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ORIGINAL
Value of the fibrinogen–platelet ratio in patients withresectable pancreatic cancer
Yusuke Arakawa, M.D, Katsuki Miyazaki, M.D, Masato Yoshikawa, M.D, Shinichirou Yamada, M.D, Yu Saito, M.D,
Tetsuya Ikemoto, M.D, Satoru Imura, M.D, Yuji Morine, M.D and Mitsuo Shimada, M.D, PhD
Department of Digestive Surgery and Transplantation, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan

Abstract : Background : Several prognostic factors were reported in pancreatic cancer. The fibrinogen–platelet
ratio (FPR) was reported as a prognostic factor of resectable gastric cancer. In this report, the FPR was evaluated in patients with resectable pancreatic cancer. Methods : Between 2004 and 2019, 163 patients with curative
resection for pancreatic cancer were enrolled. Cases of non-curative resection were excluded. The FPR was calculated using the preoperative plasma fibrinogen and the platelet counts and the cut-off value was determinedby receiver operating characteristic (ROC) curve analysis. The patients were divided into high and low FPR
groups according to this cut-off value. Results : The cut-off value of FPR was 25.2. Among age, sex, body massindex (BMI), and surgical factors including surgery type, volume of blood loss and surgery time, there was no
significant difference between the two groups. Patients in the low FPR group had significantly better overall survival (OS) and relapse-free survival (RFS) compared with the high FPR group (P < 0.05). On multivariate analysis,a high FPR, CA19-9 > 300 U / ml, and receipt of adjuvant chemotherapy were independent risk factors for OS and
DFS. Conclusions : The FPR might be a prognostic factor for patients with resectable pancreatic cancer. J. Med.
Invest. 68 : 342-346, August, 2021
Keywords : fibrinogen, platelets, pancreatic cancer

INTRODUCTION
The prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) is extremely poor. In the United States, the 5-year
overall survival rate is only 8% (1). Surgical resection is an effective treatment procedure for PDAC. Nowadays, adjuvant chemotherapy has been recommended for pathological stage morethan II after surgical resection in Japan (2). However, the rateof recurrence after surgery is still high. Therefore, to administer adjuvant chemotherapy and understand the mechanism ofcancer progression, novel predictive markers for postoperative
survival and recurrence are required.
Various studies were performed to identify appropriate molecular biomarkers for prediction of postoperative prognosis. Several predictive markers based on immune-nutritional status werereported, including the neutrophil–lymphocyte ratio (NLR), theplatelet–lymphocyte ratio (PLR), and the prognostic nutritional
index (PNI) (3, 4).
Coagulation system disorders are frequently observed in patients with malignancies, and these disorders, including thosethat activate platelets, are associated with poor prognosis (5, 6).
Recently, Wakatsuki et al. reported that the fibrinogen–platelet
ratio (FPR) is a poor prognostic factor of overall survival (OS)and relapse-free survival (RFS) in stage Ⅱ/Ⅲ gastric cancer patients (7). Furthermore, Watanabe et al. reported the multiplication of d-dimer, which is a fibrin-cleaved product in platelets thatcan predict postoperative recurrence and prognosis for patientswith cholangiocarcinoma (8).
The aim of this study was to clarify the impact of fibrinogen
Abbreviations
PDAC, pancreatic ductal adenocarcinoma ; NLR, neutrophil–lymphocyte
ratio ; PLR, platelet–lymphocyte ratio ; PNI, prognostic nutritional
index ; FPR, fibrinogen–platelet ratio ; OS, overall survival ; RFS,
relapse-free survival ; ROC, receiver operation characteristic ; CRP,
C-reactive protein ; mGPS, modified Glasgow prognostic score ; HR,hazard ratio ; CI, confidential interval

and platelets as prognostic markers after curative resection forpatients with pancreatic cancer using the FPR.

