ORIGINAL RESEARCH

Clinical and Prognostic Significance of Coagulation Assaysin Gastric Cancer

Faruk Tas &RumeysaCiftci &LeylaKilic &Murat Serilmez &

Senem Karabulut & Derya Duranyildiz

# Springer Science+Business Media New York 2013

AbstractPurpose Activation of coagulation and fibrinolysis is fre-quently found among cancer patients. Such tumors are con-sidered to be associated with a higher risk of invasion,metastases, and eventually, worse outcome. The aim of thisstudy is to explore the clinical and prognostic value of bloodcoagulation tests in gastric cancer (GC) patients.Materials and Methods A total of 44 consecutive patientswith a pathologically confirmed diagnosis of GC were en-rolled into the study. Pretreatment blood coagulation testsincluding prothrombin time (PT), activated partial thrombo-plastin time (APTT), international normalized ratio (INR),D-dimer (DD), fibrinogen (F) levels, and platelet (PLT)counts were evaluated. Control group comprised 50 age-and sex-matched individuals without history of malignancyand coagulation disorder.Results Median age at diagnosis was 55 years, range 19–80 years; most had men (n=32, 73 %) and metastatic disease(n=31, 70 %). The level of blood coagulation tests showed astatistically significant difference between the patient andthe control groups (P<0.001 for all, but p=0.07 for PT). DDlevels were significantly associated with elevated PLT andLDH levels (p=0.009 and p=0.01, respectively). Patientswith metastatic disease had higher levels of F (p=0.001) andINR (p=0.027) levels. Elevated DD levels tended to be apoor prognostic factor on outcome (p=0.06).Conclusion Change in almost all coagulation tests are found inGC patients and only DD level seems to be of prognostic value.

Keywords Coagulation tests . Gastric cancer . Survival

Introduction

The relationship between cancer and coagulation is character-ized by several mechanisms indicating that tumor biology andcoagulation are closely linked processes [1]. It is now wellestablished that activation of clotting is frequently found incancer, typically manifesting as a low-grade disseminatedintravascular coagulation (DIC) or venous thromboembolism(VTE) either as a result of cancer or its therapy. Patients withtumors of the lung, pancreas, and gastrointestinal tract areconsidered to be more prone to hypercoagulable state [2].Incidence of thrombosis is the highest in metastatic, fast-growing, biologically aggressive cancers and associated witha poor prognosis [3].

Tumors can cause hypercoagulability by expressingprocoagulant proteins, compromising venous blood flowby extrinsic compression of adjacent vessels, inducing pro-duction of inflammatory cytokines [3]. According to recentevidence, predictive biomarkers of VTE include platelet(PLT) and leukocyte (WBC) counts, hemoglobin (Hb), D-dimer (DD), and tissue factor (TF) [4].

Importantly, rather than being merely a trigger of increasedthromboembolic events, cancer-induced hemostatic activityhas been shown to promote tumor growth and cancer celldissemination [5, 6]. Tumors activating the coagulation sys-tem are considered to behave more aggressively, with a higherrisk of invasion and metastasis. High levels of circulatingbiomarkers resembling activated coagulation and fibrinolyticsystems such as fibrinogen (F), fibrin(ogen) split products(FDP), and DD have been associated with decreased survivalfor several tumor types in previous studies [7, 8]. Researcheson gastric cancer (GC), which is one of the most common andaggressive malignancies in humans, examining the relation-ship between activated hemostatic system and prognosis haveyielded similar results [8–14].

F. Tas (*) : R. Ciftci : L. Kilic :M. Serilmez : S. Karabulut :D. DuranyildizInstitute of Oncology, University of Istanbul, Istanbul, Turkeye-mail: faruktas2002@yahoo.com

J Gastrointest CancDOI 10.1007/s12029-013-9490-x

Activation of the coagulation system in malignancy pro-motes spreading of tumors and is, thus, associated with apoor prognosis for patient. Exact mechanisms of how thecoagulation cascade influences blood-borne metastasis,however, remain poorly understood. It was observed thattumor cells strongly accelerate plasma coagulation as aresult of: (1) expression of the blood clotting initiator pro-tein, TF, and (2) direct activation of prothrombin to throm-bin by cells [15]. It is known that two major procoagulantsfrom malignant tissue are TF and a direct activator ofcoagulation factor X called the cancer procoagulant (CP).It has been shown that F is a critical determinant of themetastatic potential of circulating tumor cells [16]. In somestudies, elevated DD levels were associated with poorersurvival in cancer patients including GC [8].

