Digestive Diseases and Sciences, Vol. 46, No. 3 (March 2001), pp.

644 648

Predictive Value of Inflammatory and

Coagulation Parameters in the Course of
Severe Ulcerative Colitis
R.K. LINSKENS, MD, A.A. VAN BODEGRAVEN, MD, M. SCHOORL, MSc,
H.A.R.E. TUYNMAN, MD, and P. BARTELS, PhD, MSc

Alterations in markers of coagulation have been found in patients with inflammatory bowel
disease. Our aim was to study the predictive value of coagulation and inflammatory parameters in the course of severe ulcerative colitis. Twenty-seven patients were included. The
disease course was followed for one year. Sensitivity, specificity, negative predictive value,
positive predictive value, and likelihood ratio, as well as the clinical predictive value of
laboratory variables were calculated. Inflammatory variables, such as ESR, CRP, and leukocyte and platelet count showed poor diagnostic accuracy. Several coagulation parameters,
such as fibrinogen and fibrin(ogen) degradation products, were increased in patients with
active ulcerative colitis, whereas coagulation factor XIII was decreased. No significant
relationship between clinical course and coagulation parameters was demonstrated, though
both inflammatory and coagulation parameters were useful in the assessment of disease
activity in patients with active ulcerative colitis.
KEY WORDS: ulcerative colitis; acute phase proteins; coagulation; fibrin degradation products; factor XIII;
fibrinolysis.

Assessment of clinical disease activity and the response to treatment by means of laboratory investigations is difficult in patients with inflammatory bowel
disease, in both Crohns disease (CD) and ulcerative
colitis (UC) (1). An important result of clinical and
laboratory evaluations in UC is the identification of
those patients who are likely to become severely ill
and those who are likely to develop complications.
Besides endoscopy, many biochemical parameters are
used in the assessment of severity and monitoring of
UC. These parameters include estimation of hemoManuscript received April 25, 2000; accepted September 1, 2000.
From the Department of Gastroenterology, Medical Center
Alkmaar and Academic Hospital Free University, Amsterdam; and
Department of Clinical Biochemistry and Department of Internal
Medicine and Gastroenterology, Medical Center Alkmaar, The
Netherlands.
Address for reprint requests: Dr. R. K. Linskens, Department of
Gastroenterology, Academic Hospital Free University, PO Box
7057, 1007 MB Amsterdam, The Netherlands.

644

globin concentration, white blood cell count (WBC),

platelet count, ESR, serum albumin concentrations,
and other acute-phase reactants including C-reactive
protein (CRP) and orosomucoid (2, 3). Orosomucoid,
ESR, and CRP correlate well with disease activity,
whereas CRP has been shown to be of value in
monitoring the response to treatment (4 6). An elevated WBC is often likely to reflect increased disease
activity, but it may be difficult to interpret results in
patients treated with steroids. Other laboratory markers, such as albumin and hemoglobin concentration,
correlate less well with clinical disease activity, particularly in UC (3). None of these parameters has
been useful in predicting the course or clinical outcome in patients with UC, although CRP might be of
prognostic value (4, 7).
More recently, variables of coagulation and fibrinolysis have been examined in UC, documenting subDigestive Diseases and Sciences, Vol. 46, No. 3 (March 2001)

