenal glands. Surg Gynecol Obstet 1972; 135:261-6.

5. Delaney JP, Solomkin JS, Jacobson ME, Doe RP. Surgical management of Cushing’s syndrome. Surgery 1978; 84:465-70.

6. Pezzulich RA, Mannix H, Jr. Immediate complications of adrenal surgery. Ann Surg 1970; 172:125-30.7. Boscaro M, Sonino N, Scarda A, Barzon L, Fallo F, Sartori MT, Patrassi GM, Girolami A. Anticoagulant

prophylaxis markedly reduces thromboembolic complications in Cushing’s syndrome. J Clin Endocrinol Metab 2002; 87:3662-6.

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12. Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

To interpret the presented results on haemostatic parameters, some understanding of the coagulation and fibrinolytic system, including the use of its specific tests, is needed. For example, an increased plasma level (antigen) or activity of each of the individual coagulation factors indicates the presence of a hypercoagulable state, whereas actual coagulation activation with subsequent thrombin generation is measured by levels of fragments or peptides released during the clotting process, such as prothrombin fragment 1+2 and thrombin-antithrombin complexes. Thrombin itself activates the fibrinolytic system to counterbalance coagulation. Therefore, increased levels of D-dimer, fibrin degradation products (FDP) and PAP, all products released during the process of fibrinolysis, suggest not only apt activation of the fibrinolytic system but also enhanced in vivo thrombin generation. In general, decreased fibrinolytic activity, for instance by increased levels of inhibitory factors, will add to an increased risk of thrombosis[50]. Based on this information, the available evidence revealed four important findings: 1) glucocorticoid excess in patients with Cushing’s syndrome modifies coagulation and fibrinolytic parameters; 2) the hypothesis of a glucocorticoid-induced hypercoagulable state in patients with Cushing’s syndrome is supported by the presence of high levels of factor VIII, factor IX and von Willebrand factor, with subsequent shortening of aPTT and evidence of enhanced thrombin generation; 3) levels of factor VIII, factor IX and von Willebrand factor tend to normalise after successful treatment; and 4) impaired fibrinolytic activity can not be established as both stimulators and inhibitors of fibrinolysis are increased. In summary, glucocorticoid-induced hypercoagulability and enhanced thrombin generation in patients with Cushing’s syndrome are likely, but the overall effect on fibrinolysis remains unclear. Putative mechanisms by which glucocorticoids may influence haemostatic parameters are ill-defined, yet it is most likely that they do so by glucocorticoid-receptor mediated upregulation of gene transcription[51-55].

Several limitations of our systematic review should be addressed. First, use of quality scoring in meta-analyses for observational studies is controversial[56;57]. For this reason, we used the Newcastle-Ottawa Scale as a guide to assess study quality and a simple Cochrane Collaboration approach for summarising study validity[17]. A scoring scale and quality cut-off scores were introduced to simplify the rating. Albeit quality scoring is arbitrary, we feel that it does provide relevant information on study design and identifies studies at low, medium ,or high risk for bias. Second, only 2 cohort studies specifically focused on the occurrence of thromboembolic events in patients with Cushing’s syndrome. All others were primarily concerned with operative management in transsphenoidal or adrenal surgery, and solely described the occurrence of venous thrombosis in the context of overall morbidity and mortality. Underreporting of VTE is therefore conceivable. On the other hand, we have possibly overlooked studies with a null outcome of VTE-related morbidity and mortality following surgical treatment for Cushing’s syndrome by means of our search strategy, thereby inadvertently overestimating the risk for venous thrombosis to develop. However, it is most likely that in those studies that do not specifically describe whether or not venous thromboembolic complications have occurred, VTE was merely not evaluated rather than being absent. Last, the number of studies investigating haemostatic parameters in Cushing’s syndrome was small, the strength of medium quality studies was tempered by the limited

178

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syndrome. Acta Med Scand 1985; 217:507-11.21. Patrassi GM, Dal Bo ZR, Boscaro M, Martinelli S, Girolami A. Further studies on the hypercoagulable state

of patients with Cushing’s syndrome. Thromb Haemost 1985; 54:518-20.22. Patrassi GM, Sartori MT, Viero ML, Scarano L, Boscaro M, Girolami A. The fibrinolytic potential in patients

with Cushing’s disease: a clue to their hypercoagulable state. Blood Coagul Fibrinolysis 1992; 3:789-93.23. Tauchmanova L, Rossi R, Biondi B, Pulcrano M, Nuzzo V, Palmieri EA, Fazio S, Lombardi G. Patients

with subclinical Cushing’s syndrome due to adrenal adenoma have increased cardiovascular risk. J Clin Endocrinol Metab 2002; 87:4872-8.

