
==== Front
Ann Med
Ann Med
Annals of Medicine
0785-3890
1365-2060
Taylor & Francis

39239880
10.1080/07853890.2024.2400315
2400315
Version of Record
Research Article
Gastroenterology
Relationship between platelet-to-lymphocyte ratio and early rebleeding after endoscopic variceal ligation: a bicenter retrospective study
W. Wang et al.
Wang Wei a*
Ju Honglei a*
Zhang Wei b
Ma Chao b
He Chiyi a
a Department of Gastroenterology, Yijishan Hospital of Wannan Medical College, Wuhu, China
b Department of Gastroenterology, Fuyang Second People’s Hospital, Fuyang, China
* These authors contributed equally to this work.

Supplemental data for this article can be accessed online at https://doi.org/10.1080/07853890.2024.2400315.

CONTACT Chao Ma 2728328645@qq.com Departments of Gastroenterology, Fuyang Second People’s Hospital, No.1088 Yinghe West Road, Fuyang, Anhui Province 236015, China
Chiyi He hechiyi11@wnmc.edu.cn Departments of Gastroenterology, Yijishan Hospital of Wannan Medical College, No.2 Zheshan West Road, Wuhu, Anhui Province 241001, China
6 9 2024
2024
6 9 2024
56 1 240031521 5 2024
27 8 2024
28 8 2024
KnowledgeWorks Global Ltd.5 9 2024
published online in a building issue5 9 2024
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
2024
The Author(s)
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

Abstract

Background

Endoscopic variceal ligation (EVL) is the primary treatment for esophageal variceal bleeding in patients with liver cirrhosis (LC). Postoperative rebleeding is a complication of EVL, contributing to over 20% of bleeding-related deaths. This study aims to examine the association between platelet-to-lymphocyte ratio (PLR) and rebleeding within 6 weeks after EVL in patients with LC.

Methods

The study included 145 eligible patients who underwent their first EVL procedure at Yijishan Hospital of Wannan Medical College between January 2016 and August 2022 (YJS cohort). An external validation cohort comprising 338 eligible patients from NO.2 People’s Hospital of Fuyang City (FY cohort) between July 2018 and August 2022 was also utilized.

Results

In the YJS cohort, Multivariate logistic analysis indicated that high PLR is independently associated with early rebleeding after EVL. The restricted cubic spline analysis demonstrated that the risk of rebleeding increases with rising PLR, stabilizing at PLR values greater than 150. Similar findings were validated in the FY cohort.

Conclusions

Our results have the potential to aid in the identification of high-risk patients for early rebleeding after EVL, thereby enabling improved clinical management and outcomes for these individuals.

KEY MESSAGES

This study is the first to report on the independent association between the platelet-to-lymphocyte ratio (PLR) and early rebleeding after endoscopic variceal ligation (EVL).

The restricted cubic spline analysis showed a linear correlation between PLR and the risk of early rebleeding after EVL.

An increase in PLR level is independently associated with a higher risk of early rebleeding after EVL.

Keywords

Platelet-to-lymphocyte ratio
endoscopic variceal ligation
rebleeding
This research received no external funding.
==== Body
pmcIntroduction

Bleeding from esophageal varices is a critical complication of portal hypertension, responsible for the majority of cirrhosis-related fatalities [1]. Left untreated, gastroesophageal varices result in acute variceal haemorrhage in about 12% of cases annually, posing a life-threatening risk for patients with liver cirrhosis (LC) [2]. The Baveno VII consensus recommends that the primary prophylaxis for variceal bleeding consists of either endoscopic variceal ligation (EVL) or non-selective beta-blockers (NSBBs). For secondary prophylaxis, the preferred treatment is a combination of NSBBs and EVL [3]. Carvedilol offers an added advantage by obstructing the α1 adrenergic receptors in the hepatic vessels, leading to a greater reduction in portal pressure compared to conventional NSBBs like propranolol and nadolol [4]. For acute esophageal varices bleeding (EVB), EVL is the recommended treatment according to guideline [3]. Postoperative rebleeding is a known complication of EVL [5], with reported early rebleeding incidence ranging from 4.8% to 8.5% [6–10], and medium to long-term rebleeding rates as high as 30%–50% [10–13]. Mortality caused by early post-banded ulcer rebleeding is estimated at 20%–30% [14–16]. Therefore, assessing the risk of rebleeding after EVL is crucial for effective clinical management.