0163-2116/01/0300-0644$19.50/0 2001 Plenum Publishing Corporation

PREDICTIVE LABORATORY PARAMETERS IN UC

stantial alterations in markers of coagulation and

fibrinolysis in patients with UC (8 11). However, the
diagnostic value of hemostatic parameters in the follow-up of UC has scarcely been studied. Therefore,
we conducted a longitudinal study of inflammatory
and hemostatic variables in a group of patients with
severe active UC to assess the diagnostic accuracy and
clinical value of inflammatory and coagulation markers concerning clinical outcome in patients with UC.
MATERIALS AND METHODS
Study Design. Patients with active UC were enrolled. At
baseline, disease activity was assessed by a slightly modified
endoscopic score with an 18-point scale (12). A score of
0 6 points was considered to indicate quiescent disease. A
score of 710 was considered to indicate intermediate disease activity, whereas a score above 10 points was defined as
severe UC. Only patients with macroscopically severely
inflamed mucosa were included (score above 10 points).
Following endoscopy, blood samples were drawn. In the
course of treatment, after three months, follow-up samples
were collected and a second endoscopy was performed.
Patients with diabetes mellitus, hepatitis or liver insufficiency, pregnancy, recent surgical intervention (3
months), malignancy, recent transfusion (2 weeks) of
blood products, acquired or inborn coagulopathies, or concomitant medication aimed at interference with coagulation
(such as heparin, tranexamine acid, and coumarin derivates) were excluded. Treatment of UC was aimed at attenuation of disease activity. Therapy consisted of highdose steroids and mesalazine orally and rectally, whereas
immunosuppressives were continued when used. Steroid
treatment was tapered off when clinical improvement appeared, in accordance with a dose reduction schedule.
The local hospital ethical committee approved the study.
Patients provided written informed consent.
Assessment of UC Severity by Laboratory Parameters:
Diagnostic Accuracy. The endoscopic score was used to
distinguish active disease from quiescent disease. Patients
with intermediate disease activity (ie, an endoscopic score
of 710 points) at three months were excluded from analysis. According to the endoscopic score, laboratory parameters at baseline and after three months were subdivided in
correct positive and correct negative findings. Laboratory
parameters exceeding the reference range in patients with
established active disease were considered to be correct
positive, whereas parameters within reference value in patients with established quiescent disease were defined as
correct negative. Diagnostic accuracy was defined as the
ability of the laboratory parameters to establish the activity
of disease. The diagnostic accuracy of inflammatory and
hemostatic variables was determined by means of calculation of sensitivity, specificity, positive predictive value
(PPV), negative predictive value (NPV), and the likelihood
ratio.
Prediction of Clinical Course by Means of Laboratory
Parameters: Clinical Value. The clinical value of the laboratory parameters was defined as their ability to discriminate between a favorable and unfavorable clinical outcome.
Digestive Diseases and Sciences, Vol. 46, No. 3 (March 2001)

The patient group was subdivided in accordance with the

clinical outcome at three months and at 12 months, respectively. Firstly, the patients condition was monitored at
three months. An unfavorable course was defined as a
persistent endoscopic score above 10 points at three
months, or when a colectomy had to be performed during
this period, or initiation of treatment with cyclosporine.
Secondly, at 12 months, criteria for the definition of unfavorable disease course included a year-long cumulative
steroid dose of 3000 mg in order to control symptoms,
initiation of azathioprine, or colectomy during follow-up.
To assess the clinical value of laboratory parameters, patients with an unfavorable clinical outcome were compared
to patients with a favorable outcome, at three and 12
months, respectively.
Laboratory Methods. Blood samples were drawn from an
antecubital vein with minimal compression after 15 min of
rest. The first 10 ml of blood was not used for determination
of coagulation parameters. Platelet-poor plasma was prepared by centrifugation at 2000g for 20 min at 4C. Aliquots
were stored at 70C until further use. Variables of inflammation (CRP, ESR, leukocyte count, granulocyte count,
platelet count, albumin) and parameters concerning hemostasis were established. Antithrombin III (AT III) was
established by a chromogenic substrate assay (Instrumentation Laboratory, Breda, The Netherlands). Thrombin
antithrombin complexes (TAT) were used as markers of
thrombin generation and were determined by a sandwichtype immunoassay (Dade Behring, Leusden, The Netherlands). Fragment 12 (F12) was used as a marker of the
generation of prothrombinase and was determined by a
sandwich-type immunoassay (Organon Teknika, Boxtel,
The Netherlands). Fibrin degradation products (FbDP)
were used as markers of coagulation activation and determined by sandwich-type immunoassay (Organon Teknika).
The ratio between FgDP and FbDP was used as an indicator for the balance between coagulation and fibrinolysis.
Fibrinogen degradation products (FgDP) were used as a
marker of fibrinolysis and were also determined by a sandwich-type immunoassay (Organon Teknika). Furthermore,
fibrinogen (Fg) was determined by application of a clotting
assay (Instrumentation Laboratory), and coagulation factor
XIII (F XIII) by chromogenic substrate assay (Dade Behring). Hemostatic variables were measured in triplicate
from three different samples with citrated plasma in order
to reduce technical errors (13, 14).
Reference ranges for laboratory parameters were set at:
ESR 10mm/hr, CRP 5 mg/liter, leukocyte count 4 10
109/liter, granulocyte count 1.5 6.5 109/liter, platelet
count 150 400 109/liter, albumin 3552 g/liter, AT III
80 120%, TAT 5 g/liter, F12 2 nmol/liter, FgDP
300 g/liter, FbDP 300 g/liter, FgDP/FbDP ratio 0.4
2.1, Fg 2 4 g/liter, and FXIII 70 140%.
Statistical Analysis. Data are presented as median values
and ranges. For laboratory parameters, sensitivity, specificity, NPV, PPV, and likelihood ratio were determined. Results of active and quiescent disease were compared by
means of the Wilcoxon signed rank test. Median values of
inflammatory and hemostatic parameters of patients with
clinical remission were compared with those of patients
with active disease during follow-up by means of the Mann-

