!.Guo,etal.

www.hepatogastroenterology.org

DOI10.5754/hge10790
Volume58(106),326330,2011

Clinical()riginal

Hepato-Gastroenterology

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INTRODUCTION
The liver is an important organ for metabolism and is also the site of coagulation
factor synthesis. This organ plays an important regulatory role in maintaining
homeostasis between the coagulation and anticoagulation systems. When liver cells
are injured or damaged because of liver disease, the synthesis of coagulation factors
and anticoagulant proteins is altered, which results in disordered coagulation and
anticoagulation (1). Patients with liver cancer, especially those with advanced liver
cancer, often exhibit dysfunctional coagulation (2,3), which leads to complex
pathological changes in coagulation and fibrinolysis that are closely related to tumor
formation and development and can directly affect the prognosis of cancer patients
(4). The aim of this study was to explore coagulation in primary liver cancer patients
at different clinical stages, examine the effect of coagulation parameters on survival,
and provide guidelines for clinical treatment and prognosis.

METHODOLOGY
Study subjects
A total of 228 patients diagnosed with primary liver cancer between May 2007 and
July 2010 were included in the first group and comprised 172 men and 56 women
with a mean age of 55.41 12.90 years. Each patient had undergone a detailed
physical examination. Patients who had serious heart, liver, or kidney damage, or
diabetes, rheumatoid arthritis, chronic obstructive pulmonary disease, infectious
disease, anemia, history of long-term hormone use, surgery, or trauma within the
previous month were excluded. Pathological type and TNM stage (International
UICCl997 staging criteria) of the tumors were determined by chest radiography and
computed tomography (CT), head CT, bronchoscopy, radioactive bone scan, and
abdominal B-mode ultrasound. The patients were divided into groups I, II, III and IV
according to their clinical stage. Group I included 58 cases, group II included 76
cases, and groups III + IV included 94 cases. Fifty-two patients (mean age:
48.2113.82 years) with common liver disease were recruited in the second group;
among these, 28 were male and 24 were female. Patients were diagnosed with
hepatitis B if they were positive for HBsAg, HBeAg, or anti-HBc; fatty liver was
diagnosed by B-mode ultrasound or other methods, and patients with liver cancer,

cirrhosis, or ascites were all excluded. All patients exhibited normal heart, liver and
kidney function. The third group included 52 healthy controls: 24 men and 28 women
with a mean age of 4513.32 years. Liver cancer patients were divided into normal
coagulation [prothrombin time (PT), 1014s; D-dimer, 01.0mg/L; fibrinogen
degradation products (FDP), 05mg/L; and fibrinogen (FIB), 24g/L] and abnormal
coagulation groups [PT, >14s; D-dimer, >1.0mg/L; FDP, >5mg/L; and FIB, >4g/L].
Reagents and Instruments
PT, thrombin time (TT), activated partial thromboplastin time (APTT), and FIB levels
were determined by a Japanese Sysmex-7000 blood coagulation analyzer with
Sysmex original reagent. The levels of FDP and D-dimer were determined by the
ACL TOP coagulation analyzer (Beckman Coulter, US) with reagents from Sekisui,
Japan. Routine blood tests were performed using the XE-2100 blood analyzer
(Sysmex, Japan) and Sysmex original reagents; liver and kidney function were
determined by the Olympus AU5431 automatic biochemical analyzer and Olympus
original reagents.
Research Methods
Blood samples were collected from all patients upon admission following primary
liver cancer diagnosis. Patients did not use hemostatic drugs or anticoagulant
medications in the 2 weeks prior to blood collection. In the morning, 3mL of fasting
venous blood was collected. The blood was stored in 0.3mL anticoagulant vacuum
tubes with 109mM sodium citrate. After 10 min of centrifugation at 3000 r/min, the
supernatant (plasma) was collected, and coagulation parameters were determined 2h
later. In addition, 1mL of venous blood was drawn and added to an EDTA
anticoagulant tube for routine blood testing, and 3mL of blood were added to a
clotting tube for determination of biochemical parameters.
Using the contact information provided in the medical records, telephone follow-up
and interviews were conducted to gather survival and prognostic information. The
follow-up endpoint event was death and secondary endpoint event was thrombotic
disease. The deadline for gathering follow-up data was August 29, 2010.

Statistical analysis
The SPSS 13.0 software package was used for statistical analysis; all continuous data
were presented as the mean standard deviation (SD). Single factor analysis of
variance was used for intergroup comparison. A life table was prepared for survival
analysis. The Cox proportional hazards model for survival analysis was used in
multivariate analysis. All data were subjected to a double-sided test, and the level of
significance was set at p<0.05.