In recent years, hematological markers have gained attention as predictors of rebleeding after EVL, including prothrombin time, haemoglobin, serum bilirubin, albumin-bilirubin score (ALBI), and AST platelet ratio index (APRI) [6–9,17]. Previous studies have linked the platelet-to-lymphocyte ratio (PLR) with disease severity in conditions like ankylosing spondylitis, rheumatoid arthritis, and peripheral arterial occlusive disease [18–20]. Additionally, PLR has been independently associated with the prognosis of various diseases including different types of cancer, acute myocardial infarction, langerhans cell histiocytosis and COVID-19 [21–27]. However, there is currently no reported correlation between PLR and early rebleeding after EVL. Consequently, this study aims to explore this issue.

Materials and methods

Patients

This retrospective analysis involved individuals who experienced EVB and underwent their initial EVL treatment at Yijishan Hospital of Wannan Medical College between January 2016 and August 2022 (referred to as the YJS cohort). Additionally, individuals with EVB who received their first EVL treatment at Fuyang Second People’s Hospital, from July 2018 to August 2022, were included in the validation cohort (referred to as the FY cohort). The exclusion criteria comprised of: (1) prior TIPS placement, (2) prophylactic EVL, (3) splenectomy, (4) severe infectious diseases, (5) use of medication impacting serological parameters, and (6) incomplete data. The patient selection process is illustrated in Figure 1. Our research protocol was conducted following the Declaration of Helsinki statements and was approved by the Scientific Research and New Technology of Wannan Medical College Yijishan Hospital Institutional Review Board (2023-051) and the Institutional Review Board of Fuyang Second People’s Hospital (20230508007). As this was a retrospective study, the need for informed consent from the patients was waived by the Scientific Research and New Technology of Wannan Medical College Yijishan Hospital Institutional Review Board and the Institutional Review Board of Fuyang Second People’s Hospital.

Figure 1. Flow depicting the patient selection process.

Data collection

Upon admission, demographic data, laboratory parameter, and clinical information of the patients were collected, encompassing gender (female/male), age, hematological parameters, presence of hepatocellular carcinoma (no/yes), portal vein thrombosis (no/yes), severity of ascites (none or mild/moderate or severity), extent of esophageal varices, and causes of LC. The study’s endpoint was determined as the occurrence of hematemesis, and/or melena, along with clinical and/or laboratory evidence of acute blood loss from the upper gastrointestinal tract within 6 weeks after EVL [8]. NSBBs (carvedilol or propranolol) were used in accordance with the previous description [28]. In accordance with the research by the Japanese Society of Portal Hypertension, varicose veins were classified into three forms (F1, F2, F3) [29]. Hematological parameters were retrieved from patients within the initial 24 h after admission or before urgent EVL. The PLR was calculated by dividing the platelet count (109/L) by the lymphocyte count (109/L) [24]. The APRI was calculated as follows: the [aspartate aminotransferase/upper normal limit] divided by the platelet count (109/L) multiplied by 100 [30]. The ALBI score was calculated as [(0.66 × log10 bilirubin (µmol/L)] + [(−0.085 × albumin (g/L)] [31].

Statistical analysis

The quantitative data were presented as mean and standard deviation for normal distribution, and as median (interquartile range) for non-normal distribution. Categorical data were expressed as frequency and percentage. The t-test or Mann-Whitney U test was employed for comparing differences in continuous variables, while the chi-square test or Fisher’s exact test was used for categorical variables. The prediction accuracy of PLR was assessed by analyzing the area under the receiver operating characteristic (ROC) curve (AUC), and the optimal cut-off value of PLR was determined using Youden’s index based on the ROC [32]. The Delong test was employed to evaluate the significance of differences in the AUC [33]. Patients were categorized into high and low PLR groups in accordance with the cut-off value. Variables that exhibited significant in the univariate logistic regression analysis (p < .05) were integrated into the multivariate analysis. Additionally, restricted cubic spline (RCS) analysis was used to assess the non-linear relationship between PLR and the risk of rebleeding based on multivariate analysis [34,35]. The statistical analyses were carried out using R (version 4.0.2), SPSS (version 26.0) and Medcalc (version 15.2). All statistical tests were two-sided, and p values < .05 were deemed statistically significant.

