THE AMERICAN JOURNAL OF GASTROENTEROLOGY
1, 2000
© 2000 by Am. Coll. of Gastroenterology
Published by Elsevier Science Inc.
Resistance to Activated Protein C
and Low Levels of Free Protein S in
Greek Patients With Inflammatory Bowel Disease
I. E. Koutroubakis, M.D., A. Sfiridaki, M.D., I. A. Mouzas, M.D., A. Maladaki, M.S., A. Kapsoritakis, M.D.,
M. Roussomoustakaki, M.D., E. A. Kouroumalis, M.D., Ph.D., and O. N. Manousos, M.D., Ph.D.
Department of Gastroenterology, University Hospital of Heraklion; and Regional Blood Bank Center,
Venizelion Hospital, Heraklion, Crete, Greece
OBJECTIVE: Patients with inflammatory bowel disease (IBD)
frequently suffer from thromboembolic events. A recently
identified mechanism for thrombophilia, the poor anticoag-
ulant response to activated protein C, has been suggested as
one of the leading risk factors for thrombosis. The aim of
this study was to evaluate the frequency of thrombophilic
abnormalities, including activated protein C-resistance
(APCR), in Greek patients with ulcerative colitis (UC) and
Crohn’s disease (CD).
METHODS: Forty-eight patients with UC, 36 with CD, and
61 matched healthy controls (HC) were studied. Cases with
presence of lupus anticoagulant, use of anticoagulants or
heparin, and pregnancy were excluded. Disease activity in
CD was evaluated by use of the Crohns Disease Activity
Index (CDAI) score and in UC by the Truelove-Witts grad-
ing system. Plasma levels of protein C, free protein S,
antithrombin III (AT-III), activated protein C resistance
(APCR), and fibrinogen were determined in IBD patients, as
well as in HC. All the cases and controls with abnormal
APCR were further studied by genetic testing for the factor
V Leiden mutation.
RESULTS: Mean fibrinogen levels in UC and CD patients
were significantly elevated (p ⬍ 0.0001), compared with
HC. The mean values of free protein S, as well as mean
APCR, were significantly lower in UC and CD patients than
in the HC (p ⬍ 0.0001). Seven (five UC and two CD) of 84
IBD patients (8.3%) and three of the HC (4.9%) had the
factor V Leiden mutation. No significant difference was
observed for the other thrombophilic parameters. Fibrino-
gen levels and profound free protein S deficiency were
found related to disease activity.
CONCLUSIONS: Thrombophilic defects are common in
Greek patients with IBD and they could interfere either in
the disease manifestation or in the thrombotic compli-
cations. (Am J Gastroenterol 2000;95:190 –194. © 2000 by
Am. Coll. of Gastroenterology)
Vol. 95, No.
ISSN 0002-9270/00/$20.00
PII S0002-9270(99)00742-X
INTRODUCTION
Thromboembolic complications are frequent events in pa-
tients with inflammatory bowel disease (IBD). The inci-
dence of arterial and venous thromboembolic disease in
patients with ulcerative colitis (UC) and Crohn’s disease
(CD) is between 1% and 8% (1–3), rising to an incidence of
39% in some postmortem studies (4). The thrombotic risk of
IBD has been attributed to a hypercoagulable state and a
relationship between the degree of inflammatory activity
and prothrombotic abnormalities has been found (5). More-
over, several laboratory studies using various sensitivity
markers of activation of the coagulation system have shown
endothelial injury and increased thrombin generation in both
active and inactive disease (5– 8). Low levels of coagulation
inhibitors such as antithrombin III (AT-III), protein C, and
protein S in IBD patients have been found in some (9 –11),
but not all studies so far (5, 12, 13). A high prevalence of
anticardiolipin antibodies and anti ␤2 glycoprotein I anti-
bodies has also been reported in IBD patients (14, 15).
