!. Guo, et al.   www.hepato­gastroenterology.org

  DOI 10.5754/hge10790

  Volume 58(106), 326­330, 2011

Hepato-Gastroenterology

  Clinical( )riginal          )pen Access( Ahead of 4rint

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2

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:

48.21±13.82 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,

3

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 45±13.32 years. Liver cancer patients were divided into normal

coagulation [prothrombin time (PT), 10–14s; D-dimer, 0–1.0mg/L; fibrinogen

degradation products (FDP), 0–5mg/L; and fibrinogen (FIB), 2–4g/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.

4

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. One-

hundred 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.

5

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, TT-

R, 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.

6

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

7

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.

8

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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

11

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

(n = 58)

Stage II

(n = 76)

Stage III+ IV

(n = 94)

p-value

PT(s) 13.17 ± 1.11 14.04 ± 3.26!

16.07 ± 3.60#* <0.01

PTR 1.07 ± 0.09 1.12 ± 0.27 1.24 ± 0.27 >0.05

INR 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

Comparison between 2 groups: !

stage I and II, p < 0.01;

# stage I and III + IV, p < 0.01; * stage II and III + IV, p < 0.01

12

TABLE 3. Mean and median of life table data for the normal-coagulation and

abnormal-coagulation function groups

Meana Median

95% Confidence

Intervals

95% Confidence

Intervals Group Estimate

(days)

Standard

error Lower

limit

Upper

limit

Estimate

(days)

Standard

error Lower

limit

Upper

limit

Normal

coagulation

group

357.162 81.703 197.023 517.300 203.000 25.664 152.699 253.301

Abnormal

coagulation

group

263.635 71.318 123.851 403.419 123.000b 30.824 62.585 183.415

a 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

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TABLE 4. Cox proportional hazards model for the relationship between survival and

coagulation parameters in patients with median and advanced stage primary liver

cancer

Parameter Coefficient B Coefficient SE Wald p Related risk Exp (B)

PT (s) -5.154 6.782 0.577 0.447 0.896

PTR 4.539 63.919 0.005 0.943 0.637

INR 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