Results

Patients’ characteristics

The YJS cohort consisted of a total of 145 eligible patients, with an average age of 56.7 ± 11.0 years, and approximately 66% of the patients were male. In the FY cohort, there were 338 eligible patients with an average age of 54.4 ± 10.4 years, and approximately 76% of the patients were male. The leading cause of LC was chronic infection with the hepatitis B virus. The rebleeding rate after EVL within 6 weeks was 11% in the YJS cohort and 13% in the FY cohort. In the YJS cohort, the PLR in the rebleeding group was significantly higher than in the non-rebleeding group. However, the hemoglobin (HB) levels in the rebleeding group were significantly lower than in the non-rebleeding group (p < .05). In the FY cohort, the presence rate of hepatocellular carcinoma (HCC) in the rebleeding group was significantly higher than in the non-rebleeding group (p < .001). No significant differences were found between the two groups in white blood cell (WBC), lymphocyte (LYM), alanine aminotransferase (ALT), albumin (ALB), total bilirubin (TBIL), gamma-glutamyl transpeptidase (GGT), creatinine (Cr), international normalized ratio (INR), fibrinogen (Fib), model for end stage liver disease (MELD) score, the proportion of portal vein thrombosis (PVT), treatment after EVL and gender. The clinical and laboratory characteristics between the non-rebleeding group and the rebleeding group in the YJS cohort and FY cohort are presented in Table 1.

Table 1. Clinical and laboratory characteristics of the patients who underwent their first endoscopic variceal ligation.