24. Terzolo M, Allasino B, Bosio S, Brusa E, Daffara F, Ventura M, Aroasio E, Sacchetto G, Reimondo G, Angeli A, Camaschella C. Hyperhomocysteinemia in patients with Cushing’s syndrome. J Clin Endocrinol Metab 2004; 89:3745-51.

25. Chee GH, Mathias DB, James RA, Kendall-Taylor P. Transsphenoidal pituitary surgery in Cushing’s disease: can we predict outcome? Clin Endocrinol (Oxf) 2001; 54:617-26.

26. Rees DA, Hanna FW, Davies JS, Mills RG, Vafidis J, Scanlon MF. Long-term follow-up results of transsphenoidal surgery for Cushing’s disease in a single centre using strict criteria for remission. Clin Endocrinol (Oxf) 2002; 56:541-51.

27. Semple PL, Laws ER, Jr. Complications in a contemporary series of patients who underwent transsphenoidal surgery for Cushing’s disease. J Neurosurg 1999; 91:175-9.

28. Siren J, Haglund C, Haapiainen R. An institutional experience with 40 first lateral transperitoneal laparoscopic adrenalectomies. Surg Laparosc Endosc Percutan Tech 2000; 10:382-6.

29. Small M, Lowe GD, Forbes CD, Thomson JA. Thromboembolic complications in Cushing’s syndrome. Clin Endocrinol (Oxf) 1983; 19:503-11.

30. Sudhakar N, Ray A, Vafidis JA. Complications after trans-sphenoidal surgery: our experience and a review of the literature. Br J Neurosurg 2004; 18:507-12.

31. Zografos GN, Markou A, Ageli C, Kopanakis N, Koutmos S, Kaltsas G, Piaditis G, Papastratis G. Laparoscopic surgery for adrenal tumors. A retrospective analysis. Hormones (Athens ) 2006; 5:52-6.

32. Patil CG, Lad SP, Harsh GR, Laws ER, Jr., Boakye M. National trends, complications, and outcomes following transsphenoidal surgery for Cushing’s disease from 1993 to 2002. Neurosurg Focus 2007; 23:E7.

33. Huber O, Bounameaux H, Borst F, Rohner A. Postoperative pulmonary embolism after hospital discharge. An underestimated risk. Arch Surg 1992; 127:310-3.

34. White RH, Romano PS, Zhou H, Rodrigo J, Bargar W. Incidence and time course of thromboembolic outcomes following total hip or knee arthroplasty. Arch Intern Med 1998; 158:1525-31.

35. Black PM, Zervas NT, Candia GL. Incidence and management of complications of transsphenoidal operation for pituitary adenomas. Neurosurgery 1987; 20:920-4.

36. Ciric I, Ragin A, Baumgartner C, Pierce D. Complications of transsphenoidal surgery: results of a national survey, review of the literature, and personal experience. Neurosurgery 1997; 40:225-36.

37. Emeriau D, Vallee V, Tauzin-Fin P, Ballanger P. [Morbidity of unilateral and bilateral laparoscopic adrenalectomy according to the indication. Report of a series of 100 consecutive cases]. Prog Urol 2005; 15:626-31.

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1.3 Cohort studies.1) Representativeness of exposed cohort (1 point was given if patients suffered from endogenous

hypercortisolism and the underlying cause of hypercortisolism was described for all patients);2) Ascertainment of exposure (1 point was given if diagnostic tests were described);3) Demonstration that outcome of interest was not present at start of study (1 point was given

if history of VTE was explicitly described for all patients); 4) Assessment of outcome (1 point was given if outcome was assessed using validated imaging

tests or post mortem examination);5) Assessment of state/severity of exposure (retrospective studies: 1 point was given if state

or severity of exposure was described, or cortisol concentration was measured around the time of outcome; prospective studies: 1 point was given if cortisol concentration was measured within 48 hours of outcome);

6) Time of follow-up (1 point was given if time of follow-up was explicitly stated in the method section on study design and was adequate considering the specific aim of the study);

7) Adequacy of follow-up of cohort (1 point was given if complete follow-up was reached; all subjects were accounted for; subjects lost to follow-up were unlikely to introduce bias; a small number was lost; ≥95 % follow-up was reached; or a description of those lost was provided).

A total of 6 points or more was considered a high quality study; 4 or 5 points, a medium quality study; 3 points or less, a low quality one.

Appendix 1. Main items of quality assessment and their scoring.