The aims of the current study are (1) to confirm whethersome coagulation abnormalities are more frequently foundwith GC, (2) to delineate the correlation of these coagulationfactors with other clinical and laboratory variables, andfinally, (3) to explore the prognostic value of such dailypractice coagulation pathway tests and other laboratory pa-rameters for survival.

Patients and Methods

This study included 44 consecutive patients admitted to theInstitute of Oncology, Istanbul University. All patients hadhistologically confirmed GC and had not received chemother-apy (CT) or chemoradiation in the last 6 months. Staging wasdetermined according to the American Joint Committee onCancer (AJCC) and International Union against Cancer(UICC) staging systems. Pretreatment evaluation includedassessment of detailed clinical history and physical examina-tion with a series of biochemistry tests including lactate de-hydrogenase (LDH), complete blood cell counts includingthrombocytes (PLTs), leukocytes (WBCs), Hb, and coagula-tion tests including DD, F, prothrombin time (PT), activatedpartial thromboplastin time (APTT), and international normal-ized ratio (INR). Those with Eastern Cooperative OncologyGroup (ECOG) performance status 2 or less and adequaterenal, hepatic, cardiac, and bone marrow functions receivedCTon an outpatient basis that included different combinationsof fluorouracil, folinic acid, capecitabine, docetaxel, cisplatin,and epirubicine, with/without radiotherapy according to stageof disease. Follow-up programs included clinical, laboratory,and radiological assessments performed at 8-week intervalsafter CT or every 12 weeks for no anticancer treatment.Response to CT was determined according to the revisedresponse evaluation criteria in solid tumors (RECIST)criteria version 1.1 [17]. For comparison, 50 age- and sex-matched healthy controls (30male andmedian age of 53 years,range 23–78 years) who had no malignant disease or

thromboembolic event were included in the analysis. In-formed consent was obtained from all patients, and the studywas reviewed and approved by a local ethical committeebefore the commencement of the study.

Coagulation Assays

Venous blood samples were collected before initiation of ther-apy in sodium citrate for measurement of DD, F, PT, APTT,and INR and stored for a maximum of 2 days at −20 °C. DDvalues were determined by microparticle enzyme immunoas-say using an AxSYM analyzer (Abbott Laboratories, Chicago,IL, USA) following the manufacturer's instructions. Commer-cially available reagents provided by the kinetic nephelometricdetection system using Diagon Dia-Timer 4 (Diagon Ltd.,Budapest, Hungary) were used for PT, APTT, and Fmeasurements.

Statistical Analysis

Continuous variables were categorized using median values asthe cutoff point. Assessment of relationships, comparisonsbetween various clinical/laboratory parameters, and coagula-tion tests were carried out using the Mann–Whitney U test.Survival was calculated from the date of first admission tohospital to death resulting from any cause or to last contactwith the patient or any family member. The Kaplan–Meiermethod was used for the estimation of the survival of patientsand differences in survival were assessed using logrank statis-tics. Multivariate survival analysis was performed using Cox'sproportional hazards regression model. A p value less than 0.05 was considered significant. Statistical analysis was carriedout using SPSS 18.0 software (SPSS Inc., Chicago, IL, USA).

Results

From September 2009 to July 2011, 44 consecutive patientswith a pathologically confirmed diagnosis of GC were en-rolled into this study. The demographic and histopatholog-ical characteristics of the patients are listed in Table 1. Themedian age at diagnosis was 55 years, range 19–80 years;73 % (n=32) of the patients in the group were men. Most ofthe patients (70 %) had metastatic disease.

The serum levels of coagulation assays showed a statis-tically significant difference between the patient and controlgroups (p<0.001 for all but p=0.07 for PT) (Table 2). DDlevels were higher among patients with elevated serum LDHlevels and higher PLT counts (1271 vs. 536 IU/ml, p =0.01;838 vs. 388 IU/ml, p=0.009, respectively) (Table 3). Thelevels of INR and F in metastatic patients were significantlyhigher than nonmetastatic patients (1.14 vs. 1.06, p=0.027;425 vs. 282 mg/dl, p=0.001 respectively).