PATIENTS AND METHODSOne hundred sixty-three patients who underwent curative
surgical resection for PDAC during 2004 to 2019 at the University of Tokushima Hospital were enrolled in this retrospective
study. Fourteen patients were excluded because of non-curative(R2) resection which meant macroscopic residual tumor and distant metastasis. All patients had PDAC proven histologically. Finally, 149 patients were analyzed in this study. Laboratory data
including serum fibrinogen, platelet, C-reactive protein (CRP),
and albumin were collected within 1 month before surgery.
Patients were followed up monthly for tumor markers including
CEA and CA19-9 and underwent computed tomography every
4–6 months. When recurrence was suspected, precise diagnostic
imaging studies including positron emission tomography were
performed. After confirmation of recurrent pancreatic cancer,
systemic chemotherapy, radiation therapy, or best supportive
care were indicated. All patients signed informed consent forthis study, which was approved by the clinical ethics committee
at University of Tokushima Institution-Review Board (#3325).
This study has been reported in line with the strengthening thereporting of cohort studies in surgery criteria (9).
The NLR, PNI, PLR, and modified Glasgow prognostic score(mGPS) were calculated and the cutoff values were 3, 45, 150,
and 1, respectively. The fibrinogen–platelet ratio was calculated.
Received for publication July 12, 2021 ; accepted August 10, 2021.
Address correspondence and reprint requests to Yusuke Arakawa,
Department of Surgery, Tokushima University Graduate School of
Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503,
Japan and Fax : +81-88-631-9698.

The Journal of Medical Investigation Vol. 68 2021

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The Journal of Medical Investigation Vol. 68 August 2021
To determine the appropriate cutoff value of the FPR, receiver
operating characteristic (ROC) curve analysis was performed.
The cutoff value of the FPR was 25.2 and the AUC value was
0.54223. The clinicopathological characteristics of the patientsare shown in Table 1.

Table 1. Clinicopathological characteristics of patients with surgical

Statistical analysis

female / male

77 (51.3) / 72 (48.7)

Body mass index kg / m2

22.1 (19.7-24.2)

Fibrinogen, g / ml

439 (367-510)

C reactive protein, mg / L

0.09 (0.05-0.27)

Statistical comparisons for significance were made using chisquared test or Fisher’s exact test with one degree of freedom,
as appropriate. Cumulative OS and RFS were determined using
the Kaplan–Meier method with a log-rank test. Univariate andmultivariate analyses were performed using a Cox proportional
hazard model. A p-value of less than 0.05 was considered statistically significant. Statistical analysis was performed with JMP
14 software (SAS Institute, Cary, NC, USA).

RESULTS

Comparison of prognostic factors for OS in patients with surgicalresection for PDAC
The OS rate was significantly worse in patients with a highFPR compared with those with a low FPR (Figure 1A). The
prognostic factors for OS in patients with surgical resection for
PDAC are shown in Table 2. In the univariate analysis, sevenfactors were independent prognostic factors for OS including
FPR (hazard ratio (HR) 2.256, 95% confidence interval (CI)
1.392–3.659, P < 0.001), PNI (HR 2.250, 95% CI 1.384–3.645,
P = 0.007), PLR (HR 1.643, 95% CI 1.022–2.684, P = 0.0045),
CA19-9 (HR 2.085, 95% CI 1.314–3.311, P = 0.0013), adjuvant
chemotherapy (HR 2.208, 95% CI 1.396–3.491, P = 0.0022),
T3+4 (HR 2.873, 95% CI 1.700–5.114, P < 0.001), lymph nodemetastasis (HR 1.846, 95% CI 1.143–2.945, P = 0.0095) andresection margin R0 (HR 1.700, 95% CI 1.018-2.751, P = 0.0331).
In multivariate analysis of these eight factors, three were independent prognostic factors for OS including FPR (HR 2.013, 95%
CI 1.202–3.370), CA19-9 (HR 1.687, 95% CI 1.033–2.753), andadjuvant chemotherapy (HR 2.329, CI 1.435–3.781).