Recently, in an attempt to find other factors that might
contribute to the development of thrombosis in IBD an
important thrombophilic marker, the resistance to activated
protein C, is under investigation (13, 16, 17). Activated
protein C resistance (APCR) was first recognized by Dahl-
back et al. (18) in 1993 as a new mechanism for familial
thrombophilia. It is characterized by in vitro resistance to
the anticoagulant effects of activated protein C and its cause
was proved to be the replacement of Arg by Glu at residue
506 in the factor V molecule (factor V Leiden mutation)
(19). Recent studies have shown that 11–20% of acute
venous thrombotic events are caused by APCR (20, 21).
In IBD patients, the role of APCR is still unclear. APCR
was found to be uncommon (13, 22, 23) and the prevalence
of factor V Leiden mutation was not increased in IBD
patients (16, 24, 25). On the other hand, two recent reports
showed that 45% of CD patients (26) and four of 11 IBD
patients with thrombosis had inherited the factor V Leiden
mutation (17).
The aim of this study was first to estimate the frequency
of APCR and other physiological inhibitors of coagulation
AJG – January, 2000 Greek Patients With IBD 191

Table 1. Clinical Details of the Patients Included in the Study agnostics, France; normal range, 65–140%). Protein S (total
Ulcerative Crohn’s and free) was also assayed by ELISA (Biochem Diagnos-
Colitis Disease Total tics). Normal range of free protein S was considered to be
Number 48 36 84 70 –140%. Antithrombin III (AT-III) activity was measured
Male 30 22 52 using a chromogenic substrate kit (Organon Technica,
Female 18 14 32 Durham, NC; normal range, 85–111%). APCR was mea-
Active 19 19 38 sured by determining the activated partial thromboplastin
Inactive 29 17 46
Disease type (Crohn’s) time (APTT) in the absence and presence of APC (Coatest
Stenotic 10 activated protein C resistance kit, Chromogenix, Moendal,
Fistulizing 7 Sweden). Normal values of APCR were considered to be
Inflammatory 19 1.8 –5 s.
Treatment* All the cases and controls with abnormal APCR were
Salazopyrine 4 3 7
5-ASA 41 27 68 further studied using genetic testing. Genomic DNA isola-
Oral steroids 11 10 21 tion from EDTA blood, polymerase chain reaction, and
Topical steroids 8 2 10 detection of the factor V Leiden mutation were done using
Azathioprine 4 7 11 the Factor V Gene Mutation Assay (Vienna Lab, Vienna,
Metronidazole 0 13 13 Austria).
None 3 2 5
Previous thrombotic disease 3 1 4
Statistical Analysis
*Some patients were taking more than one drug. Statistics were calculated using Instat version 2.02 (Graph-
5-ASA ⫽ 5-aminosalicylic acid.
pad Software, Inc.). Results are expressed as mean ⫾ SD.
Statistical significance of differences in group mean values
in a homogeneous Greek IBD population. Our second aim
was determined by two-tailed Student’s t test. The discrep-
was to examine the clinical significance of these thrombo-
ancy of the prevalence of thrombophilic defects between the
philic factors in our patients.
study groups was studied by means of 2-⫻-2 table analysis
using ␹2 (with Yates correction) or Fisher’s exact test. A 5%
MATERIALS AND METHODS significance threshold was adopted. To show the strength of
the associations, we have included p values, odds ratios
Patients
(OR), and the 95% confidence intervals (CI) in the text.
Eighty-four IBD patients followed-up at the Department of
Gastroenterology of the University Hospital of Heraklion
Crete were included in the study (Table 1). In the UC group RESULTS
there were 30 men and 18 women, with a mean age of 47 yr.