1.1 Cross-sectional studies.1) Definition of patients with endogenous Cushing’s syndrome of benign origin (1 point was given if

definition of hypercortisolism was based on serum, salivary or urinary free cortisol concentration combined with dexamethasone suppression test; underlying cause of Cushing’s syndrome was described; interval between cortisol measurement and coagulation tests was less than 48 hours);

2) Selection of patients (1 point was given if they were consecutive or obviously representative series of cases);

3) Definition of a normocortisolaemic control group (1 point was given if it was explicitly stated that controls had no history of hypercortisolism or if cortisol concentration was measured at inclusion);

4) Selection of control group (1 point was given if it was a community control group);5) Comparability on the basis of design or analysis (1 point was given if controls were age- and gender-

matched, or if there was an adequate adjustment for age and gender in the statistical analysis).

A total of five points was considered a high quality study; 4 points, a medium quality study; 3 points or less, a low quality one.

1.2 Intervention studies.1) Definition of patients with endogenous Cushing’s syndrome of benign origin (1 point was given if

definition of hypercortisolism was based on serum, salivary or urinary free cortisol concentration combined with dexamethasone suppression test; underlying cause of Cushing’s syndrome was described; interval between cortisol measurement and coagulation tests was less than 48 hours);

2) Selection of patients (1 point was given if they were consecutive or obviously representative series of cases);

3) Definition of post-intervention cortisol concentration (1 point was given if cortisol measurement was repeated to define post-intervention cortisol status; interval between assessment of cortisol concentration and coagulation tests was less than 48 hours);

4) Comparability of post-intervention status (2 or 1 points were given if 100% or more than 90% of patients (but not all), respectively, had returned to normocortisolism).

A total of five points was considered a high quality study; 4 points, a medium quality study; 3 points or less, a low quality one.

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Table 3. Individual study quality assessment of cohort study design.

Source Rep

rese

nta

tive

nes

s o

f co

ho

rt

Asc

erta

inm

ent

of

exp

osu

re

Ou

tco

me

no

t p

rese

nt

Ass

essm

ent

of

ou

tco

me

Stat

e o

f ex

po

sure

Tim

e o

f fo

llow

-up

Ad

equ

acy

of

foll

ow-u

p

Sco

re

Quality

Small et al 1983[29] 1 1 1 1 0 0 0 4 Medium

Semple et al 1999[27] 1 1 0 0 0 0 0 2 Low

Siren et al 2000[28] 1 0 0 1 0 0 0 2 Low

Chee et al 2001[25] 1 1 0 0 0 1 1 4 Medium

Boscaro et al 2002[7] 1 1 0 1 1 1 0 5 Medium

Rees et al 2002[26] 1 1 0 0 0 1 1 4 Medium

Sudhakar et al 2004[30] 1 0 0 0 0 0 0 1 Low

Zografos et al 2006[31] 0 0 0 0 0 0 0 0 Low

Total (n, %) 7 (88%) 5 (63%) 1 (13%) 3 (38%) 1 (13%) 3 (38%) 2 (25%)

N indicates number.

Appendix 2. Overview of quality assessment.

Table 1. Individual study quality assessment of cross-sectional study design.

SourceDescription of controls Pa

tien

ts

defi

nit

ion

Pati

ents

se

lect

ion

Co

ntr

ols

d

efin

itio

n

Co

ntr

ols

se

lect

ion

Gen

der

-age

co

mp

arab

ilit

y

Sco

re

Quality

Ikkala et al 1985[20] No description 0 1 0 0 0 1 Low

Patrassi et al 1985[21] Normal subjects 0 0 0 0 1 1 Low

Patrassi et al 1992[22] Normal subjects 0 0 0 0 1 1 Low

Fatti et al 2000[19] Healthy subjects 0 0 0 0 1 1 Low

Fatti et al 2000[19] CS in remission 0 0 1 1 0 2 Low

Tauchmanova et al 2002[23]

Patients undergoing abdominal US

0 1 1 1 1 4 Medium

Terzolo et al 2004[24] Healthy subjects 1 1 0 1 1 4 Medium

Terzolo et al 2004[24] CS in remission 1 1 1 1 0 4 Medium

Total (n, %) 2 (25%) 4 (50%) 3 (38%) 4 (50%) 5 (63%)

CS indicates Cushing’s syndrome; US, ultrasound; and n, number.

Table 2. Individual study quality assessment of interventional study design.

Source Pati

ents

d

efin

itio

n

Pati

ents

sel

ecti

on

Defi

nit

ion

of

pos

t-in

terv

enti

on

cort

isol

Co

mp

arab

ilit

y o

f p

ost

-in

terv

enti

on

st

atu

s

Sco

re

Quality

Dal Bo Zanon et al 1982[18] 0 0 0 2 2 Low

Tauchmanova et al 2002[23] 0 1 0 0 1 Low

Total (n, %) 0 (0%) 1 (50%) 0 (0%) 2 (50%)

N indicates number.

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