J Gastrointest Canc

Between coagulation tests and clinicopathologic vari-ables, only serum LDH level was significantly associatedwith overall survival (Table 4). Elevated serum LDH levelwas a poor prognostic factor on survival (p=0.01). Howev-er, only patients with elevated DD (p=0.07) tended to havea worse outcome (p=0.06). Multivariate analyses performedwith Cox's proportional hazards regression analyses, includ-ing all of the coagulation tests and prognostically significantclinical variables with a p value of 0.05 or less, showed thatthe statistical significance of the LDH level on survival inunivariate analysis disappeared and there was no other sig-nificant variable on survival.

Discussion

GC, which is often diagnosed at advanced stage (50 % ofpatients), is the fourth most common cancer worldwide [9].The risk factors for GC include Helicobacter pylori infec-tion, smoking, high salt and alcohol intake, and family

history of nonhereditary GC [18]. Poor prognostic factorsfor GC are advanced disease, surgical stage (if resectable),poor performance status of patient, metastasis, and elevatedalkaline phosphates [19]. Median overall survival for meta-static GC is only 5–8 months [20].

A systematic activation of coagulation has been observedin cancer patients and is usually indicated by subclinicalabnormalities in conventional tests for blood coagulation[21, 22]. So far, although little is known about GC, variousmarkers reflecting an activated hemostatic system such asthrombocytosis, hyperfibrinogenemia, and elevated DDlevels have been found in different types of cancer, involv-ing cancers of head and neck, colon, prostate, lung, andmelanoma [8, 23, 24].

Procoagulant factors are intimately involved in all as-pects of hemostatic process, cell proliferation, and cellularsignaling systems [5]. It has been well understood thatclotting activation in malignancy not only plays an impor-tant role in the evolution of VTE or systemic coagulationdisorders such as DIC but also that hemostatic and fibrino-lytic systems are directly involved in tumor progression byfacilitating invasiveness and metastases [5, 6]. Thus, theextent of this activation has been interrelated with tumorstage and prognosis in some malignancies such as breast,colorectal, and lung cancers [7, 24, 25]. It is known that twomajor procoagulants from malignant tissue are TF and adirect activator of coagulation factor X called CP [15, 26].TF and CP are elevated in patients with cancer [27]. CP isresponsible for blood coagulation disorders in malignantneoplasms, incorrect metabolism of fibrin, and its accumu-lation around malignant tissues [26]. Fibrin formation isinvolved in the process of tumor spreading and metastasis[6]. TF acts as a receptor for factor VII triggering thecoagulation cascade and it is also activated during apoptosisof the cell [15]. In human GC cell lines, thromboplasticactivity was factor VII dependent and factor IX indepen-dent, indicating the importance of TF [28]. In addition, TFplays an important role in vascular development, angiogen-esis, and tumor cell metastasis. In addition to tumor cells,TF is expressed by tumor-associated macrophages andtumor-associated endothelial cells. In lung cancer, melano-ma, and breast cancer, TF and vascular endothelial growthfactor (VEGF) colocalize in tumor tissue; a close correlationexists between TF and VEGF synthesis, suggesting that TFis necessary for tumor cell VEGF synthesis [29].

A thrombotic effect of malignancy results from tumoralproduction of procoagulants (TF and CP), inflammatory cy-tokines, interaction between tumor cells in the blood(monocytes/macrophages and PLTs) and endothelial cells,decreased levels of coagulation inhibitors, impaired fibrinoly-sis, central venous catheter, and hemodynamic compromise(i.e., stasis) and anticancer therapy (surgery, CT, hormonetherapy, and radiotherapy) [30]. Several biomarkers for

Table 1 Patient characteristics

Variables Percent

No. of patients: 44 100

Age (years)

Median (range): 55 (19–80)

Gender

Male 73

Female 27

Histology

Adenocarcinoma 50

Signet ring cell 50

Histological grade

III 59

Others 41

Stage of disease

Nonmetastatic 30

Metastatic 70

Serum hemoglobin level

Low (<12 g/dl) 59

Normal (>12 g/dl) 41

Serum WBC count

Normal (<11,000) 91

Elevated (>11,000) 9

Serum platelet count

Normal (<350,000) 52

Elevated (>350,000) 48

Serum LDH level

Normal (<450 U/L) 77

Elevated (>450 U/L) 23

J Gastrointest Canc

cancer-associated thrombosis have also been identified in-cluding WBCs, PLTs, levels of TF, DD, C-reactive protein,and soluble P-selectin [31].