Comparison of prognostic factors for RFS in patients with surgicalresection for PDAC
The RFS was significantly worse in patients with a highFPR compared with those with a low FPR (Figure 1B). The
prognostic factors for RFS with surgical resection for PDAC
are shown in Table 3. In the univariate analysis, five factors
were independent prognostic factors for OS including FPR(HR 1.958, 95% CI 1.282–2.990, P = 0.0015), PNI (HR 1.542,

resection for PDAC
Parameters
Age, years

70 (63-76)

Serum albumin, g / dl

3.9 (3.7-4.2)

WBC, 109  / L

5450 (4400-6600)

Neutrophils, 109 / L

3650 (2600-4495)

Lymphocytes, 10 / L

1290 (1040-1715)

CEA ng / ml

2.3 (1.4-3.9)

CA19-9 U / ml

126 (27.5-670)

Type of resection (DP / PD / TP)

46/98/5

PV resection (n, %)22 (14.7)

Neoadjuvant chemotherapy (n, %)16 (10.7)

Postoperative chemotherapy (n, %)89 (59.3)

9UICC stage (n, %)ⅠA

20 (15.4)

ⅠB

16 (16)ⅡA

47 (31.5)

ⅡB

43 (28.9)

Ⅲ

23 (15.4)

Resection margin R0

115 (76.7)

Tumor size ≥ 2 cm

113 (75.6)

Lymph node metastasis (n)52 (35.1)

Lymphatic invasion (ly)100 (68.0)

Vascular invasion (v)114 (77.6)

Perineural invasion (ne)119 (81.5)

Anterior serosal invasion (s)34 (29.6)

Retroperitoneal invasion (rp)45 (38.1)

Microscopic portal vein invasion (pv)

23 (22.3)

Microscopic arterial invasion (a)6 (5.7)

Plexus invasion (pl)11 (12.5)

Data are expressed as median (IQR) or n(%)
DP : distal pancreatectomy, PD : pancreaticoduodenctomy, TP : total pancreatectomy, PV : portal vein resection

Figure 1. Kaplan–Meier curves of overall survival and disease-free survival according to the FPR.
(A) Overall survival. (B) Relapse-free survival.

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Y. Arakawa, et al. Fibrinogen–platelet ratio and pancreatic cancer

Table 2. Comparison of prognostic factors for overall survival (OS) in patients with surgical resection for pancreatic ductal adenocarcinoma
Univariate
FactorMultivariate

p-valueHR (95% CI)

p-valueHR (95% CI)

2.873 (1.700-5.114)

0.09191.713 (0.916-3.203)

0.00951.846 (1.143-2.945)

0.14591.459 (0.882-2.415)

0.44741.190 (0.726-1.951)

R0 / R1

0.03311.700 (1.018-2.751)

0.18781.428 (0.840-2.428)

PV resection

No / yes

0.47311.310 (0.575-2.600)

NAC(-)

No / yes

0.92231.039 (0.433-2.116)
0.00062.329 (1.435-3.781)

0.0364

1.687 (1.033-2.753)

Age< 70/ ≥ 70

0.15581.391 (0.874-2.201)

Genderfemale / male

0.70231.315 (0.829-2.087)

BMI kg / m2

< 25/ ≥ 25

0.5203

1.216 (0.639-2.143)

T(3+4)

No / yes< 0.001N(+)

No / yes

Resection type

PD / DP / TP

Resection marginAC(-)

No / yes

0.00222.208 (1.396-3.491)

CEA ng / ml

< 5/ ≥ 5

0.58781.203 (0.578-2.248)

CA19-9 U / ml

< 300/ ≥ 300

0.00132.085 (1.314-3.311)

NLR< 3/ ≥ 3

0.941

1.021 (0.603-1.672)

PNI< 45/ ≥ 45

0.00072.250 (1.384-3.645)

0.18671.397 (0.815-2.415)

PLR< 150/ ≥ 150

0.00451.643 (1.022-2.684)

0.4714

1.219 (0.711-2.089)mGPS

0 / 1,2

0.67992.270 (0.806-5.190)

FPR< 25.2/ ≥ 25.2

< 0.001

2.256 (1.392-3.659)

0.00782.013 (1.202-3.370)

DP : distal pancreatectomy, PD : pancreaticoduodenctomy, TP : total pancreatectomy, PV : portal vein resection, NAC : neoadjuvant chemotherapy, AC : adjuvant chemotherapy

Table 3. Comparison of prognostic factors for relapse-free survival (RFS) in patients with surgical resection for pancreatic ductal adenocarcinoma

Univariate
FactorMultivariate

p-valueHR (95% CI)

Age > 70

< 70/ ≥ 70

0.4904

1.176 (0.780-1.759)