645

LINSKENS ET AL
TABLE 1. PATIENT CHARACTERISTICS
INCLUSION

AND

TREATMENT

TABLE 3. DIAGNOSTIC ACCURACY OF LABORATORY PARAMETERS

TO DISCRIMINATE ACTIVE FROM QUIESCENT UC*

AT

Baseline measurement
N
Age [yr; mean (range)]
Male / female
Extent of UC
Left-sided
Pancolitis
Endoscopic score [mean (range)]
Treatment
None
Mesalazine
Steroids
Azathioprine

27
42 (2277)
18/9

UC I
UC II
(N 27) (N 23) Sens Spec NPV PPV LR
ESR
CRP
Leukocytes
Granulocytes
Platelets
Albumin
AT III
TAT
F12
Fibrinogen
FgDP
FbDP
FgDP/FbDP
Factor XIII

10
17
13 (1016)
4
22
17
3

Whitney test. All statistics were calculated by means of

Instat 2.0. The level of significance was set at 0.05.

RESULTS
Diagnostic Accuracy. Twenty-seven patients with
active UC were included. Demographic data are described in Table 1. Eighteen males and nine females
were studied; mean age was 42 years (range 2277).
Seventeen patients had pancolitis, whereas 10 patients were diagnosed with left-sided disease. After
three months of therapy, 23 patients had quiescent
disease. One patient developed a deep venous thrombosis during follow-up and needed anticoagulant
therapy, for which she was excluded from further
study. Three patients still had active UC, according to
the previously described endoscopic score.

24
20
7
11
4
7
2
22
24
19
21
24
7
6

7
16
21
18
20
22
21
9
8
16
7
8
18
23

0.89
0.74
0.26
0.41
0.15
0.26
0.07
0.81
0.89
0.70
0.78
0.89
0.58
0.22

0.30
0.70
0.91
0.78
0.87
0.96
0.91
0.39
0.35
0.70
0.30
0.35
0.47
1.0

0.70
0.70
0.51
0.54
0.47
0.52
0.46
0.64
0.73
0.66
0.54
0.73
0.78
0.52

0.60
0.74
0.78
0.69
0.57
0.88
0.52
0.61
0.62
0.73
0.57
0.62
0.26
1.0

1.27
2.47
2.89
1.86
1.15
6.5
0.78
1.33
1.37
2.33
1.11
1.37
1.09

*Abbreviations of laboratory parameters are described in Materials

and Methods. Sens sensitivity, spec specificity, NPV negative predictive value, PPV positive predictive value, LR
likelihood ratio. The numbers in columns 1 and 2 reflect the actual
number of correct test results for patients with established active
(UC I) and quiescent (UC II) disease, respectively.

Median baseline and median follow-up laboratory

variables of active and quiescent disease were compared (Table 2). During convalescence, most parameters significantly decreased. Only TAT, F12, and
FgDP did not decrease significantly, while median
values of TAT and FgDP remained above the upper
reference value. Changes in biochemical parameters
are shown in Table 3, together with results of calculations of sensitivity, specificity, PPV, NPV, and likelihood ratio.

TABLE 2. INFLAMMATORY AND HEMOSTATIC LABORATORY PARAMETERS IN

ACTIVE UC AT BASELINE AND QUIESCENT DISEASE AT THREE MONTHS*

Laboratory parameter

Active disease
at inclusion
(N 27)

Quiescent disease
at three months
(N 23)

ESR (mm/hr)
CRP (mg/liter)
Leukocyte count (109/liter)
Granulocyte count (109/liter)
Platelets (109/liter)
Albumin (g/liter)
AT III (%)
TAT (mg/liter)
F12 (mg/liter)
fibrinogen (g/liter)
FgDP (g/liter)
FbDP (g/liter)
FgDP/FbDP
F XIII (%)

26 (468)
12 (3271)
8.3 (5.217.3)
6.3 (3.714.9)
325 (178684)
37.9 (17.750.4)
101 (77165)
8 (2.990)
1.9 (1.013.3)
4.6 (3.19.2)
395 (2001560)
535 (2356000)
0.68 (0.091.70)
89 (35135)

16 (385)
3 (344)
6.4 (3.411.7)
4.2 (2.19.0)
264 (167447)
43.3 (34.664.1)
98 (72147)
6.2 (1.5110)
1.3 (0.815.0)
3.8 (2.16.5)
400 (185680)
400 (1202440)
0.87(0.242.61)
114 (81165)

0.05
0.001
0.001
0.001
0.01
0.01
0.05
NS
0.05
0.01
NS
0.01
0.01
0.001

*Results are expressed as median with minimum and maximum values in parentheses. P values were calculated by means of Wilcoxon signed rank test. Abbreviations
of laboratory parameters are described in Materials and Methods. section. NS
not significant.