Venous thrombosis in GC was described by Trousseau in1865 and Billroth observed intravascular thrombus formationin association with metastasis in 1878 [32]. Data about com-monly used plasma coagulation assays in daily practice ofpatients with GC especially metastatic GC is limited andconflicting [8, 10–14, 33–35]. Previous studies about coagu-lation assays and GC usually included only operable GC [13,34, 36] or assessed coagulation proteins on cancer tissue not inplasma [37, 38]. The aim of this study was to obtain furtherevidence whether routine coagulation tests are impaired orwould aid clinicians in predicting GC patients' outcome withother prognostic indicators.

Kovacova et al. suggested that patients with GC are athigh risk for both thromboembolism (20.1 %) and hemor-rhagic diathesis (6 %) [10]. In this study, patients hadhypercoagulability (31.1 %), DIC (47.8 %), and remarkablehypocoagulability with DIC (6 %). In addition, advance-ment of tumor to metastatic stage was followed by devel-opment of subacute DIC [10, 39]. Tiutrin et al. demonstratedthat GC depleted the compensatory potential of the fibrino-lytic system and antiaggregan capacity of vasculaturepredisposing to hypercoagulable state that was also corre-lated with the stage of disease (28 % for stage III and 81 %for stage IV) [33].

Rahr et al. compared plasma levels of F, FDP, fibrinopep-tide A (FPA), and prothrombin fragment 1+2 (PF) of GCpatients to benign gastric lesions, and only FPA and FDPwerehigher in GC group [11]. Yamamura et al. showed that PLT, F,and FDP levels were increased; however, plasminogen, alpha-2 macroglobulin, antithrombin III (AT) levels were decreasedwhile the stage of GC progressed independently from histo-logical features [12]. Regarding operable GC patients, amongplasma levels of PLT, APTT, FPA, AT, F, DD, F, and FPA,factors Vand VII levels were increased in most of the patientsand only F and FPA levels were positively correlated withdepth of tumor invasion [34]. In another study, prolonged PTwas associated with lymph node involvement, while elevatedDD was associated with depth of invasion and nodal

involvement of operable GC patients [36]. Additionally, DiMicco et al. revealed that plasma levels of tissue plasminogenactivator, DD, PF, and F were significantly higher innonmetastatic GC patients than controls [13].

F is believed to be a critical determinant of the metastaticpotential of circulating tumor cells by supporting theirsustained adhesion to target tissue [16]. Factors of bothplasma hemostatic systems (coagulation and fibrinolysis)are also “misused” by malignant cells for the purposes ofgrowth and metastasis [40]. The protective fibrin formationagainst the endogenous defense mechanisms and the localdegradation of tissues for tumor proliferation as well as forcell permeation and invasion support this “misuse” [40]. Inelderly patients with breast cancer, ovarian cancer, or GC,electron microscopy revealed fibrin on the surface of tumorcells and increased plasma F level was associated withhigher tumor occurrence, suggesting that anticoagulantscould help cytotoxic agents to be more effected [37]. Inour study, the median F level and the rate of those withelevated F levels were significantly higher in the GC group.However, elevated F level did not have a significant impacton survival.

The fibrinolytic system is important for not only hemo-static balance but also tissue remodeling, tumor invasion,and angiogenesis. The main enzyme is plasmin that de-grades fibrin into soluble degradation products (FDP andDD) [41]. High DD levels have been associated with pooroverall survival in a large study including 1,178 cancerpatients [8]. Another study also confirmed that DD levelsof metastatic GC were higher than controls [14]. However,plasma fibrinolytic activity and antiplasmin activity weredecreased and plasma F level was increased in both gastricand peripheral veins of GC patients in another study [35].