The CD patients included 22 men and 14 women, with a After examination of the patients’ records, four cases with a
mean age of 39 yr. These were compared with 61 blood history of a thrombotic event were found. Three had deep
donors (healthy controls, HC) who were matched to the venous thrombosis of the legs confirmed by Doppler ultra-
patient population for age and gender. Cases with presence sound, and one had pulmonary embolism confirmed by
of lupus anticoagulant, use of anticoagulants or heparin, or pulmonary scintigraphy. The prevalence of thrombotic
pregnancy were excluded. UC and CD diagnosis was based events in our patients was thus found to be 4.8%. The results
on standard criteria (27). Disease activity in CD was eval- of the thrombophilic parameters measured in our IBD pa-
uated by use of the Crohn’s Disease Activity Index (CDAI) tients are shown in Table 2. Mean fibrinogen levels in UC
score (28) and in UC by the Truelove-Witts grading system and CD patients were significantly elevated (p ⬍ 0.0001),
(29). The patients records were retrospectively examined to compared with HC. The mean values of free protein S, as
identify patients in whom thromboembolism had been doc- well as mean APCR, were significantly lower in UC (p ⬍
umented. The clinical data of the IBD patients are summa- 0.0001) and in CD patients, compared with HC (p ⬍
rized in the Table 1. 0.0001). No significant difference was observed for protein
C and AT-III.
Laboratory Studies Thirty-three of 84 IBD patients (39.3%) and seven of the
Venous blood samples were collected and centrifuged at 61 HC (11.5%) showed fibrinogen levels higher than 4 g/L
2000 ⫻ g for 10 min at 4°C. Plasma was removed, recen- (p ⫽ 0.0003). Eighteen of our patients (seven UC, 11 CD)
trifuged, and stored at ⫺70°C until assayed. and five HC had deficiency of free protein S (p ⫽ 0.0384).
Plasma fibrinogen concentration was measured by the Protein C deficiency was observed in three IBD patients
Clauss method (30), using bovine thrombin (Brownes) and (one UC, two CD) and in none of the controls. Nine IBD
Qwren’s buffered saline. Normal values of plasma fibrino- patients (five UC, four CD) and four HC had deficiency of
gen were considered to be 2– 4 g/L. Protein C was deter- the AT-III (p ⫽ 0.558). Eight (six UC, two CD) of the 84
mined by enzyme-linked immunosorbent assay (ELISA) patients (9.5%) and three of the 61 HC (4.9%) had APCR
according to the manufacturer’s instructions (Biochem Di- lower than 1.8 s (p ⫽ 0.253). Four of the eight patients with
192 Koutroubakis et al. AJG – Vol. 95, No. 1, 2000

Table 2. Plasma Levels (Mean ⫾ SD) of Thrombophilic Parameters in Greek IBD Patients
Parameter Healthy Controls Ulcerative Colitis Crohn’s Disease Normal Range
Fibrinogen (g/L) 2.9 ⫾ 0.8 3.9 ⫾ 1.2* 3.9 ⫾ 1.3* 2–4
Protein C (%) 105.3 ⫾ 29.6 103.3 ⫾ 23.7 100.8 ⫾ 24.8 65–140
Protein S (%) 92.5 ⫾ 19.3 76.3 ⫾ 23.8* 71.0 ⫾ 25.9* 70–140
AT-III (%) 98.7 ⫾ 17.5 93.4 ⫾ 19.6 98.3 ⫾ 14.8 85–111
APCR (s) 3.5 ⫾ 0.9 2.7 ⫾ 0.7* 2.8 ⫾ 0.6* 1.8–5
*Significant difference with HC.
IBD ⫽ inflammatory bowel disease; APCR ⫽ activated protein C resistance; AT-III ⫽ antithrombin III.

low APCR had simultaneously low levels of free protein S.
One of them also had low levels of AT-III, whereas all had
normal levels of protein C. Seven of the eight patients (five
UC, two CD) with low APCR were subsequently deter-
mined to be heterozygous for factor V Leiden, whereas all
the three HC with low APCR were found to be heterozygous
for this mutation. In one UC patient with low APCR (1.7 s)
the mutation was not detected. The prevalence of factor V
Leiden mutation in our IBD patients was found to be 8.3%,
which was not significantly different, compared with HC
(4.9%, p ⫽ 0.519).
