2.1 Demographic and clinicopathological features of two patient groups before PSM
We retrospectively enrolled 1771 consecutive cases and 903 remained for analysis after excluding 868 patients according to exclusion criteria (18 cases of gastric stump cancer, 12 cases with D-dimer data missing, 435 cases at stage IV, 20 cases treated with palliative surgery, 5 cases treated with exploratory laparotomy, 44 cases with R1 resection, 48 cases treated with neoadjuvant chemotherapy before surgery, 86 cases concurrent with thrombotic disease, 200 cases lost to follow-up) (Fig. 1). Among all patients, 687 were (76.1%) men and 290 (32.1%) patients were over 65 years old. To assess the relationship between hypercoagulability and disease progression, the whole series were divided into NDG group (D-dimer < 1mg/l, n = 742) and EDG group (D-dimer ≥ 1 mg/l, n = 161) according to the upper limit of normal value of clinical reference of D-dimer. Patients in EDG had a higher proportion of female (30.4% vs 22.5%, p = 0.041), higher INR(median: 1.03 vs 1.02, p = 0.012), FIB (median: 3.44 g/l vs 3.12 g/l, p < 0.001), FDP (median: 3.2 mg/l vs 0.9 mg/l, p < 0.001), more advanced TNM stage (p < 0.001), higher LPR (median: 0.21 vs 0.05, p < 0.001), larger tumor size (median: 4.5 cm vs 4 cm, p = 0.005), shorter OS (median: 19 months vs 39 months, p < 0.001) and shorter DFS (median: 18.5 months vs 39 months, p < 0.001) (Table 1). No significant difference was found in PT, PTA, PTR, TT, APTT, tumor location and histology. Correlations of D-dimer and other clinicopathologic features was listed. Spearman correlation analysis demonstrated a greatly relationship between plasma D-dimer and age (P < 0.001), tumor size (P = 0.002), T stage (P = 0.001), N stage (< 0.001) and TNM stage (P < 0.001) (see Supplementary Table S1 online).
Table 1
Demographic and baseline characteristics of the two patient groups before PSM (N = 903).
Characteristics | Total | NDG | EDG | P value |
(N = 903) | (N = 742) | (N = 161) |
Gender, no. (%) | | | | 0.041 |
Female | 216(23.9) | 167(22.5) | 49(30.4) | |
Male | 687(76.1) | 575(77.5) | 112(69.6) | |
Age ≥ 65 years, no. (%) | 290(32.1) | 211(28.4) | 79(49.1) | < 0.001 |
PT, second | 13(12.5–13.5) | 13(12.5–13.5) | 13.1(12.6–13.7) | 0.091 |
PTA, % | 96.46 ± 17.25 | 96.91 ± 16.95 | 94 ± 18.67 | 0.096 |
PTR | 1.02(0.98–1.07) | 1.02(0.98–1.07) | 1.02(0.99–1.08) | 0.156 |
APTT, second | 34.6(32-37.2) | 34.55(32.1-37.33) | 34.7(31.55–36.95) | 0.382 |
INR | 1.02(0.98–1.07) | 1.02(0.98–1.07) | 1.03(1-1.09) | 0.012 |
TT, second | 16.3(15.7–16.9) | 16.3(15.8–16.9) | 16.2(15.6-16.85) | 0.333 |
FIB, g/l | 3.2(2.64–3.8) | 3.12(2.62–3.7) | 3.44(2.81–4.2) | < 0.001 |
D-dimer, mg/l | 0.5(0.2–0.9) | 0.4(0.1–0.6) | 1.7(1.2–2.75) | < 0.001 |
FDP, mg/l | 1.1(0.6–1.83) | 0.9(0.6–1.4) | 3.2(2.3–5.4) | < 0.001 |
Platelet | 202(157–254) | 202.5(157–255) | 200(155.8-250.5) | 0.77 |
Tumor location, no. (%) | | | | 0.992 |
proximal stomach | 294(32.6) | 241(32.4) | 53(32.9) | |
distal stomach | 478(52.9) | 393(53) | 85(52.8) | |
total stomach | 131(14.5) | 108(14.6) | 23(14.3) | |
T stage, no. (%) | | | | < 0.001 |
T1 | 190(21) | 172(23.2) | 18(11.2) | |
T2 | 76(8.4) | 68(9.2) | 8(5) | |
T3 | 153(16.9) | 114(15.4) | 39(24.2) | |