 	YJS cohort	FY cohort (validation cohort)	
Variables	All (N = 145)	Rebleeding (N = 16)	Non-Bleeding (N = 129)	p value	All (N = 338)	Rebleeding (N = 44)	Non-Bleeding (N = 294)	p value	
Gender (n,%)	 	 	 	.177	 	 	 	.559	
 Male	96 (66.2%)	13 (81.3%)	83 (64.3%)	 	257 (76.0%)	35 (79.6%)	222 (75.5%)	 	
 Female	49 (33.8%)	3 (18.8%)	46 (35.7%)	 	81 (24.0%)	9 (20.5%)	72 (24.5%)	 	
Age (years)	56.7 ± 11.0	51.6 ± 10.8	57.3 ± 11.3	.624	54.4 ± 10.4	54.8 ± 10.4	54.3 ± 10.4	.940	
PVT (n, %)	24 (16.6%)	3 (18.8%)	21 (16.3%)	.730	23 (6.8%)	3 (6.8%)	20 (6.8%)	1.000	
HCC (n, %)	15 (10.3%)	3 (18.8%)	12 (9.3%)	.218	75 (22.2%)	21 (47.7%)	54 (18.4%)	<.001	
WBC (109/L)	4.00 (2.75–6.40)	5.25 (1.83–12.43)	3.90 (2.80–6.00)	.190	4.30 (2.57–6.76)	4.69 (3.17–7.64)	4.16 (2.54–6.65)	.203	
LYM (109/L)	0.71 (0.50–1.00)	0.65 (0.40–1.35)	0.80 (0.50–1.00)	.520	0.75 (0.50–1.16)	0.68 (0.48–0.91)	0.76 (0.50–1.18)	.187	
HB (g/L)	73.0 (59.0–90.0)	65.5 (56.3–73.8)	77.0 (60.0–95.0)	.042	78.0 (64.8–94.3)	84.0 (68.0–98.8)	77.1 (63.8–94.0)	.145	
PLT (109/L)	66.0 (49.5–96.5)	88.5 (59.0–187.8)	62.0 (49.0–90.0)	.036	69.0 (49.0–103.3)	82.0 (55.0–122.3)	67.0 (48.0–101.5)	.052	
ALB (g/L)	29.8 ± 5.4	26.3 ± 4.4	30.2 ± 5.4	.198	30.7 ± 5.3	32.3 ± 4.4	30.5 ± 5.3	.116	
TBIL (µmol/L)	21.6 (15.3–32.3)	29.6 (15.4–62.7)	21.4 (15.3–29.7)	.066	20.7 (13.1–30.3)	20.9 (12.4–46.0)	20.5 (13.2–29.9)	.343	
ALT (U/L)	21.0 (15.0–34.5)	31.5 (16.5–67.8)	21.0 (15.0–33.0)	.054	28.0 (19.0–44.0)	26.0 (20.3–42.8)	28.0 (19.0–44.0)	.899	
GGT (U/L)	33.0 (17.5–66.5)	41.0 (22.5–107.0)	30.0 (16.5–63.0)	.203	38.0 (19.0–77.8)	63.0 (29.3–95.8)	36.0 (18.0–75.0)	.022	
Cr (µmol/L)	65.1 (52.5–86.1)	61.5 (54.4–89.2)	65.7 (52.2–85.3)	.860	63.0 (52.0–75.0)	52.5 (48.3–75.8)	63.0 (52.8–75.0)	.869	
INR	1.28 (1.18–1.41)	1.28 (1.13–1.40)	1.28 (1.18–1.41)	.740	1.27 (1.14–1.44)	1.24 (1.10–1.44)	1.27 (1.14–1.43)	.622	
Fib (g/L)	1.65 (1.25–2.09)	1.50 (1.01–2.32)	1.70 (1.27–2.07)	.421	1.57 (1.24–2.05)	1.87 (1.23–2.48)	1.56 (1.24–1.99)	.054	
PLR	88.8 (64.0–128.8)	121.3 (96.7–188.5)	84.3 (63.3–125.0)	.006	97.1 (65.3–138.1)	135.2 (96.9–156.8)	93.2 (63.8–131.5)	<.001	
MELD score	10.62 (8.62–15.57)	11.90 (9.49–14.83)	10.63 (8.55–12.93)	.253	9.76 (8.15–12.12)	10.15 (7.37–14.32)	9.72 (8.18–11.97)	.598	
Ascites (n, %)	 	 	 	.007	 	 	 	.772	
 none/mild	107 (73.8%)	7 (43.7%)	100 (77.5%)	 	279 (82.5%)	37 (84.1%)	242 (82.3%)	 	
 moderate/severe	38 (26.2%)	9 (56.3%)	29 (22.5%)	 	59 (17.5%)	7 (15.9%)	52 (17.7%)	 	
Treatment after EVL (n,%)	 	 	 	.324	 	 	 	.895	
 No	83 (57.2)	11 (68.8)	72 (55.8)	 	243 (71.9)	32 (72.7)	211 (71.8)	 	
 Yesa	62 (42.8)	5 (31.3)	57 (44.2)	 	95 (28.1)	12 (27.3)	83 (28.2)	 	
Aetiology (n, %)	 	 	 	 	 	 	 	 	
 HBV	106 (73.1%)	13 (81.3%)	93 (72.1%)	 	270 (79.9%)	37 (84.1%)	233 (79.3%)	 	
 HCV	8 (5.5%)	0 (0%)	8 (6.2%)	 	21 (6.2%)	1 (2.3%)	20 (6.8%)	 	
 Alcoholism	5 (3.5%)	1 (6.3%)	4 (3.1%)	 	37 (11.0%)	5 (11.4%)	32 (10.9%)	 	
 Others	26 (17.9%)	2 (12.5%)	24 (18.6%)	 	10 (3.0%)	1 (2.3%)	9 (3.1%)	 	
Esophageal varix grade	 	 	 	N/A	 	 	 	.008	
 F2	0	0	0	 	37	0	37	 	
 F3	145	16	129	 	301	44	257	 	
aPatients were treatment with nonselective beta-receptor blocker or endoscopic treatment or nonselective beta-receptor blocker + endoscopic treatment.

Data are expressed as number, mean ± standard deviation, median (25th–75th percentiles), or frequency (percentage (%).

PVT: portal vein thrombosis; HCC: hepatocellular carcinoma; WBC: white blood cell; LYM: lymphocyte; HB: haemoglobin; PLT: platelet; ALB: albumin; TBIL: total bilirubin; ALT: alanine aminotransferase; GGT: gamma-glutamyl transpeptidase; Cr: creatinine; INR: international normalized ratio; Fib: fibrinogen; PLR: platelet to lymphocyte ratio; MELD: model for end stage liver disease; HBV: hepatitis B virus; HCV: hepatitis C virus.