Table 3 shows the thrombophilic parameters in relation to
disease activity. The evaluation of disease activity was si-
multaneous with the plasma collection. Mean fibrinogen
was significantly higher in active UC, compared with inac-
tive UC (p ⬍ 0.0001), as well as in active CD, compared
with inactive CD (p ⫽ 0.0005). No differences in plasma
levels of protein C, free protein S, AT-III, and APCR were
found in any of the subgroups with respect to disease ac-
tivity in both diseases. In the majority of cases, the values of
free protein S were slightly below the threshold for the
normal level. However, in seven cases (three UC, four CD)
a more profound free protein S deficiency (⬍50%), similar
to that observed in the genetically deficient groups, was
found. In terms of disease activity it is interesting to note
that all these cases except one (a UC patient) had active
disease.
In relation to the clinical data, of the four IBD patients
with a history of thrombosis, one CD patient with past
pulmonary embolism had low APCR (0.73 s) and was
heterozygous for the factor V Leiden mutation. Another UC
patient with previous deep vein thrombosis of the right leg
had low free protein S (62.1%). All thrombophilic param-
eters were normal in the remaining two IBD patients with
past thromboembolism. Another way of approaching of
disease severity was the division of our patients, regarding
their medical therapy, in two groups. The first group was
taking only salazopyrine, 5-aminosalicylic acid, or metro-
nidazole (52 patients) and the second taking steroids or
azathioprine (32 patients). Analysis of the frequency of the
thrombophilic markers in these two groups didn’t show
statistical differences, except that fibrinogen levels were
significantly higher in the second group (p ⬍ 0.0001). Ten
of the 18 patients deficient in free protein S were in the first
group, with the remaining eight in the second group. Four of
the seven patients with the factor V Leiden mutation were in
the first and three were in the second group.
DISCUSSION
Deficiencies and functional abnormalities of antithrombin
III, protein C, and protein S are well-recognized causes of
thrombotic disease and account for 14 –24% of cases of
familial thrombotic disease; however, they are implicated in
fewer than 8% of sporadic cases of venous thrombosis (31).
On the other hand, resistance to activated protein C (factor
V Leiden mutation) is now recognized as the single most
common cause of hereditary thrombophilia (32).
The increased risk of thrombosis in IBD patients has been
attributed to a hypercoagulable state, the nature of which
remains to be elucidated. Concerning CD, there is a hypoth-
esis that a systemic prothrombotic environment may aggra-
vate the intestinal microvascular inflammation (33). The
response of UC to heparin therapy (34) and the low risk of
IBD in patients with hemophilia and von Willebrand’s dis-
ease (35) suggest also that thrombosis and vascular occlu-
sion may be important in the pathogenesis of IBD.
Several independent risk factors for thrombotic vascular
disease have been found to be present in IBD patients (5– 8).
The role of the well-recognized inherited thrombophilic

Table 3. Plasma Levels (Mean ⫾ SD) of the Thrombophilic Parameters in Relation to the Disease Activity
Ulcerative Colitis Crohn’s Disease
Active Nonactive Active Nonactive
Parameter (N ⫽ 19) (N ⫽ 29) p Value (N ⫽ 19) (N ⫽ 17) p Value
Fibrinogen (g/L) 4.88 ⫾ 1.23 3.26 ⫾ 0.71 ⬍0.001 4.65 ⫾ 1.35 3.16 ⫾ 0.87 0.0005
Protein C (%) 102.1 ⫾ 23.9 104.6 ⫾ 24.1 0.9211 98.2 ⫾ 27.9 103.3 ⫾ 22.1 0.7894
Protein S (%) 74.8 ⫾ 27.8 77.3 ⫾ 21.1 0.7297 69.2 ⫾ 28.1 72.6 ⫾ 24.6 0.7056
AT-III (%) 87.8 ⫾ 19.7 97.9 ⫾ 18.7 0.0924 94.1 ⫾ 15.3 102.6 ⫾ 13.6 0.0865
APCR (s) 2.59 ⫾ 0.56 2.86 ⫾ 0.73 0.1844 2.67 ⫾ 0.71 2.85 ⫾ 0.58 0.4113
Abbreviations as in Table 2.