T4 | 484(53.6) | 388(52.3) | 96(59.6) | |
N stage, no. (%) | | | | < 0.001 |
N0 | 385(42.6) | 334(45) | 51(31.7) | |
N1 | 143(15.8) | 122(16.4) | 21(13) | |
N2 | 166(18.4) | 138(18.6) | 28(17.4) | |
N3 | 209(23.1) | 148(19.9) | 61(37.9) | |
TNM stage, no. (%) | | | | < 0.001 |
I | 223(24.7) | 199(26.8) | 24(14.9) | |
II | 149(16.5) | 130(17.5) | 19(11.8) | |
III | 531(58.8) | 413(55.7) | 118(73.3) | |
Chemotherapy | | | | 0.053 |
yes | 546(60.5) | 456(61.5) | 112(69.6) | |
no | 335(37.1) | 286(38.5) | 49(30.4) | |
Histology, no. (%) | | | | 0.78 |
differentiated | 289(32) | 236(31.8) | 53(32.9) | |
undifferentiated | 614(68) | 506(68.2) | 108(67.1) | |
OS, month | 37(19–59) | 39(24–61) | 19(10-42.5) | < 0.001 |
DFS, month | 37(18–59) | 39(23–61) | 18.5(9-43.25) | < 0.001 |
LPR (%) | 0.07(0-0.31) | 0.05(0-0.28) | 0.21(0-0.56) | < 0.001 |
Tumor size, cm | 4(2.5–5.5) | 4(2.5–5.5) | 4.5(3–6) | 0.005 |
Abbreviations: |
PSM, Propensity Score Matching; NDG, normal D-dimer group (< 1 mg/l); EDG, elevated D-dimer group (≥ 1 mg/l); PT, prothrombin time; PTA, prothrombin activity; PTR, prothrombin ratio; APTT, activated partial prothrombin time; INR, international normalized ratio; TT, thrombin time; FIB, fibrinogen; FDP, fibrin degradation products; TNM, Tumor-node-metastasis; OS, overall survival; DFS, disease free survival; LPR, Lymph node biopsy positive rate. |
2.2 Plasma D-dimer is an independent risk factor for GC survival
We divided age (cut-off: 65 years), PT (cut-off: 13.2 second), PTA (cut-off: 102.6%), PTR (cut-off: 1), INR (cut-off: 0.96), APTT (cut-off: 38.9 second), TT (cut-off: 16.5 second), FIB (cut-off: 3.8 g/l), D-dimer (cut-off: 1 mg/l) and FDP (cut-off: 2.1 mg/l) into two groups (see Supplementary Table S2, Supplementary Fig. 1–3 online) and performed univariate and multivariate COX regression analysis for the whole study series before PSM. In univariate analysis, elder age, distal stomach (proximal stomach for reference), higher coagulation indicators (PTA, INR, TT, FIB, D-dimer and FDP), higher LPR, larger tumor size and advanced TNM stage were significantly associated with shorter OS. In multivariate analysis, age (HR: 1.918, 95%CI: 1.436–2.561, P < 0.001), D-dimer (HR: 1.633, 95%CI: 1.178–2.264, P = 0.003), LPR (HR: 4.707, 95%CI: 2.886–7.677, P < 0.001), tumor size (HR: 1.085, 95%CI: 1.032–1.141, P = 0.002), chemotherapy (HR: 0.42, CI%: 0.286–0.615, P < 0.001) and TNM stage (TNM II stage: HR: 4.063, 95%CI: 1.897–8.705, P = 0.001, TNM III stage: HR: 9.296, 95%CI: 4.669–18.51, P < 0.001) were independent prognostic factors for OS (Table 2). The 5-year OS rate in EDG was markedly lower than in NDG (32.8% vs 62.6%, p < 0.001) (Fig. 2A). Independently prognostic factors for DFS were the same as for OS: age (HR:1.914, 95%CI: 1.448–2.531, P < 0.001), D-dimer (HR: 1.58, 95%CI: 1.151–2.169, P = 0.005), LPR (HR: 4.865, 95%CI: 3.037–7.793, P < 0.001), tumor size (HR: 1.084, 95%CI: 1.034–1.141, P = 0.001), chemotherapy (HR: 0.434, CI%: 0.3–0.63, P < 0.001) and TNM stage (TNM II stage: HR: 3.615, 95%CI: 1.792–7.293, P < 0.001, TNM III stage: HR: 7.803, 95%CI, 4.136–14.722, P < 0.001) (see Supplementary Table S3 online). Significant difference was found between NDG and EDG for 5-year DFS rate (29% vs 59.6%, p < 0.001) (Fig. 3A).