In a large study including different cancer types (n=50 forGC), high DD levels were associated with poor outcome andan increased risk of mortality in cancer patients [8]. DD levelswere categorized into four groups on the basis of the first,second, and third quartiles of the DD distribution in the totalstudy population, not classified as elevated/nonelevated. Thesurvival results according to these quartiles were 78, 66, 50,and 30 % (p<0.001). DD levels had a significant impact on

Table 2 The values of serumcoagulation tests in patients withgastric cancer and healthycontrols

PT prothrombin time, APTT ac-tivated partial thromboplastintime, INR international normal-ized ratio

Patients (n=44) Controls (n=50)

Coagulation tests Median Range Median Range p

D-Dimer (IU/ml) 620 0–8,763 37.8 0–118.5 <0.001

Fibrinogen (mg/dl) 408 232–856 245 166–463 <0.001

PT (s) 14.5 13–31 14.2 10.5–16.8 0.07

APTT (s) 27.8 18.8–51.1 31.8 24.6–48.0 <0.001

INR 1.09 0.99–1.76 1.01 0.76–1.29 <0.001

Platelet (×103/mm3) 340.5 44–822 201 163–254 <0.001

J Gastrointest Canc

Tab

le3

Results(m

edianandrang

e)of

comparisons

betweenthecoagulationtestsandvariou

sclinical

andlabo

ratory

parametersin

GCpatients

Param

eters

Coa

gulation

tests

D-D

imer

(IU/m

l)Fibrino

gen(m

g/dl)

PT(s)

APTT(s)

INR

PLT

(x10

3/m

m3)

Age

ofpatients(years)

>median(>55

)53

6(43–87

63)

416(243–63

9)14

.7(13.8–31

.0)

28.6

(24.0–36

.3)

1.1(0.99–1.76

)32

7(192–51

4)

<median(<55

)65

7(0–50

00)

375(232–85

6)14

.4(13.0–18

.0)

26.1

(18.8–51

.0)

1.2(0.99–1.36

)35

6(44–82

2)

P0.27

0.29

0.21

0.27

0.63

0.47

Gender

Male

565(43–87

63)

422(340–59

)13

.9(13.8–16

.4)

28.3

(19.1–30

.9)

1.08

(0.99–1.16

)33

7(250–43

1)

Fem

ale

648(0–50

00)

382(232–75

6)14

.7(13.0–31

.0)

27.4

(18.0–51

.1)

1.12

(0.99–1.76

)34

1(44–82

2)

P0.65

0.32

0.27

0.48

0.14

0.55

Histology

Signet-ring

cell

623(0–50

00)

425(232–85

6)14

.4(13.0–31

.0)

27.8

(18.8–51

.0)

1.09

(0.99–1.36

)32

7(44–59

4)

Adeno

carcinom

a53

9(0–87

03)

388(250–63

9)14

.7(13.1–25

.3)

28.1

(19.1–36

.7)

1.10

(0.99–1.76

)35

3(192–82

2)

P0.74

0.40

0.37

0.49

0.56

0.99

Histologicalgrade

III

606(0–87

63)

413(269–71

9)14

.5(13.0–18

.3)

28.6

(18.8–51

.1)

1.12

(0.99–1.36

)32

2(192–55

0)

Others

646(0–50

00)

381(232–85

6)14

.4(13.6–31

.0)

26.7

(19.1–36

.3)

1.08

(0.99–1.76

)35

4(44–82

2)

P0.75

0.94

0.97

0.47

0.38

0.68

Stage

ofdisease

Non

metastatic

399(0–36

31)

283(242–41

9)14

.3(13.0–31

.0)

26.1

(18.8–51

.0)

1.06

(0.99–1.18

)24

7(192–55

5)

Metastatic

640(43–87

63)

425(132–85

6)14

.5(13.0–25

.3)

28.6

(19.1–37

.6)

1.14

(0.99–1.76

)36

0(44–82

2)

P0.33

0.00

10.21

0.28

0.02

70.09

Hem

oglobin(g/dl)

Low

(<12

)72

1(0–87

63)

408(232–85

6)15

.0(13.1–31

.0)

28.6

(19.1–51

.1)

1.14

(0.99–1.36

)36

2(44–82

2)

Normal

(>12

)56

6(0–3119

)40

2(250–71

9)14

.3(13.0–25

.3)

27.6

(18.8–32

.7)

1.08

(0.99–1.76

)30

6(192–43

1)

P0.13

0.62

0.60

0.61

0.13

0.15

WBC

Normal

(<1100

0)62

0(0–87

61)