Clinical and laboratory characteristics in high and low PLR groups

Figure 2 demonstrates that the AUC values of PLR are 0.711 in the YJS cohort and 0.672 in the FY cohort. In the YJS cohort, patients were categorized into high- and low-PLR groups using Youden’s index, with a cut-off value of 96.7. The high-PLR group was significantly associated with higher PLT, lower LYM, and lower INR. Notably, the rebleeding rate was significantly higher in the high-PLR group compared to the low-PLR group (p < .05). Similar clinical and laboratory characteristics were observed in the high-PLR group in the FY cohort. The detailed characteristics in the high- and low-PLR groups are outlined in Table 2. Further ROC analysis showed that the predictive ability of PLR was comparable to that of ALBI (Delong test p > .05), while demonstrating a higher predictive ability compared to APRI (Delong test p < .05) in the both cohorts (Supplementary Figure 1).

Figure 2. Receiver operating characteristic curves of the PLR for predicting rebleeding within 6 weeks in (A) YJS cohort and (B) FY cohort.

Table 2. Comparison of clinical and laboratory characteristics between low and high PLR groups in patients who underwent their first endoscopic variceal ligation.

 	YJS cohort	 	FY cohort (validation cohort)	 	
Variables	PLR ≤ 96.7 (n = 79)	PLR > 96.7 (n = 66)	p value	PLR ≤ 96.7 (n = 169)	PLR > 96.7 (n = 169)	p value	
Gender	 	 	0.646	 	 	.251	
 Male (n,%)	51 (64.6%)	45 (68.2%)	 	133 (78.7%)	124 (73.4%)	 	
 Female (n,%)	28 (35.4%)	21 (31.8%)	 	36 (21.3%)	45 (26.6%)	 	
Age (years)	56.2 ± 10.8	57.2 ± 12.0	.248	53.1 ± 10.1	55.6 ± 10.6	.290	
PVT (n,%)	13 (16.5%)	11 (16.7%)	.973	6 (3.6%)	17 (10.1%)	.018	
HCC (n,%)	8 (10.1%)	7 (10.6%)	.925	24 (14.2%)	51 (30.2%)	<.001	
WBC (109/L)	4.20 (3.00–6.50)	3.95 (2.45–6.38)	.495	4.66 (2.85–7.35)	3.82 (2.38–6.01)	.005	
LYM (109/L)	0.80 (0.70–1.20)	0.60 (0.40–0.90)	<.001	0.95 (0.71–1.38)	0.56 (0.38-0.80)	<.001	
HB (g/L)	79.1 ± 24.6	66.0 ± 18.7	.137	78.0 (65.1–97.0)	79.0 (63.1–93.5)	.464	
PLT (109/L)	57.0 (41.0–71.0)	85.0 (58.8–129.0)	<.001	61.0 (44.5–81.5)	87.0 (56.0–124.0)	<.001	
ALB (g/L)	29.4 ± 5.2	30.2 ± 5.7	.277	30.0 ± 5.5	31.5 ± 4.9	.125	
TBIL (µmol/L)	23.5 (16.5–37.1)	18.6 (14.5–28.3)	.050	20.8 (13.5–30.8)	20.5 (12.7–30.2)	.345	
ALT (U/L)	21.0 (16.0–36.0)	20.0 (14.0–33.0)	.180	31.0 (22.0–49.0)	25.0 (16.0–37.5)	.001	
GGT (U/L)	30.0 (18.0–55.0)	35.5 (16.0–83.5)	.482	44.0 (20.0–75.0)	36.0 (18.0–87.0)	.637	
Cr (µmol/L)	61.0 (50.0–80.8)	68.8 (55.3–89.6)	.131	65.0 (54.0–79.0)	61.0 (51.0–71.5)	.040	
INR	1.32 (1.19–1.46)	1.25 (1.14–1.37)	.030	1.30 (1.67–1.48)	1.25 (1.10–1.90)	.009	
Fib (g/L)	1.69 (1.24–2.06)	1.64 (1.31–2.21)	.574	1.46 (1.16–1.90)	1.65 (1.30–2.17)	.001	
MELD score	11.15 (8.93–13.55)	10.34 (8.35–12.07)	.041	9.90 (8.45–12.33)	9.52 (7.95–11.71)	.010	
Ascites (n,%)	 	 	.305	 	 	.316	
 none/mild	61 (77.2%)	46 (69.7%)	 	143 (84.6%)	136 (80.5%)	 	
 moderate/severe	18 (22.8%)	20 (30.3%)	 	26 (15.4%)	33 (19.5%)	 	
Aetiology (n,%)	 	 	 	 	 	 	
 HBV (n,%)	58 (73.4%)	48 (72.7%)	 	138 (81.7%)	132 (78.1%)	 	
 HCV (n,%)	5 (6.3%)	3 (4.6%)	 	4 (2.4%)	17 (10.1%)	 	
 Alcoholism (n,%)	2 (2.5%)	3 (4.6%)	 	23 (13.6%)	14 (8.28%)	 	
 Others (n,%)	14 (17.7%)	12 (18.2%)	 	4 (2.4%)	6 (3.55%)	 	
Treatment after EVL (n,%)	 	 	.009	 	 	.011	
 No	53 (67.1%)	30 (45.5%)	 	111 (65.7%)	132 (78.1%)	 	
 Yesa	26 (32.9%)	36 (54.5%)	 	58 (34.3%)	37 (21.9%)	 	
Esophageal varix grade	 	 	 	 	 	.009	
 F2 (n,%)	0 (0%)	0 (0%)	 	26 (15.4%)	11 (6.5%)	 	
 F3 (n,%)	79 (100%)	66 (100%)	 	143 (84.6%)	158 (93.5%)	 	
Rebleeding (n,%)	4 (5.1%)	12 (18.2%)	.012	11 (6.5%)	33 (19.5%)	<.001	
a Patients were treatment with nonselective beta-receptor blocker or endoscopic treatment or nonselective beta-receptor blocker + endoscopic treatment.