RESULTS
A comparison of the coagulation results among primary liver cancer patients,
common liver disease patients, and normal healthy individuals is shown in Table 1.
Statistically significant intergroup differences were observed in the PT, PTR, INR,
APTT, TT, TT-R, FIB, D-dimer, FDP, and platelet (PLT) values (p<0.05).
Comparison of blood coagulation parameters among primary liver cancer patients at
different clinical stages (groups I, II and III + IV) is shown in Table 2.
Relationship between survival and coagulation parameters in patients with liver
cancer
Follow-up examinations were performed for primary liver cancer patients. Onehundred and seventy cases were followed-up between May 2007 and August 2010.
Twenty-two cases were lost during the process. A primary endpoint event occurred in
82 cases, which accounted for 43.35% of the follow-up cases. Fourteen cases reached
a secondary endpoint (thrombosis). The liver cancer patients were divided into 2
overall groups: normal coagulation function group (38 cases) and abnormal
coagulation function group (44 cases). The life-table method for survival analysis was
used to calculate the median survival of primary liver cancer patients in the 2 groups
(Table 3).
Correlation analysis between coagulation parameters and survival in primary liver
cancer patients at different clinical stages (I, II and III + IV) was performed using Cox
proportional hazards model in survival analysis. The levels of D-dimer, FDP, FIB,
and PLT demonstrated significant effects on the endpoint events. D-dimer, FDP, FIB,
and PLT levels were negatively correlated with long-term survival of patients with
advanced liver cancer. The results are shown in Table 4.

Relationship between the primary liver cancer stage and thrombotic disease
In the follow-up observation period, 1 case of thrombosis (peripheral deep vein)
occurred in groups I and II. In the stage III + IV group, 13 patients developed
thrombosis or related events (peripheral deep vein thrombosis in 1 case, superior vena
cava thrombosis in 2 cases, pulmonary embolism in 3 cases, peripheral vascular
thrombosis in 1 case, myocardial infarction in 2 cases, acute ischemic stroke in 1 case,
disseminated intravascular coagulation function (DIC) in 2 cases, and mesenteric
artery thrombosis in 1 case). Secondary endpoint events in I + II groups and in III +
IV group accounted for 0.59% and 7.65% of the follow-up patients, respectively. The
chi-square test demonstrated statistical difference (p<0.05).

DISCUSSION
Clinical value of monitoring changes in blood coagulation function in patients
with primary liver cancer
Coagulation function abnormalities increase the incidence of malignant tumors,
especially in liver cancer patients (5). Liver cells with a certain degree of damage
show reduced synthesis of various proteins (6) and coagulation factors (7). Tissue
clearance of thromboplastin as well as the capacity of activated fibrinolytic factors
also decreases (8). Malignant cells can activate coagulation factors by secreting
cancer procoagulant, invading and metastasizing, which cumulatively result in a
hypercoagulable state in patients with liver cancer. Patients with malignant cancer
exhibit obvious coagulopathy, and coagulation disorder, in turn, can promote tumor
growth and metastasis (9).
This study shows that coagulation parameters such as PT, PTR, INR, APTT, TT, TTR, FIB, D-dimer, FDP and PLT in patients with primary liver cancer show
statistically significant differences from the corresponding values in normal controls
and in patients with common liver disease. The APTT-R value did not show
statistically significant differences among the 3 groups. Even in the cases of primary
liver cancer with different stages, PT, INR, APTT, FIB, D-dimer, FDP and PLT all
exhibited significant differences, and the coagulation dysfunction aggravated with an
increase in the clinical stage of primary liver cancer.
5

FIB is a glycoprotein synthesized by the liver and plays an important physiological

