Combination of preoperative fibrinogen and D-dimer as a prognostic indicator in pancreatic ductal adenocarcinoma patients undergoing R0 resection

Table 1 Baseline characteristics of 282 pancreatic ductal adenocarcinoma patients undergoing radical R0 resection, n (%)

Characteristic	Patients (n = 282)	TNM stage
		IA (n = 20, 7.1%)	IB (n = 92, 32.6%)	IIA (n = 49, 17.4%)	IIB (n = 92, 32.6%)	III (n = 29, 10.3%)	P value
Age (yr)	61 (31-81)	63.5 (50-73)	62 (31-81)	63 (38-78)	59 (31-74)	59 (42-70)	0.076
> 60	136 (48.2)	12 (60.0)	52 (56.5)	31 (63.3)	39 (42.4)	12 (41.4)
≤ 60	146 (51.8)	8 (40.0)	40 (43.5)	18 (36.7)	53 (57.6)	17 (58.6)
Sex							0.421
Male	151 (53.5)	7 (35.0)	50 (54.3)	25 (51.0)	51 (55.4)	18 (62.1)
Female	131 (46.5)	13 (65.0)	42 (45.7)	24 (49.0)	41 (44.6)	11 (37.9)
Blood type							0.475
A	87 (30.9)	5 (25.0)	26 (28.3)	13 (26.5)	30 (32.6)	13 (44.8)
B	93 (33.0)	7 (35.0)	34 (37.0)	14 (28.6)	27 (29.3)	11 (37.9)
AB	22 (7.8)	1 (5.0)	6 (6.5)	4 (8.2)	11 (12.0)	0
O	80 (28.4)	7 (35.0)	26 (28.3)	18 (36.7)	24 (26.1)	5 (17.2)
Diabetes							0.816
Absent	201 (71.3)	15 (75.0)	66 (71.7)	33 (67.3)	64 (69.6)	23 (79.3)
Present	81 (28.7)	5 (25.0)	26 (28.3)	16 (32.7)	28 (30.4)	6 (20.7)
Smoking status							0.604
Absent	215 (76.2)	13 (65.0)	74 (80.4)	37 (75.5)	68 (73.9)	23 (79.3)
Present	67 (23.8)	7 (35.0)	18 (19.6)	12 (24.5)	24 (26.1)	6 (20.7)
Alcohol consumption							0.296
Absent	235 (83.3)	14 (70.0)	78 (84.8)	41 (83.7)	75 (81.5)	27 (93.1)
Present	47 (16.7)	6 (30.0)	14 (15.2)	8 (16.3)	17 (18.5)	2 (6.9)
Family history of cancer							0.604
Absent	271 (96.1)	20 (100.0)	88 (95.7)	46 (93.9)	88 (95.7)	29 (100.0)
Present	11 (3.9)	0	4 (4.3)	3 (6.1)	4 (4.3)	0
Clinical symptoms							0.021
Absent	57 (20.2)	8 (40.0)	24 (26.1)	7 (14.3)	16 (17.4)	2 (6.9)
Present	225 (79.8)	12 (60.0)	68 (73.9)	42 (85.7)	76 (82.6)	27 (93.1)
Open surgery approach							< 0.001
Pancreaticoduodenectomy	130 (46.1)	11 (55.0)	48 (52.2)	10 (20.4)	40 (43.5)	21 (72.4)
Distal pancreatectomy with splenectomy	152 (53.9)	9 (45.0)	44 (47.8)	39 (79.6)	52 (56.5)	8 (27.6)
Tumor location							< 0.001
Head and neck	130 (46.1)	11 (55.0)	48 (52.2)	10 (20.4)	40 (43.5)	21 (72.4)
Body and tail	152 (53.9)	9 (45.0)	44 (47.8)	39 (79.6)	52 (56.5)	8 (27.6)
Degree of differentiation							0.410
Well	34 (12.1)	0	11 (12.0)	6 (12.2)	13 (14.1)	4 (13.8)