Data are expressed as number, mean ± standard deviation, median (25th–75th percentiles), or frequency (percentage (%).

PVT: portal vein thrombosis; HCC: hepatocellular carcinoma; WBC: white blood cell; LYM: lymphocyte; HB: haemoglobin; PLT: platelet; ALB: albumin; TBIL: total bilirubin; ALT: alanine aminotransferase; GGT: gamma-glutamyl transpeptidase; Cr: creatinine; INR: international normalized ratio; Fib: fibrinogen; PLR: platelet to lymphocyte ratio; MELD: model for end stage liver disease; HBV: hepatitis B virus; HCV: hepatitis C virus.

High PLR was independently association with early rebleeding in patients after EVL

In the YJS cohort, univariate logistic analysis revealed that moderate/severe ascites, high PLR, high TBIL, low ALB, and low HB were significantly correlated with early rebleeding. These variables were included in the multivariate logistic analysis, which demonstrated that a high PLR was independently associated with early rebleeding after EVL. External validation using the FY cohort yielded the same conclusion (Table 3).

Table 3. Multivariate analysis of the association between platelet-to-lymphocyte ratio and rebleeding within 6-week after EVL.

 	Univariate analysis	Multivariate analysis	
 	YJS cohort	YJS cohort	FY cohort (validation cohort)	
Variables	OR (95% CI)	p	OR (95% CI)	p	OR (95% CI)	p	
Gender (n,%)	 	0.189	 	 	 	 	
 Male	Ref	 	 	 	 	 	
 Female	0.42 (0.09–1.37)	 	 	 	 	 	
Age (years)	0.96 (0.91–1.00)	0.063	 	 	 	 	
PVT	 	0.802	 	 	 	 	
 No	Ref	 	 	 	 	 	
 Yes	1.19 (0.26–4.08)	 	 	 	 	 	
HCC	 	0.252	 	 	 	 	
 No	Ref	 	 	 	 	 	
 Yes	2.25 (0.47–8.27)	 	 	 	 	 	
WBC (109/L)	1.04 (0.98–1.11)	0.181	 	 	 	 	
LYM (109/L)	1.02 (0.43–1.89)	0.947	 	 	 	 	
HB (g/L)	0.97 (0.94–1.00)	0.035	0.98 (0.95–1.02)	0.392	1.00 (0.98–1.01)	0.813	
PLT (109/L)	1.00 (1.00–1.01)	0.091	 	 	 	 	
ALB (g/L)	0.86 (0.77–0.96)	0.009	0.90 (0.77–1.04)	0.172	1.08 (0.99–1.16)	0.072	
TBIL (µmol/L)	1.03 (1.01–1.05)	0.004	1.03 (1.00–1.06)	0.027	1.02 (1.01–1.04)	0.002	
ALT (U/L)	1.01 (1.00–1.01)	0.151	 	 	 	 	
GGT (U/L)	1.00 (1.00–1.01)	0.116	 	 	 	 	
Cr (µmol/L)	1.00 (0.97–1.01)	0.656	 	 	 	 	
INR	0.69 (0.04–6.12)	0.772	 	 	 	 	
Fib (g/L)	0.95 (0.46–1.62)	0.874	 	 	 	 	
MELD score	1.08 (0.93–1.25)	0.317	 	 	 	 	
Ascites	 	0.006	 	0.021	 	0.869	
 none/mild	Ref	 	Ref	 	Ref	 	
 moderate/severe	4.43 (1.53–13.41)	 	4.34 (1.27–16.09)	 	0.92 (0.33–2.27)	 	
Treatment after EVL	 	0.328	 	 	 	 	
 No	Ref	 	 	 	 	 	
 Yesa	0.57 (0.17–1.68)	 	 	 	 	 	
PLR	 	0.007	 	0.012	 	0.001	
 Low	Ref	 	Ref	 	Ref	 	
 High	6.02 (1.83–27.18)	 	6.50 (1.69–34.42)	 	3.43 (1.66–7.61)	 	
a Patients were treatment with nonselective beta-receptor blocker or endoscopic treatment or nonselective beta-receptor blocker + endoscopic treatment.