Table 2
Univariate and multivariate analyses for overall survival of GC patients before PSM (N = 903).
Parameters | Univariate analysis | Multivariate analysis |
HR | 95%CI | P value | HR | 95%CI | P value |
Gender, Female vs male | | | 0.196 | | | |
Age, < 65 vs ≥ 65 | 1.72 | 1.389–2.13 | < 0.001 | 1.918 | 1.436–2.561 | < 0.001 |
Tumor location, no. (%) | | | | | | |
proximal stomach | 1 | | < 0.001 | | | |
distal stomach | 0.549 | 0.434–0.694 | < 0.001 | | | |
full stomach | 1.118 | 0.832–1.504 | 0.459 | | | |
PT, < 14 vs ≥ 14 | 1.131 | 0.913–1.401 | 0.259 | | | |
PTA, < 128 vs ≥ 128 | 0.714 | 0.552–0.925 | 0.011 | | | |
PTR, < 1.24 vs ≥ 1.24 | 1.095 | 0.871–1.378 | 0.436 | | | |
INR, < 1.3 vs ≥ 1.3 | 1.57 | 1.116–2.209 | 0.01 | | | |
APTT, < 43.5 vs ≥ 43.5 | 1.162 | 0.874–1.543 | 0.301 | | | |
TT, < 21 vs ≥ 21 | 0.733 | 0.587–0.915 | 0.006 | | | |
FIB, < 4 vs ≥ 4 | 1.729 | 1.388–2.153 | < 0.001 | | | |
D-dimer, < 1 vs ≥ 1 | 2.486 | 1.982–3.118 | < 0.001 | 1.633 | 1.178–2.264 | 0.003 |
FDP, < 5 vs ≥ 5 | 1.838 | 1.241–2.724 | 0.002 | | | |
Platelet | | | 0.453 | | | |
LPR | 9.42 | 6.67-13.303 | < 0.001 | 4.707 | 2.886–7.677 | < 0.001 |
Tumor size, cm | 1.158 | 1.119–1.198 | < 0.001 | 1.085 | 1.032–1.141 | 0.002 |
Histology | | | 0.641 | | | |
differentiated | | | | | | |
undifferentiated | | | | | | |
TNM stage | | | | | | |
I | 1 | | < 0.001 | 1 | | < 0.001 |
II | 2.631 | 1.618–4.277 | < 0.001 | 4.063 | 1.897–8.705 | 0.001 |
III | 6.166 | 4.15–9.161 | < 0.001 | 9.296 | 4.669–18.51 | < 0.001 |
Chemotherapy | 2.163 | 1.689–2.769 | < 0.001 | 0.42 | 0.286–0.615 | < 0.001 |
HR, hazard ratio; CI, confidence interval. Coagulation parameters were divided into two groups according to the cutoff values in Supplementary Table 2. |
2.3 Survival analysis of two patient groups after PSM
To eliminate the influence of other covariates on D-dimer prognostic analysis, PSM using a one-to-one nearest neighbor matching method was implemented. After matching, 161 patients in NDG were matched to EDG after adjusting age, gender, TNM stage, tumor location and histology (Fig. 1). There was no significant difference in gender, age, PTA, PTR, INR, TT, APTT, TNM stage, histology and LPR in matched series. Patients in EDG still had shorter OS (median: 19 months vs 25 months, p = 0.005) and shorter DFS (median: 18.5 months vs 24 months, p = 0.007) (Table 3). To our surprise, Spearman correlation analysis indicated a relationship between D-dimer and tumor size (P = 0.002) and N stage (0.011) (see Supplementary Table S4 online). Whereas age (P = 0.053), T stage (P = 0.117) and TNM stage (P = 0.056) showed no correlation with D-dimer. After PSM, the 5-year OS rate in EDG was still shorter than in NDG (32.8% vs 40.6%, p = 0.005) (Fig. 2B), so was DFS (29% vs 36.6%, p = 0.008) (Fig. 3B).