Moderately	217 (77.0)	16 (80.0)	67 (72.8)	38 (77.6)	73 (79.3)	23 (79.3)
Poorly	31 (11.0)	4 (20.0)	14 (15.2)	5 (10.2)	6 (6.5)	2 (6.9)
Lymphovascular invasion							< 0.001
Absent	203 (72.0)	17 (85.0)	73 (79.3)	40 (81.6)	62 (67.4)	11 (37.9)
Present	79 (28.0)	3 (15.0)	19 (20.7)	9 (18.4)	30 (32.6)	18 (62.1)
Perineural invasion							0.091
Absent	70 (24.8)	5 (25.0)	25 (27.2)	17 (34.7)	21 (22.8)	2 (6.9)
Present	212 (75.2)	15 (75.0)	67 (72.8)	32 (65.3)	71 (77.2)	27 (93.1)
Capsular invasion							0.182
Absent	49 (17.4)	4 (20.0)	18 (19.6)	13 (26.5)	10 (10.9)	4 (13.8)
Present	233 (82.6)	16 (80.0)	74 (80.4)	36 (73.5)	82 (89.1)	25 (86.2)
Maximal tumor diameter (cm)							< 0.001
> 4	88 (31.2)	0	1 (1.1)	48 (98.0)	33 (35.9)	6 (20.7)
≤ 4	194 (68.8)	20 (100.0)	91 (98.9)	1 (2.0)	59 (64.1)	23 (79.3)
T stage							< 0.001
T1	34 (12.1)	20 (100.0)	0	0	12 (13.0)	2 (6.9)
T2	159 (56.4)	0	91 (98.9)	0	47 (51.1)	21 (72.4)
T3	89 (31.6)	0	1 (1.1)	49 (100.0)	33 (35.9)	6 (20.7)
Lymph node metastasis							< 0.001
Absent	161 (57.1)	20 (100.0)	92 (100.0)	49 (100.0)	0	0
Present	121 (42.9)	0	0	0	92 (100.0)	29 (100.0)
N stage							< 0.001
N0	161 (57.1)	20 (100.0)	92 (100.0)	49 (100.0)	0	0
N1	92 (32.6)	0	0	0	92 (100.0)	0
N2	29 (10.3)	0	0	0	0	29 (100.0)
Preoperative CA19-9 level (U/mL)	172.4 (0.6-55412.0)	125.6 (3.4-908.8)	157.0 (0.6-16827.0)	172.4 (1.4-4510.0)	189.5 (12.9-55412.0)	186.2 (29.8-4839.0)	0.158
> 336.4	77 (27.3)	2 (10.0)	21 (22.8)	13 (26.5)	31 (33.7)	10 (34.5)
≤ 336.4	205 (72.7)	18 (90.0)	71 (77.2)	36 (73.5)	61 (66.3)	19 (65.5)
Preoperative fibrinogen concentration (g/L)	3.02 (1.20-6.70)	3.21 (1.20-5.00)	3.27 (1.98-6.70)	3.40 (1.83-5.92)	3.13 (2.06-5.53)	3.67 (1.49-5.94)	0.099
> 3.31	141 (50.0)	8 (40.0)	44 (47.8)	30 (61.2)	40 (43.5)	19 (65.5)
≤ 3.31	141 (50.0)	12 (60.0)	48 (52.2)	19 (38.8)	52 (56.5)	10 (34.5)
Preoperative D-Dimer concentration (g/L)	0.52 (0.12-582.00)	0.48 (0.16-145.00)	0.52 (0.12-430.00)	0.53 (0.12-582.00)	0.52 (0.16-159.00)	0.54 (0.15-157.00)	0.608
> 0.53	117 (41.5)	8 (40.0)	37 (40.2)	23 (46.9)	34 (37.0)	15 (51.7)
≤ 0.53	165 (58.5)	12 (60.0)	55 (59.8)	26 (53.1)	58 (63.0)	14 (48.3)
Adjuvant therapy							0.621
Absent	124 (44.0)	6 (30.0)	42 (45.7)	24 (49.0)	41 (44.6)	11 (37.9)
Present	158 (56.0)	14 (70.0)	50 (54.3)	25 (51.0)	51 (55.4)	18 (62.1)

TNM: Tumor, node and metastasis.