408(232–71

9)14

.4(13.0–25

.3)

27.8

(18.8–51

.0)

1.09

(0.99–1.76

)31

3(44–82

2)

Elevated(>1100

0)95

3(367–43

29)

397(242–75

6)15

.6(14.4–31

.0)

28.4

(23.2–36

.7)

1.10

(1.06–1.25

)44

5(362–59

4)

P0.49

0.91

0.13

0.64

0.71

0.03

Platelet

Normal

(<35

0000

)38

9(0–50

00)

378(232–71

9)14

.3(13.0–25

.3)

27.4

(18.8–51

.0)

1.08

(0.99–1.76

)–

Elevated(>35

0000

)83

8(43–87

63)

416(242–85

6)15

.5(13.1–31

.0)

28.6

(19.1–37

.6)

1.10

(0.99–1.36

)

P0.00

90.45

0.06

0.88

0.07

LDH

(U/l)

Normal

(<45

0)53

6(43–43

29)

385(242–71

9)14

.5(13.0–31

.0)

27.4

(18.8–51

.1)

1.09

(0.99–1.76

)30

5(192–55

9)

J Gastrointest Canc

Table 4 Univariate analysis of overall survival

Characteristic Overall survival

Median(weeks)

6-month (±SD)(%)

p

Age (years)

<Median 62.5 82.2 (9.4) 0.5>Median 69.5 92.3 (7.4)

Gender

Male 69.5 82.5 (11.3) 0.28Female 47.1 89.1 (7.4)

Histology

Adenocarcinoma 69.5 80.5 (10.6) 0.85Signet ring cell carcinoma 49.2 92.3 (7.4)

Grade

III 73.1 83.7 (9.0) 0.63Others 62.5 90.0 (9.5)

Stage of disease

Nonmetastatic 69.5 87.5 (11.7) 0.19Metastatic 47.4 87.8 (6.7)

Serum hemoglobin level (g/dl)

Low (<12) 69.5 87.5 (11.7) 0.74Normal (>12) 49.2 90.9 (8.7)

Serum WBC count

Normal (<11,000) NR# 89.1 (8.8) 0.07Elevated (>11,000) 62.5 75.0 (21.7)

Serum LDH level (U/l)

Normal (<450) 69.5 91.9 (5.5) 0.01Elevated (>450) 41 66.7 (20.8)

Response to chemotherapy

Responsive 47.1 87.5 (11.7) 0.78Nonresponsive 32.5 62.5 (21.3)

D-Dimer

Normal (<median value) 73.1 87.5 (11.7) 0.06Elevated (>median value) 47.1 62.5 (21.3)

Fibrinogen

Normal (<median value) 47.1 82.1 (11.7) 0.17Elevated (>median value) 41 83.3 (11.2)

PT

Normal (<median value) 47.1 72.4 (14.2) 0.20Prolonged (>median value) 69.5 93.8 (6.1)

APTT

Normal (<median value) 69.5 87.5 (11.7) 0.21Prolonged (>median value) 49.2 75.8 (10.5)

INR

Normal (<median value) 47.1 77.9 (14.1) 0.32Prolonged (>median value) 62.5 87.1 (18.6)

Platelet

Normal (<median value) 69.5 94.1 (5.7) 0.35Elevated (>median value) 41 76.2 (13.4)

The median values of all coagulation assays are shown in Table 2

# means not reached (NR)

Tab

le3

(con

tinued)

Param

eters

Coa

gulation

tests

D-D

imer

(IU/m

l)Fibrino

gen(m

g/dl)

PT(s)

APTT(s)

INR

PLT

(x10

3/m

m3)

Elevated(>45

0)12

71(367–87

63)

410(232–85

6)15

.1(13.6–17

.8)

28.9

(23.2–

32.7)

1.16

(1.04–

1.33

)39

6(44–82

2)

P0.01

0.68

0.55

0.68

0.22

0.04

Respo

nseto

chem

otherapy

Respo

nsive

609(43–

3631

)42

7(356–51

2)15

.2(13.8–18

.3)

29.0

(22.1–

30.9)

1.16

(0.99–

1.36

)36

0(265–38

7)

Non

respon

sive

536(43–

4329

)42

5(242–85

6)14

.4(13.0–31

.0)