Table 3
Demographic and baseline characteristics of the two patient groups after PSM (N = 322).
Characteristics | Total | NDG | EDG | P value |
(N = 322) | (N = 161) | (N = 161) |
Gender, no. (%) | | | | 0.211 |
Female | 88(27.3) | 39(24.2) | 49(30.4) | |
Male | 234(72.7) | 122(75.8) | 112(69.6) | |
Tumor location, no. (%) | | | | 0.011 |
proximal stomach | 131(40.7) | 78(48.4) | 53(32.9) | |
distal stomach | 145(45) | 60(37.3) | 85(52.8) | |
most or total stomach | 46(14.3) | 23(14.3) | 23(14.3) | |
Age ≥ 65 years. No. (%) | 157(48.8) | 78(48.4) | 79(49.1) | 0.911 |
PT, second | 13(12.4-13.53) | 12.9(12.35–13.4) | 13.1(12.6–13.7) | 0.02 |
PTA, % | 94.1(82.9-105.45) | 94.45(86.2-108.5) | 94.9(78.9-104.7) | 0.142 |
PTR | 1.03(0.99–1.08) | 1.03(0.99–1.07) | 1.02(0.99–1.08) | 0.942 |
APTT, second | 34.6(31.7–37) | 1.02(0.98–1.07) | 1.03(1-1.09) | 0.669 |
INR | 1.03(0.99–1.08) | 34.5(32-37.2) | 34.7(31.55–36.95) | 0.086 |
TT, second | 16.2(15.7–16.8) | 16.2(15.75–16.75) | 16.2(15.6-16.85) | 0.953 |
FIB, g/l | 3.35(2.71-4) | 3.18(2.7–3.8) | 3.44(2.81–4.2) | 0.04 |
D-dimer, mg/l | 1.01(0.3–1.71) | 0.3(0.1–0.6) | 1.7(1.2–2.75) | < 0.001 |
FDP, mg/l | 1.62(0.9–3.2) | 1(0.6–1.3) | 3.2(2.3–5.4) | < 0.001 |
Platelet | 199(153–252) | 198(151-255.5) | 200(155.8-250.5) | 0.8 |
T stage, no. (%) | | | | 0.737 |
T1 | 33(10.2) | 15(9.3) | 18(11.2) | |
T2 | 20(6.2) | 12(7.5) | 8(5) | |
T3 | 81(25.2) | 42(26.1) | 39(24.2) | |
T4 | 188(58.4) | 92(57.1) | 96(59.6) | |
N stage, no. (%) | | | | 0.01 |
N0 | 91(28.3) | 40(24.8) | 51(31.7) | |
N1 | 50(15.5) | 29(18) | 21(13) | |
N2 | 77(23.9) | 49(30.4) | 28(17.4) | |
N3 | 104(32.3) | 43(26.7) | 61(37.9) | |
TNM stage, no. (%) | | | | 0.057 |
I | 41(12.7) | 17(10.6) | 24(14.9) | |
II | 53(16.5) | 34(21.1) | 19(11.8) | |
III | 228(70.8) | 110(68.3) | 118(73.3) | |
Chemotherapy | | | | 0.204 |
yes | 238(73.9) | 114(70.8) | 124(77) | |
no | 84(26.1) | 47(29.2) | 37(23) | |
Histology, no. (%) | | | | 0.051 |
differentiated | 123(38.2) | 70(43.5) | 53(32.9) | |
undifferentiated | 199(61.8) | 91(56.5) | 108(67.1) | |
OS, month | 24(13–44) | 25(15-47.5) | 19(10-42.4) | 0.005 |
DFS, month | 23(12–44) | 24(14–48) | 18.5(9-43.25) | 0.007 |
LPR (%) | 0.21(0-0.44) | 0.21(0-0.36) | 0.21(0-0.57) | 0.921 |
Tumor size, cm | 4(3-5.5) | 3(2.5-4) | 4.5(3–6) | < 0.001 |