Table 2 Correlation between preoperative fibrinogen concentration and clinicopathological characteristics in pancreatic ductal adenocarcinoma patients undergoing radical R0 resection, n (%)

Characteristics	Preoperative fibrinogen concentration		P value
	> 3.31 g/L (n = 141)	≤ 3.31 g/L (n = 141)
Age (yr)			0.812
> 60	72 (25.5)	74 (26.2)
≤ 60	69 (24.5)	67 (23.8)
Sex			0.283
Male	71 (25.2)	80 (28.4)
Female	70 (24.8)	61 (21.6)
Blood type			0.565
A	39 (13.8)	48 (17.0)
B	51 (18.1)	42 (14.9)
AB	10 (3.5)	12 (4.3)
O	41 (14.5)	39 (13.8)
Diabetes			0.357
Absent	97 (34.4)	104 (36.9)
Present	44 (15.6)	37 (13.1)
Smoking status			0.889
Absent	107 (37.9)	108 (38.3)
Present	34 (12.1)	33 (11.7)
Alcohol consumption			0.263
Absent	121 (42.9)	114 (40.4)
Present	20 (7.1)	27 (9.6)
Family history of cancer			0.356
Absent	137 (48.6)	134 (47.5)
Present	4 (1.4)	7 (2.5)
Clinical symptoms			< 0.001
Absent	15 (5.3)	42 (14.9)
Present	126 (44.7)	99 (35.1)
Open surgery approach			< 0.001
Pancreaticoduodenectomy	80 (28.4)	50 (17.7)
Distal pancreatectomy with splenectomy	61 (21.6)	91 (32.3)
Tumor location			< 0.001
Head and neck	80 (28.4)	50 (17.7)
Body and tail	61 (21.6)	91 (32.3)
Degree of differentiation			0.079
Well	20 (7.1)	14 (5.0)
Moderately	111 (39.4)	106 (37.6)
Poorly	10 (3.5)	21 (7.4)
Lymphovascular invasion			0.233
Absent	97 (34.4)	106 (37.6)
Present	44 (15.6)	35 (12.4)
Perineural invasion			0.054
Absent	28 (9.9)	42 (14.9)
Present	113 (40.1)	99 (35.1)
Capsular invasion			0.271
Absent	21 (7.4)	28 (9.9)
Present	120 (42.6)	113 (40.1)
Maximal tumor diameter (cm)			1.000
> 4	44 (15.6)	44 (15.6)
≤ 4	97 (34.4)	97 (34.4)
T stage			0.991
T1	17 (6.0)	17 (6.0)
T2	80 (28.4)	79 (28.0)
T3	44 (15.6)	45 (16.0)
Lymph node metastasis			0.718
Absent	82 (29.1)	79 (28.0)
Present	59 (20.9)	62 (22.0)
N stage			0.110
N0	82 (29.1)	79 (28.0)
N1	40 (14.2)	52 (18.4)
N2	19 (6.7)	10 (3.5)
TNM stage			0.099
IA	8 (2.8)	12 (4.3)
IB	44 (15.6)	48 (17.0)
IIA	30 (10.6)	19 (6.7)
IIB	40 (14.2)	52 (18.4)
III	19 (6.7)	10 (3.5)
Preoperative CA19-9 level (U/mL)			0.023
> 336.4	47 (16.7)	30 (10.6)
≤ 336.4	94 (33.3)	111 (39.4)
Preoperative D-Dimer concentration (g/L)			0.040
> 0.53	67 (23.8)	50 (17.7)
≤ 0.53	74 (26.2)	91 (32.3)
Adjuvant therapy			0.631
Absent	64 (22.7)	60 (21.3)
Present	77 (27.3)	81 (28.7)

Table 3 Correlation between preoperative D-Dimer concentration and clinicopathological characteristics in pancreatic ductal adenocarcinoma patients undergoing radical R0 resection, n (%)