AJG – January, 2000
states such as deficiencies of plasma antithrombin III, pro-
tein C, and protein S, as well as resistance to activated
protein C, is under investigation. Deficiency of the proteins
C and S in IBD patients have been proposed by the studies
of Jorens et al. (9) and Aadland et al. (10, 11). Other studies
did not confirm these data (5, 7, 12, 13, 16). However, in our
study, levels of free protein S were significantly reduced in
both UC and CD, in comparison to HC. Moreover, cases
with profound free protein S deficiency had a more active
disease. It is known that 60% of protein S circulates in
plasma bound to C4b binding protein and only the free,
unbound protein S can function as a cofactor for activated
protein C. Measurement of the total antigenic protein S may
be misleading (36). A possible explanation for the discrep-
ancy in the results of the studies cited could be the mea-
surement of the total and not the free protein S in some of
these. The main physiological thrombin inhibitor, AT-III,
was also found significantly reduced in IBD patients in some
studies (5, 12, 13, 37), but this was not confirmed by others
(16). Our data did not show significantly lower mean levels
of AT-III in IBD patients, compared with HC. However,
there was a trend more IBD patients (nine, 10.7%) than HC
(four, 6.5%) to have AT-III deficiency. Increased plasma
fibrinogen levels in IBD patients were also found in our
study. It is known that fibrinogen is an acute-phase protein,
values of which increase with inflammation. The finding of
positive correlation with disease activity confirms this
knowledge.
It is now recognized that APCR caused by factor V
Leiden mutation is the most prevalent inherited cause of
thrombophilia. However, preliminary results showed that
APCR is uncommon in IBD patients (13, 16, 22). In a recent
study APCR was not found to be associated with IBD but,
when present, there was an increased risk of thromboem-
bolism (23). Examination by genetic testing of factor V
Leiden mutation in 20 IBD patients with a history of throm-
boembolic events showed only one patient heterozygous for
factor V Leiden (16). In another study only one of 49 IBD
patients had inherited the factor V Leiden mutation (24). In
a large Finnish study the frequency of this mutation (4.5%)
was not significantly different from that in HC (2.1%) (25).
On the other hand, in a recent study of 43 UC patients, eight
were heterozygous and one homozygous for factor V Leiden
mutation whereas in 20 CD patients, eight were heterozy-
gous and one was homozygous for the mutation (26). Lieb-
man et al. (17) also found that four of 11 IBD patients with
thrombosis and two of 51 IBD controls had inherited the
factor V Leiden mutation.
In our study the mean APCR was significantly lower in
IBD patients than in HC. However, the prevalence of factor
V Leiden mutation in Greek IBD patients was not found to
be significantly higher than in HC (8.3% vs 4.9%). In
relation to the history of thrombosis, only one of four
patients with a history of thromboembolic event had the
factor V Leiden mutation, but the prevalence of this muta-
tion in patients with thromboembolism (25%) was signifi-
Greek Patients With IBD 193
cantly higher than in patients without thromboembolism
(3.75%) or in HC (4.9%). In our study the frequency of
factor V mutation in IBD patients was higher (but not
statistically different, compared with HC) than in other
studies (24, 25). This discrepancy may be due to the small
number of patients in the existing studies or it may reflect
genetic differences between the populations of these studies.
From all the data presented it is reasonable to assume that
there is a subpopulation of IBD patients in whom thrombo-
philic abnormalities are probably important for either dis-
ease manifestation or for thrombotic complications. These
hemostatic abnormalities could be either inherited or sec-
ondary to the disease process; from the existing data we
could not reach any firm conclusions. Further studies are
required to clarify these possibilities. Moreover, in view of
the lack of an association between thrombophilic markers
with disease activity and the low frequency of factor V
Leiden mutation in patients with established thrombotic
episodes, it seems more plausible that a multifactorial series
of events—rather than a single abnormality— be implicated
in the pathogenesis of thrombotic manifestations.
Reprint requests and correspondence: Ioannis E. Koutroubakis,
M.D., Department of Gastroenterology, University Hospital Her-
aklion, P.O. BOX 1352, 71110 Heraklion, Crete, Greece.
Received Jan. 18, 1999; accepted Aug. 23, 1999.
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