EVL: endoscopic variceal ligation; PVT: portal vein thrombosis; HCC: hepatocellular carcinoma; WBC: white blood cell; LYM: lymphocyte; HB: haemoglobin; PLT: platelet; ALB: albumin; TBIL: total bilirubin; ALT: alanine aminotransferase; GGT: gamma-glutamyl transpeptidase; Cr: creatinine; INR: international normalized ratio; Fib: fibrinogen; PLR: platelet to lymphocyte ratio; MELD: model for end stage liver disease; OR, odds ratio; CI, confidence interval.

Relationship between the PLR and the risk of early rebleeding

RCS were used to flexibly model and visualize the relationship between the PLR and the risk of rebleeding based on multivariate analysis. Results indicated that the risk of rebleeding increases with an increase in PLR, which stabilizes when PLR is greater than 150 (Figure 3).

Figure 3. Associations of the platelet-to-lymphocyte ratio with the risk of rebleeding within 6 weeks in (A) YJS and (B) FY cohort.

Discussion

Our research findings indicate that a high PLR is independently associated with rebleeding within 6 weeks after EVL in patients with LC. Furthermore, we observed that the risk of rebleeding rises as PLR increases, but stabilizes when PLR exceeds 150. Previous studies have identified hematological indicators like the ALBI and APRI, as independent risk factors for rebleeding after EVL in various clinical settings [6,17]. To our knowledge, our study is the first to demonstrate the independent association of PLR with rebleeding within 6 weeks after EVL.

Systemic inflammation is a well-known feature of decompensated LC, with several studies emphasizing the role of the inflammatory response in the development of advanced LC and its association with unfavourable outcomes [36,37]. The intensity and duration of systemic inflammation may correlate with characteristics of LC, including the severity of acute decompensation, clinical course, and patient survival [37,38]. The clinical course of patients with unstable LC is largely related to the severity of portal hypertension, which is linked to systemic inflammation [37]. Zanetto et al. concluded that the severity of systemic inflammation is one of the most important predictors of bleeding and should be considered when assessing bleeding risk in patients with acute decompensated LC [38].

Studies have demonstrated that platelets play a crucial role in inflammation and immune responses by recognizing surface receptors of pathogens and immune complexes. The combination of platelet P-selectin and leukocyte P-selectin ligand-1 forms aggregates between platelets and leukocytes, creating a bridge between leukocytes and the endothelium [39,40]. Basili et al.'s study demonstrated that PLT alone cannot predict bleeding events in patients with LC [41]. Previous studies have also indicated that rebleeding after EVL is not related to PLT [8,42–44], which aligns with the viewpoint of Zanetto et al. [38]. These findings suggest that estimates of bleeding risk after EVL should not only consider PLT’s role in hemostatic function, but should also account for PLT's role in the systemic inflammatory response, including the release of cytokines and other mediators to stimulate the inflammatory response and activate leukocytes [45].