Gender (F/M)

Female / male

0.91961.040 (0.698-1.553)

BMI > 25 kg / m2

< 25/ ≥ 25

0.37001.295 (0.729-2.158)

T(3+4)

No / yes

0.00321.890 (1.232-2.966)

N(+)

No / yes

0.05611.494 (0.979-2.252)

Resection type

PD / DP / TP

0.44151.322 (0.850-2.058)

Resection margin

R0 / R1

0.15761.382 (0.865-2.141)

PV resection

No / yes

0.19371.466 (0.809-2.478)

NAC(-)

No / yes

0.41351.306 (0.709-2.405)

AC(-)

No / yes

0.00201.884 (1.257-2.824)

CEA > 5 ng / ml

< 5/ ≥ 5

0.1032

1.604 (0.886-2.713)

CA19-9 > 300 U / ml

< 300/≥ 300

0.00311.864 (1.239-2.797)

NLR< 3/ ≥3

0.3812

1.176 (0.759-1.792)

PNI< 45/ ≥ 45

0.03081.542 (1.008-2.340)

PLR< 150/ ≥ 150

0.22351.270 (0.840-1.928)

mGPS (0/1+2)

0 / 1,20.05291.956 (0.662-4.642)

FPR< 25.2/ ≥ 25.2

0.0015

1.958 (1.282-2.990)

p-valueHR (95% CI)

0.05361.596 (0.993-2.574)

0.00201.923 (1.269-2.916)

0.01501.686 (1.107-2.569)

0.55381.146 (0.730-1.797)

0.00291.967 (1.259-3.072)

DP : distal pancreatectomy, PD : pancreaticoduodenctomy, TP : total pancreatectomy, PV : portal vein resection, NAC : neoadjuvant chemotherapy, AC : adjuvant chemotherapy

The Journal of Medical Investigation Vol. 68 August 2021
95% CI 1.008–2.340, P = 0.0308), CA19-9 (HR 1.864, 95% CI
1.239–2.797, P = 0.0031), adjuvant chemotherapy (HR 1.884,
95% CI 1.257–2.824, P = 0.0020), and T(3+4) (HR 1.890, 95% CI
1.232–2.966, P = 0.0032). In the multivariate analysis of these
five factors, three were independent prognostic factors for RFS
including FPR (HR 1.967, 95% CI 1.259–3.072, P = 0.0029),
CA19-9 (HR 1.686, 95% CI 1.107–2.569, P = 0.0150), and adjuvant chemotherapy (HR 1.923, 95% CI 1.269–2.916, P = 0.0020).

Clinicopathological features according to the FPR
Clinicopathological factors are compared between the highand low FPR groups in Table 4. Among the tumor-related factors, the high FPR group was significantly correlated with neoadjuvant chemotherapy and T(3+4). Also, the high FPR group
showed an association with portal vein resection but was notstatistically significant. The other factors showed no significant
differences between these two groups.
Table 4. Clinicopathological features according to fibrinogen andplatelet ratio
FactorFPR High(n = 47)

FPR Low(n = 102)

p-valueAge ≥70 / <70

21 / 26

50 / 52

0.6219Male / Female

24 / 23

48 / 540.6494

BMI kg / m2 ≥25 / <25

5 / 4217 / 850.3230T 3+4 / 1+2

37 / 1038 / 640.0474N -/+16 / 3136 / 66

0.2373

DP / PD / TP

18 / 27 / 2

28 / 71 / 3

0.3532

PV resection - / +36 / 1190 / 120.0753NAC - / +38 / 995 / 70.0317AC - / +25 / 2238 / 640.2709