role in the coagulation process (10). D-dimer is a plasmin-mediated specific
breakdown product of cross-linked fibrin and is present in very low levels in the
plasma of healthy humans. Increased levels of D-dimer can be considered as a
molecular marker for hypercoagulability and hyperfibrinolysis (11). Plasma levels of
FIB, FDP, D-dimer and PLT in patients with primary liver cancer increased
significantly for 1 or more of several reasons: 1) The liver synthesized less plasmin
inhibitor and cleared less fibrin (fibrinogen) degradation products (12); 2) After being
released into the blood stream, cancer cells interacted with endothelial cells and
platelets, released bioactive substances, and activated the platelets (4,13). Activated
platelets then released FIB molecules from !-particles into the blood, which were
involved in tumor metastasis; 3) Upon severe liver cell damage, plasminogen was
activated and converted into plasmin, which hydrolyzed fibrinogen and fibrin (14)
and thus increased the concentrations of FDP and blood D-dimer. Therefore,
abnormal increases in plasma FIB and D-dimer levels in primary liver cancer patients
not only suggest increased blood viscosity, hyperfibrinolysis, and bleeding tendency,
but they are also closely related to the clinical stage (15) and thus can be used as
important prognostic indicators.
Relationship between coagulation parameters and survival in patients with
advanced liver cancer or thrombotic disease
This study showed that the levels of PLT, FIB, FDP, and D-dimer in patients with
stage III and IV (late) primary liver cancer were significantly higher than those in
patients with stage I and II primary liver cancer and common liver disease.
Correlation analysis between coagulation parameters and survival in the stage III and
IV (late) primary liver cancer patients was performed using Cox proportional hazards
model in survival analysis. D-dimer, FDP, FIB and PLT levels had significant effects
on the endpoint events, so they were included in the hazard model. D-dimer, FDP,
FIB and PLT levels were negatively correlated with long-term survival of advanced
liver cancer patients. Coagulation parameters, including D-dimer, FDP, FIB and PLT
levels, can be used as effective indicators for evaluating the severity, treatment and
prognosis in advanced primary liver cancer (16), which helps comprehensive
assessment and prediction of disease conditions in clinical practice.
Cancer patients with abnormal coagulation often experience serious thrombotic
6

adverse events. Because the liver is an important organ for metabolism and is the
synthesis site for coagulation factors, patients with advanced liver cancer often have
abnormal coagulation function, which is complicated by thrombotic disease. The
pathological mechanisms of thrombotic disease include hypercoagulability, vascular
damage, and blood stasis (17). Malignant cells can secrete angiogenic factors, which
enrich the microvasculature of a solid tumor, while a thrombus formed in blood
circulation can lead to stasis of blood circulation (18,19). Increased levels of FIB and
D-dimer can facilitate thrombosis. Fibrinogen degradation products (FDP) generated
in secondary fibrinolysis can stimulate the production of plasma FIB via a feedback
mechanism. In this study, patients with advanced liver cancer showed an increased
risk of thrombosis, which may be because of the high tumor load (20,21) or rapid
proliferation of cancer cells in these patients. Cytokines secreted by tumor cells can
directly activate the coagulation system or produce and express procoagulant factors
by interacting with somatic cells, which leads to abnormal coagulation function and
thrombotic disease (22).
We also observed decreased FIB levels and coagulation dysfunction in primary liver
cancer patients with liver cirrhosis or ascites. This may be because of insufficient
synthesis of coagulation and anticoagulant factors triggered by cancer-damaged liver
cells. This study also showed that plasma FIB and FDP levels are directly related to
liver cancer in other ways, which will be addressed in future studies.
In summary, this study revealed that patients with primary liver cancer may
experience complex coagulopathy, which is closely related to the degree of liver cell
damage. Coagulation function tests can detect, to a certain extent, changed disease
conditions in liver cancer patients.

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Sasisekharan R: Heparanase, heparin and the coagulation system in cancer progression.
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11 Tseng CS, Lo HW, Chen PH, Chuang WL, Juan CC, Ker CG: Clinical significance of
plasma D-dimer levels and serum VEGF levels in patients with hepatocellular carcinoma.
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Berg MP, Burgerhof JG, Hoekstra HJ, Sluiter WJ, Gietema JA: Microalbuminuria,
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15 Saxena V, Mishra DK, Subramanya H, Satyanarayana S, Sharma A: Antithrombin III
assay using thrombin in disseminated intravascular coagulation (DIC), other thromboembolic
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16 van Doormaal FF, Buller HR: Heparin and survival in cancer patients. Hematol Oncol
Clin North Am 2010; 24:777-784, ix-x.
17 Ritz JP, Lehmann KS, Zurbuchen U, Wacker F, Brehm F, Isbert C, Germer CT,
Buhr HJ, Holmer C: Improving laser-induced thermotherapy of liver metastases--effects of
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Gastroenterol 2008; 14:1549-1552.
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Kim CM: Plasma levels of D-dimer and soluble fibrin polymer in patients with
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109:125-129.
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TABLE 1. A comparison of the coagulation parameters among primary liver cancer

patients, common liver disease patients, and normal healthy individuals (mean SD)
Parameter