Lymphocytes play a pivotal role in the regulation of systemic inflammation [46]. As systemic inflammation worsens, the peripheral lymphocyte count decreases due to cell apoptosis, necrosis, and redistribution [47]. Previous studies have found that patients with HBV-related LC experience a decrease in lymphocyte count, likely due to chronic systemic inflammation, immune dysfunction, and poor nutritional status [48–51]. Wu et al. reported that systemic inflammation results in the depletion of circulating lymphocytes in patients with acute to chronic liver failure [52]. In our study, the high PLR group exhibited a significantly lower lymphocyte count than the low PLR group, suggesting that patients with high PLR may have a more severe systemic inflammatory status. Previous study has shown that the use of NSBBs resulted in an overall decrease of approximately 2.7% in WBC values in patients with advanced chronic liver disease diagnosed with clinically significant portal hypertension [53]. A recent study showed no significant difference in lymphocyte counts between liver cirrhosis patients with acute decompensation who were using NSBBs before admission and those who were not using NSBBs [54]. We speculate that the impact of using NSBBs for primary prophylaxis on lymphocyte counts in cirrhotic patients is limited. However, further investigation is warranted to determine the exact impact of using NSBBs for primary prophylaxis on lymphocyte counts in cirrhotic patients.

Previous studies have examined the relationship between PLR and the prognosis and/or severity of various diseases. Yang et al. reported that high PLR was independently associated with poor survival after hepatectomy for HCC patients [55]. Wu et al. found that PLR, as a systemic inflammatory marker, was positively linked to the severity of disease in patients with systemic lupus erythematosus [56]. Hu et al. discovered that high PLR was independently positively associated with the occurrence of post-stroke depression [57]. A meta-analysis conducted by Gong et al. showed that high PLR was an adverse factor for the prognosis of breast cancer patients [23]. Zheng et al. observed that high PLR was associated with increased overall mortality in critically ill patients with acute kidney injury [58]. Qu et al. reported that PLR was independently associated with prognosis in patients with coronavirus disease-19 [27]. Our results suggested that low PLR is associated with a low risk of rebleeding within 6 weeks after EVL. PLR, as a cost-effective and easily accessible systemic inflammation indicator [27,58], has potential applications in current clinical settings.

According to the Baveno VII consensus, the most effective approach for managing uncontrolled variceal bleeding is through salvage TIPS [3]. A multicenter randomized study conducted by Holster et al. showed that compared to the EVL plus beta-blocker group, the TIPS group had a higher hemostatic success rate but did not significantly improve survival [13]. Therefore, some scholars propose that for high-risk patients who are susceptible to bleeding control failure, TIPS should be performed as early as possible to reduce bleeding-related complications and improve survival [59,60]. Additionally, a recent randomized controlled trial showed that TIPS treatment significantly reduced the incidence of rebleeding, increased portal vein recanalization, and did not increase the risk of overt hepatic encephalopathy compared to EVL combined with drug therapy [61]. Our results indicate that patients with high PLR are a high-risk group for early rebleeding after EVL, and it is possible that this group could potentially derive benefits from receiving TIPS treatment as an initial intervention.

We acknowledge several limitations to our study. First, it is a retrospective, observational study, and selection bias cannot be avoided. Although we have conducted external validation, further validation of the results of this study is needed in large sample, multicenter prospective studies. Second, as hepatitis B virus infection is the main cause of the patients in this study, it is necessary to carefully extrapolate these results to other populations, especially those with severe alcohol and NASH effects in Western LC. Third, due to poor patient compliance, there is a relatively low proportion of patients who receive treatment after EVL (NSBBs alone, or endoscopy alone, or a combination of NSBBs and endoscopy), which may increase the risk of rebleeding events. Therefore, improved patient education is urgently needed. Fourth, in our two medical centers, the measurement of the hepatic venous pressure gradient (HVPG) is typically obtained before and after the placement of stents during the transjugular intrahepatic portosystemic shunt procedure, which is performed by the interventional radiology unit. Unfortunately, patients in our study who underwent EVL did not receive routinely HVPG measurements. This was primarily attributed to factors such as limited local resources and expertise, as well as patient characteristics and preferences. Therefore, the relationship between PLR and HVPG cannot be determined.

Conclusions

PLR, an easily measurable inflammatory marker, is a practical tool for identifying rebleeding within 6 weeks after EVL in LC patients. It is readily accessible and could effectively identify high-risk patients, allowing for adjustments in treatment strategies to reduce rebleeding in clinical practice.

Supplementary Material

Supplemental Material

Authors contributions

CYH and CM designed the project. Collected and analyzed the data with WW, HLJ and WZ. The manuscript was drafted by WW and HLJ; and revised by CYH. All authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data presented in this study are available on request from the corresponding author, upon reasonable request.
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