CEA ng / ml, ≥5 / <5

8 / 3914 / 88

0.6183

CA19-9 U / ml, ≥300 / <300

14 / 33

43 / 59

0.1448Alb ≥ g / dl, 3.5 / <3.5

41 / 680 / 220.2012

BMI : body mass index, DP : distal pancreatectomy, PD : pancreaticoduodenectomy, TP : total pancreatectomy, PV : portal vein,
NAC : neoadjuvant chemotherapy, AC : adjuvant chemotherapy,
Alb : albumin345

liver, lung, and peritoneal dissemination were excluded. Tumor
diameter, lymph node metastasis, histological differentiation,
and adjuvant chemotherapy were reported as poor prognostic
factors following curative resection for PDAC (15). The migration, invasion, and metastasis of cancer cells can contribute toinflammation through the activation of several chemokines suchas CXCR4 and its ligand CXCL12 (16). We speculated that the
local inflammation caused by local cancer invasion was correlated with the coagulation status of patients with PDAC ; therefore,
the FPR could reflect this local inflammation.
Platelets contribute to cancer progression and metastasis
through six hallmarks : sustaining proliferative signals, resisting cell death, inducing angiogenesis, evading immune detection, and supporting cancer stem cells. Antiplatelet therapies
might be a new candidate for anticancer therapy (17). Thrombocytosis was observed and reported as a poor prognostic factor forvarious types of cancer including PDAC (18).
Fibrinogen synthesized from hepatocytes is converted to fibrin
through thrombin and factor Ⅷ. Fibrin forms platelet plugs in
the wound site. The relationship between platelets and fibrinogen in cancer was associated with stromal formation, angiogenesis, and hematogenous metastasis (19, 20). In basic researchusing a fibrinogen knock-out and platelet-inactivated animalmodel, metastasis of embryonic tumor cells was significantly
decreased. Moreover, platelet and fibrinogen deposition was
found to be crucial for vascular endothelial adhesion and evasion
from NK cell-mediated elimination of cancer cells (21). The FPR
may be associated with these roles of platelets and fibrinogen incancer progression.
There were several limitations in this study. It was retrospective study and the sample size was relatively small. Further
prospective studies using more samples or propensity scorematching are required.
In conclusion, the preoperative FPR is a poor prognostic factor
in patients with resectable PDAC. FPR can be calculated easily
using preoperative serum fibrinogen and platelet values andmight reflect local inflammation caused by invasion of PDAC.

AVAILABILITY OF DATA AND MATERIALSThe datasets used and/or analyzed during the current study
are available from the corresponding author on reasonable
request.

DISCUSSION
In this study, a FPR value of more than 25.2 was a post-operative poor prognostic factor for patients with PDAC. The highFPR group showed a higher T stage and frequency of portal vein
resection and was associated with local aggressiveness of PDAC.
Serum fibrinogen and platelet number were measured in most of
the patients, and thus FPR was calculated easily.
In several reports, hemostatic status was associated withpoor prognosis in PDAC. Zhang et al. reported that prolonged
prothrombin time, high fibrinogen, and mean platelet volume
were independent prognostic factors for poor OS in patients withadvanced metastatic pancreatic cancer (10). The occurrence ofvenous thromboembolic disease is associated with reduced response rate of chemotherapy and a shorter OS and DFS among
the patients with advanced pancreatic cancer in various stage(11, 12). Hyperfibrinogen is associated with the systemic inflammatory response and predict poor prognosis for advanced
pancreatic cancer (13). Preoperative fibrinogen and high NLR
are also associated with poor prognosis in resectable breast
cancer (14).
In the current study, patients with distant metastasis such as

ACKNOWLEDGEMENTS
We thank H. Nikki March, PhD, from Edanz Group (https://
en-author-services.edanzgroup.com/ac) for editing a draft of thismanuscript.

FUNDINGNo sources for funding to be declared

AUTHOR INFORMATION
Affiliation : Department of Digestive Surgery and Transplantation, Tokushima University Graduate School of Biomedical
Sciences, Tokushima, Japan

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Y. Arakawa, et al. Fibrinogen–platelet ratio and pancreatic cancer

CONTRIBUTIONSYA, KM, MY, SY, YS, TI, SI, YM and MS : substantial contributions to the conception, or design of the work ; or the acquisition, analysis or interpretation of data ; or have drafted the workor substantively revised it. YA, KM, MY, SY, YS, TI, SI, YM andMS : have approved the submitted version.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE
This study was approved by the Institutional Review Boardof University of Tokushima, Tokushima, Japan (#3325). It followed the ethical principles (as revised in 2013) of the Helsinki
Declaration.

CONSENT FOR PUBLICATION
Not applicable.

CONSENT FOR PUBLICATION
The authors declare that they have no competing interests.

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