646

Digestive Diseases and Sciences, Vol. 46, No. 3 (March 2001)

PREDICTIVE LABORATORY PARAMETERS IN UC

Clinical Value. Three months after baseline, 19

patients had a favorable disease course, whereas eight
patients had an unfavorable course, according to discrimination criteria mentioned earlier. Four patients
had ongoing active disease, as demonstrated by a
persistent endoscopic score 10 points. Two patients
received cyclosporine treatment, whereas two other
patients with pancolitis underwent colectomy. In
these patients, markers of inflammation and hemostasis were not significantly increased, when compared with patients with a favorable clinical course.
Remarkably, CRP results did not contribute to a
distinction between both groups either.
One year after follow-up, a favorable course of
disease was found in 12 patients, whereas an unfavorable course was found in 14 patients. Of the latter 14
patients, six patients had used more than 3 g of
steroids in this one-year period, two patients underwent colectomy, and in seven patients, azathioprine
was administered. It was not possible at this point to
discriminate favorable from unfavorable clinical outcome in relation to the laboratory parameters measured.
DISCUSSION
This longitudinal study documented increased
plasma concentrations of various inflammatory and
coagulation parameters in patients with active UC.
Results for inflammatory variables, such as ESR,
CRP, leukocyte, and platelet count showed poor diagnostic accuracy as may be concluded from the likelihood ratio. After calculation of sensitivity and specificity with regard to laboratory tests, the most
favorable results were found for CRP, leukocyte and
granulocyte count, and only to a lesser extent for
ESR, platelet count, and albumin.
It has been demonstrated that in active UC hemostatic imbalance is found with activation of coagulation (1518). In this study, coagulation parameters,
such as fibrinogen, FbDP, F XIII, and AT III were
found to be changed in patients during active disease.
The baseline results of this study were comparable to
studies demonstrating activation of blood coagulation
and activated fibrinolysis in patients with UC (8, 9,
19). Our study showed a trend towards increased
values for F12 in active disease (P 0.05).
A balance in coagulation and fibrinolysis is assumed to be present in normal physiologic circumstances (20). Plasmin digestion of fibrin clots leads to
formation of fibrin degradation products (20, 21).
Products such as D-dimer and FbDP have been found
Digestive Diseases and Sciences, Vol. 46, No. 3 (March 2001)

to be increased in patients with active UC (8, 22, 23).

Thus, disturbances in the mechanisms of coagulation
will presumably be reflected in products of activation
of both coagulation and fibrinolysis (21), as is corroborated by the data of this study. In addition, we
investigated the clinical value of inflammatory and
coagulation tests defined as the capability to predict
the course of UC. This might be pivotal, since it could
help to decide when to start immunosuppressive medication in order to attain a favorable clinical outcome.
However, none of the laboratory parameters was able
to distinguish a group of patients who were likely to
have a poor outcome during follow-up from a group
of patients who were likely to achieve remission.
Thus, both inflammatory and coagulation variables
seemed to be ineffective in predicting the course of
disease.
This finding is in contrast with a recent study reporting the predictive value of coagulation markers
concerning clinical outcome in patients with myocardial infarction (24). In the latter study, higher levels of
F12, D-dimer, and fibrin monomer were found
among the patients who died or developed reinfarction during follow-up. Fibrinogen levels did not discriminate appropriately between favorable and poor
clinical outcome. However, our study concerned a
different population. Furthermore, several investigators found that FbDP might emerge as an additional
tool in the assessment of disease activity in patients
with UC (25). As a result of treatment of UC, changes
in hemostasis might occur. Both steroids and immunosuppressives could induce activation of the hemostatic cascade, but multidrug therapy is not likely to
cause consistent alteration of hemostasis (26).
The endoscopic score was considered to be the gold
standard to assess disease activity. The accuracy of
endoscopy in the management of UC is well established and has emerged as the single most important
tool in initial diagnosis and subsequent follow-up
(2729). Nevertheless, other resources, such as a patient score and histopathological findings are being
used in the assessment of disease activity, these were
not evaluated in our study (1).
This is the first study discussing the predictive value
of hemostatic data in the course of UC. Determination of hemostatic variables could identify patients
with active UC. No differences were found between
inflammatory and coagulation parameters with regard to diagnostic accuracy. The current study did not
show a relationship between disturbances of inflammatory or coagulation parameters and clinical outcome during treatment of patients with active UC.

647

LINSKENS ET AL

Nevertheless, inflammatory and coagulation findings

can be helpful to assess the clinical condition of a
patient with UC in conjunction with endoscopy and
the patients well being.
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