Characteristics	Preoperative D-Dimer concentration		P value
	> 0.53 mg/L (n = 117)	≤ 0.53 mg/L (n = 165)
Age (yr)			0.284
> 60	65 (23.0)	81 (28.7)
≤ 60	52 (18.4)	84 (29.8)
Sex			0.260
Male	58 (20.6)	93 (33.0)
Female	59 (20.9)	72 (25.5)
Blood type			0.558
A	31 (11.0)	56 (19.9)
B	40 (14.2)	53 (18.8)
AB	9 (3.2)	13 (4.6)
O	37 (13.1)	43 (15.2)
Diabetes			0.871
Absent	84 (29.8)	117 (41.5)
Present	33 (11.7)	48 (17.0)
Smoking status			0.532
Absent	87 (30.9)	128 (45.4)
Present	30 (10.6)	37 (13.1)
Alcohol consumption			0.256
Absent	101 (35.8)	134 (47.5)
Present	16 (5.7)	31 (11.0)
Family history of cancer			0.785
Absent	112 (39.7)	159 (56.4)
Present	5 (1.8)	6 (2.1)
Clinical symptoms			0.845
Absent	23 (8.2)	34 (12.1)
Present	94 (33.3)	131 (46.5)
Open surgery approach			0.231
Pancreaticoduodenectomy	49 (17.4)	81 (28.7)
Distal pancreatectomy with splenectomy	68 (24.1)	84 (29.8)
Tumor location			0.231
Head and neck	49 (17.3)	81 (28.7)
Body and tail	68 (24.1)	84 (29.8)
Degree of differentiation			0.288
Well	18 (6.4)	16 (5.7)
Moderately	85 (30.1)	132 (46.8)
Poorly	14 (5.0)	17 (6.0)
Lymphovascular invasion			0.742
Absent	83 (29.4)	120 (42.6)
Present	34 (12.1)	45 (16.0)
Perineural invasion			0.001
Absent	41 (14.5)	29 (10.3)
Present	76 (27.0)	136 (48.2)
Capsular invasion			0.831
Absent	21 (7.4)	28 (9.9)
Present	96 (34.0)	137 (48.6)
Maximal tumor diameter (cm)			0.027
> 4	45 (16.0)	43 (15.2)
≤ 4	72 (25.5)	122 (43.3)
T stage			0.097
T1	14 (5.0)	20 (7.1)
T2	58 (20.6)	101 (35.8)
T3	45 (16.0)	44 (15.6)
Lymph node metastasis			0.769
Absent	68 (24.1)	93 (33.0)
Present	49 (17.4)	72 (25.5)
N stage			0.356
N0	68 (24.1)	93 (33.0)
N1	34 (12.1)	58 (20.6)
N2	15 (5.3)	14 (5.0)
TNM stage			0.608
IA	8 (2.8)	12 (4.3)
IB	37 (13.1)	55 (19.5)
IIA	23 (8.2)	26 (9.2)
IIB	34 (12.1)	58 (20.6)
III	15 (5.3)	14 (5.0)
Preoperative CA19-9 level (U/mL)			0.056
> 336.4	39 (13.8)	38 (13.5)
≤ 336.4	78 (27.7)	127 (45.0)
Preoperative fibrinogen concentration (g/L)			0.040
> 3.31	67 (23.8)	74 (26.2)
≤ 3.31	50 (17.7)	91 (32.3)
Adjuvant therapy			0.268
Absent	56 (19.9)	68 (24.1)
Present	61 (21.6)	97 (34.4)

Table 4 Univariate analysis for overall survival in pancreatic ductal adenocarcinoma patients undergoing radical R0 resection