Primary liver cancer

group (n = 228)

Common liver
disease group (n
= 52)

Normal healthy
people (n = 52)

p-value

PT(s)

13.56 1.87#*

12.74 0.90

12.44 0.81

<0.05

PTR

1.09 0.15*

1.06 0.07

1.04 0.07

<0.01

INR

1.10 0.21*

1.06 0.08

1.04 0.07

<0.01

APTT(s)

40.17 7.41#*

34.35 4.41

34.77 4.01

<0.01

APTT-R

1.35 0.29

1.27 0.16

1.31 0.16

>0.05

TT(s)

16.87 4.46#*

15.91 0.98!

15.86 0.96

<0.05

TT-R

1.04 0.28#*

0.96 0.06

0.93 0.06

<0.05

FIB (g/L)

3.48 1.27#*

3.01 1.21!

2.59 0.51

<0.01

D-dimer (mg/L)

3.02 1.77#*

0.45 0.27!

0.48 0.24

<0.01

FDP (mg/L)

6.68 1.78#*

1.35 0.91!

1.14 0.42

<0.01

PLT " 109/L

164.7 56.32#*

129.79 36.32

125.63 23.6

<0.01

Comparison between 2 groups:

liver cancer and liver disease groups, p < 0.01;

* liver cancer and normal control groups, p < 0.01;
!
liver disease and normal control groups, p < 0.01

10

TABLE 2. Comparison of blood coagulation parameters among primary liver

cancer patients at clinical stages I, II or III + IV (mean SD)
Parameter

Stage I

Stage II

Stage III+ IV

(n = 58)

(n = 76)

(n = 94)
16.07 3.60#*

<0.01

1.12 0.27

1.24 0.27

>0.05

1.07 0.10

1.14 0.35

1.32 0.39*

<0.05

APTT(s)

38.11 4.91

41.25 5.52!

44.79 16.74#

<0.05

TT(s)

17.43 1.39

17.45 1.68

18.32 7.63

>0.05

TT-R

1.02 0.08

1.01 0.11

1.09 0.54

>0.05

FIB (g/L)

2.90 0.93

3.45 1.31!

3.77 1.75#*

<0.01

D-dimer (mg/L)

1.01 0.72

2.89 2.90!

14.92 13.14#*

<0.01

FDP (mg/L)

2.59 1.51

5.54 4.06!

31.16 38.38#*

<0.01

PLT " 109/L

131.34 49.00

158.63 54.97!

187.68 93.69#*

<0.01

PT(s)

13.17 1.11

14.04 3.26

PTR

1.07 0.09

INR

Comparison between 2 groups:

#

p-value

stage I and II, p < 0.01;

stage I and III + IV, p < 0.01;

11

* stage II and III + IV, p < 0.01

TABLE 3. Mean and median of life table data for the normal-coagulation and
abnormal-coagulation function groups
Meana

Median

95% Confidence
Group

Normal

coagulation

Estimate

Standard

Intervals

(days)

error

Lower

Upper

limit

limit

95% Confidence
Estimate

Standard

Intervals

(days)

error

Lower

Upper

limit

limit

357.162

81.703

197.023

517.300

203.000

25.664

152.699

253.301

263.635

71.318

123.851

403.419

123.000b

30.824

62.585

183.415

group
Abnormal
coagulation
group

In the absence of an estimated value, it was limited to the longest observed

survival time
b
Comparison between normal coagulation and abnormal coagulation
groups, p< 0.05

12

TABLE 4. Cox proportional hazards model for the relationship between survival and
coagulation parameters in patients with median and advanced stage primary liver
cancer
p

Related risk Exp (B)

0.577

0.447

0.896

63.919

0.005

0.943

0.637

45.307

37.062

1.494

0.222

0.563

APTT (s)

0.394

0.700

0.316

0.574

0.982

APTT_R

-11.067

22.756

0.237

0.627

0.000

TT (s)

-0.013

0.483

0.001

0.978

0.987

TT_R

-0.969

7.214

0.018

0.893

0.379

FIB (g/L)

-0.417

0.358

1.351

0.045

1.259

D-dimer (mg/L) 0.265

0.098

7.328

0.007

1.303

FDP (mg/L)

-0.075

0.035

4.447

0.035

1.038

PLT"109/L

0.026

0.041

0.395

0.040

1.026

Parameter

Coefficient B Coefficient SE Wald

PT (s)

-5.154

6.782

PTR

4.539

INR

13