27.4

(19.1–

36.3)

1.09

(0.99–

1.76

)36

2(192–82

2)

P0.76

0.84

0.41

0.48

0.18

0.77

Laststatus

Aliv

e56

7(0–

5000

)41

3(274–63

9)14

.5(13.8–25

.3)

29.0

(19.1–

36.3)

1.08

(0.99–

1.76

)35

0(192–55

0)

Dead

956(43–

8763

)40

4(232–85

6)14

.4(13.0–31

.0)

27.0

(18.8–

51.0)

1.10

(0.99–

1.33

)32

6(44–82

2)

P0.17

0.63

0.74

0.15

0.78

0.48

J Gastrointest Canc

mortality in both univariate and multivariate analyses afteradjustment for tumor subgroups [8].

Surgical specimens of 37 GC patients demonstrated thatVEGF and hemostatic proteins (fibrin; F; DD; TF; PF; proteinC; factors VII, IX, X, XII, and XIII; von Willebrand factor(vWF); and plasminogen activator inhibitor-1 (PAI-1)) werecolocalized in tumor and adjacent tissue especially in host–tumor surface, suggesting that they may cooperate in thepathogenesis of GC. However, there was no staining for TFpathway inhibitor (TFPI). Despite plasma levels of coagula-tion parameters were not measured, this study demonstratedthat GC-associated activation of TF-dependent extravascularcoagulation was not counterbalanced by TFPI or sufficientfibrinolytic activity [38].

DIC is a well-known hemostatic complication of solidtumors and its incidence was 6.8 % among 1,117 patientswith solid tumors in a study [42]. Thrombocytopenia,hypofibrinogenemia, and elevated DD and FDP are the mostcommon abnormalities of DIC. In multivariate analysis(MVA), older age, male gender, advanced disease, and necro-sis in the tumor specimen were the independent factors forDIC and DIC significantly decreased survival. In anotherstudy, it was suggested that plasma F level is not a sensitivemarker for DIC, F levels had no impact on survival despite TF,and PAI-I and IL-6 were significantly higher in patients withhigh F levels [43]. In addition, it was suggested that lessactivation of secondary fibrinolysis in DIC could be relatedto organ failure and poor outcome. In our study, both F andDD levels were increased, and if these changes are related to alatent DIC, perhaps compensatory activation of secondaryfibrinolysis (elevated DD) prevented poorer outcome.

According to recent studies, PLTs appear to contribute tometastases by their adhesive interaction with tumor cellsthrough the PLT-adhesive proteins fibronectin and vWF[44]. In our study, PLT counts were significantly higher inthe GC group than the healthy controls, but PLT counts didnot have a significant impact on the survival. PLT adhesionmolecules can be considered as important as PLT counts forcancer-related hypercoagulability. Fibronectin and vWFlevels were not measured in our study.

Elevated DD levels were significantly associated with ele-vated LDH and PLT levels, however, not with metastaticstatus, CT response, or other coagulation assays. In our study,the duration of follow-up was short and most of the patientswere alive at the time of statistical analyses. Interestingly,when metastatic patients were compared with nonmetastaticpatients, there was no difference, indicating that the follow-upperiod was not satisfactory. Similarly, when metastatic pa-tients were compared with nonmetastatic patients, DD levelstended to be higher in the metastatic patients, but not statisti-cally significant. So, the number of our patients and shortfollow-up time seem as limitations of this study. Duringfollow up, no patients developed clinically overt pulmonary

embolism or VTE or hemorrhagia. Routine venous Dopplerultrasonography was not performed because there was noclinical indication and the aim of the study was not assessingoccurrence of thromboembolism. Of course, we cannot saythat patients who died had no thromboembolic event, sinceautopsy was not performed.

In conclusion, the current study confirms that subclinicalchanges in the coagulation–fibrinolytic system are often presentin GC. In our study, which includes mostly metastatic GC,coagulation assays were significantly increased, indicating thatboth coagulation and fibrinolytic systems are strongly activatedin GC. However, these coagulation assays had no significanteffect on survival. Despite these coagulation assays commonlyused in daily practice finding no prognostic and predictive rolein this study, it is certain that larger and prospective furtherstudies are required to clarify this controversial issue.

Conflicts of interest None.

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