Characteristic	HR (95%CI)	P value
Age (yr)	1.358 (1.036-1.780)	0.027
> 60
≤ 60
Sex	1.281 (0.979-1.675)	0.071
Male
Female
Blood type	—	0.579
A
B
AB
O
Diabetes	0.903 (0.676-1.206)	0.491
Absent
Present
Smoking status	0.866 (0.635-1.181)	0.363
Absent
Present
Alcohol consumption	1.083 (0.754-1.556)	0.667
Absent
Present
Family history of cancer	1.251 (0.617-2.537)	0.535
Absent
Present
Clinical symptoms	0.600 (0.424-0.848)	0.004
Absent
Present
Open surgery approach	0.954 (0.729-1.249)	0.731
Pancreaticoduodenectomy
Distal pancreatectomy with splenectomy
Tumor location	0.954 (0.729-1.249)	0.731
Head and neck
Body and tail
Degree of differentiation	—	< 0.001
Well
Moderately
Poorly
Lymphovascular invasion	0.793 (0.590-1.065)	0.123
Absent
Present
Perineural invasion	0.905 (0.666-1.231)	0.525
Absent
Present
Capsular invasion	0.609 (0.420-0.885)	0.009
Absent
Present
Maximal tumor diameter (cm)	1.403 (1.058-1.862)	0.019
> 4
≤ 4
T stage	—	0.035
T1
T2
T3
Lymph node metastasis	0.590 (0.449-0.775)	< 0.001
Absent
Present
N stage	—	0.001
N0
N1
N2
TNM stage	—	0.003
IA
IB
IIA
IIB
III
Preoperative CA19-9 level (U/mL)	1.971 (1.469-2.644)	< 0.001
> 336.4
≤ 336.4
Preoperative fibrinogen concentration (g/L)	1.888 (1.438-2.479)	< 0.001
> 3.31
≤ 3.31
Preoperative D-Dimer concentration (g/L)	1.625 (1.244-2.123)	< 0.001
> 0.53
≤ 0.53
Adjuvant therapy	1.625 (1.244-2.123)	< 0.001
Absent
Present

TNM: Tumor, node and metastasis.

Table 5 Multivariate analysis for overall survival in pancreatic ductal adenocarcinoma patients undergoing radical R0 resection

Characteristics	HR (95%CI)	Wald	P value
Age (yr)	1.285 (0.964-1.713)	2.935	0.087
> 60
≤ 60
Degree of differentiation		33.979	< 0.001
Poorly/Well	5.014 (2.737-9.185)	27.240	< 0.001
Moderately/Well	1.667 (1.031-2.696)	4.338	0.037
Capsular invasion	0.669 (0.456-0.980)	4.269	0.039
Absent
Present
Lymph node metastasis	0.669 (0.502-0.893)	7.469	0.006
Absent
Present
Preoperative CA19-9 level (U/mL)	1.613 (1.187-2.191)	9.340	0.002
> 336.4
≤ 336.4
Preoperative fibrinogen concentration (g/L)	1.603 (1.201-2.140)	10.270	0.001
> 3.31
≤ 3.31
Preoperative D-Dimer concentration (g/L)	1.355 (1.019-1.801)	4.374	0.036
> 0.53
≤ 0.53
Adjuvant therapy	1.620 (1.233-2.128)	11.983	0.001
Absent
Present

Table 6 Correlation between preoperative combined groups and clinicopathological characteristics in pancreatic ductal adenocarcinoma patients undergoing radical R0 resection, n (%)

Characteristics	Preoperative combined groups		P value
	Any-high group (n = 191)	Low-low group (n = 91)
Age (yr)			0.590
> 60	101 (35.8)	45 (16.0)
≤ 60	90 (31.9)	46 (16.3)
Sex			0.562
Male	100 (35.5)	51 (18.1)
Female	91 (32.3)	40 (14.2)
Blood type			0.480
A	54 (19.1)	33 (11.7)
B	65 (23.0)	28 (9.9)
AB	14 (5.0)	8 (2.8)
O	58 (20.6)	22 (7.8)
Diabetes			0.969
Absent	136 (48.2)	65 (23.0)
Present	55 (19.5)	26 (9.2)
Smoking status			0.433
Absent	143 (50.7)	72 (25.5)
Present	48 (17.0)	19 (6.7)
Alcohol consumption			0.531
Absent	161 (57.1)	74 (26.2)
Present	30 (10.6)	17 (6.0)
Family history of cancer			0.767
Absent	184 (65.2)	87 (30.9)
Present	7 (2.5)	4 (1.4)
Clinical symptoms			0.002
Absent	29 (10.3)	28 (9.9)
Present	162 (57.4)	63 (22.3)
Open surgery approach			0.128
Pancreaticoduodenectomy	94 (33.3)	36 (12.8)
Distal pancreatectomy with splenectomy	97 (34.4)	55 (19.5)
Tumor location			0.128
Head and neck	94 (33.3)	36 (12.8)
Body and tail	97 (34.4)	55 (19.5)
Degree of differentiation			0.392
Well	25 (8.9)	9 (3.2)
Moderately	148 (52.5)	69 (24.5)
Poorly	18 (6.4)	13 (4.6)
Lymphovascular invasion			0.322
Absent	134 (47.5)	69 (24.5)
Present	57 (20.2)	22 (7.8)
Perineural invasion			0.290
Absent	51 (18.1)	19 (6.7)
Present	140 (49.6)	72 (25.5)
Capsular invasion			0.159
Absent	29 (10.3)	20 (7.1)
Present	162 (57.4)	71 (25.2)
Maximal tumor diameter (cm)			0.021
> 4	68 (24.1)	20 (7.1)
≤ 4	123 (43.6)	71 (25.2)
T stage			0.048
T1	23 (8.2)	11 (3.9)
T2	99 (35.1)	60 (21.3)
T3	69 (24.5)	20 (7.1)
Lymph node metastasis			0.615
Absent	111 (39.4)	50 (17.7)
Present	80 (28.4)	41 (14.5)
N stage			0.026
N0	111 (39.4)	50 (17.7)
N1	55 (19.5)	37 (13.1)
N2	25 (8.9)	4 (1.4)
TNM stage			0.002
IA	13 (4.6)	7 (2.5)
IB	56 (19.9)	36 (12.8)
IIA	42 (14.9)	7 (2.5)
IIB	55 (19.5)	37 (13.1)
III	25 (8.9)	4 (1.4)
Preoperative CA19-9 level (U/mL)			0.095
> 336.4	58 (20.6)	19 (6.7)
≤ 336.4	133 (47.2)	72 (25.5)
Adjuvant therapy			0.198
Absent	89 (31.6)	35 (12.4)
Present	102 (36.2)	56 (19.9)

The any-high group for preoperative fibrinogen concentration > 3.31 g/L and/or preoperative D-dimer concentration > 0.53 mg/L group; the low-low group for preoperative fibrinogen concentration ≤ 3.31 g/L and preoperative D-dimer concentration ≤ 0.53 mg/L group. TNM: Tumor, node and metastasis.

Table 7 Univariate and multivariate analysis for overall survival in pancreatic ductal adenocarcinoma patients undergoing radical R0 resection according to the combination of preoperative fibrinogen and D-dimer

Characteristics	HR (95%CI)	Wald	P value	MOS (mo)
Univariate analysis
Preoperative combined grouping	2.500 (1.806-3.462)	—	0.000
Any-high group				15.43
Low-low group				31.17
Multivariate analysis
Age (year)	1.308 (0.985-1.736)	3.447	0.063
> 60				16.73
≤ 60				18.67
Degree of differentiation		36.927	0.000
Poorly/well	5.267 (2.871-9.663)	28.794	0.000	8.07 vs 51.77
Moderately/well	1.631 (1.011-2.633)	4.012	0.045	18.40 vs 51.77
Capsular invasion	0.691 (0.471-1.013)	3.579	0.059
Absent				24.00
Present				16.73
Lymph node metastasis	0.663 (0.497-0.883)	7.882	0.005
Absent				19.90
Present				15.03
Preoperative CA19-9 level (U/mL)	1.699 (1.258-2.293)	11.960	0.001
> 336.4				12.23
≤ 336.4				19.90
Adjuvant therapy	1.582 (1.202-2.081)	10.731	0.001
Absent				14.17
Present				20.37
Preoperative combined grouping	2.397 (1.723-3.335)	26.908	0.000
Any-high group				15.43
Low-low group				31.17

The any-high group for preoperative fibrinogen concentration > 3.31 g/L and/or preoperative D-dimer concentration > 0.53 mg/L group; the low-low group for preoperative fibrinogen concentration ≤ 3.31 g/L and preoperative D-dimer concentration ≤ 0.53 mg/L group. MOS: Median overall survival.