Skip to main content
NCBI home page
PLOS One logoLink to PLOS One
. 2023 Aug 15;18(8):e0290164. doi: 10.1371/journal.pone.0290164

Long term prophylactic anticoagulation for portal vein thrombosis after splenectomy: A systematic review and meta-analysis

Zheng Liao 1, Zixiang Wang 1, Chenguang Su 1, Yinxuan Pei 1, Weiwei Li 1, Jinlong Liu 1,*
Editor: Redoy Ranjan2
PMCID: PMC10426921  PMID: 37582105

Abstract

Aim

The aim of this study was to evaluate the efficacy and safety of the anticoagulants for the prevention of portal vein system thrombosis (PVST) in patients with cirrhosis after splenectomy and explore the optimal time of anticoagulant administration.

Methods

A systematic literature search was performed using PubMed, Embase and China Biology Medicine disc (CBM)databases, so as to screen out studies comparing the prognoses between cirrhotic post-splenectomy patients treated with and without anticoagulants. The parameters that were analyzed included the incidence of PVST and postoperative bleeding.

Results

With a total of 592 subjects, we included 8 studies (6 observational and 2 randomized trials) that fulfilled the inclusion criteria. We found that the incidence of PVST was significantly lower in the anticoagulation group during the first 6 months of anticoagulant administration. And the largest difference in the incidence of PVST between the anticoagulation and control groups was observed at 3 months (odds ratio 0.17(0.11~0.27); P = 0.767; I2 = 0.0%) and 6 months (OR = 0.21(0.11~0.40); P = 0.714; I2 = 0.0%) postoperatively. The incidence of bleeding was not significantly higher in the anticoagulation group (odds ratio 0.71 (0.30~1.71); P = 0.580; I2 = 0.0%).

Conclusion

Low-molecular weight heparin (LMWH) and warfarin can decrease the incidence of PVST in post-splenectomy cirrhotic patients without an increased risk of bleeding. And the optimal use time of warfarin is 6 months after splenectomy.

1. Introduction

Cirrhosis is one of the increasing causes of morbidity and mortality, being the 14th most common cause of death worldwide [1]. Cirrhosis can increase portal vein pressure and lead to hypersplenism, and splenectomy is often used to treat patients with portal hypertension and hypersplenism [2]. Since splenectomy is widely used due to the large number of patients with hepatitis B, the management of post-splenectomy complications is particularly important. And the most serious complications are post-operative infection and portal vein system thrombosis (PVST) [3].

PVST refers to the blood clots that formed in the portal vein, splenic vein, superior mesenteric vein or intrahepatic portal vein branches [4]. There are some studies have shown that the incidence of PVST in post-splenectomy patients ranges from 5% [5] to 52% [6]. The clinical manifestations of PVST include fever, abdominal pain, nausea and vomiting, which may lead to intestinal infarction in severe cases [7]. There is still controversy as to whether anticoagulants should be applied early after splenectomy to prevent the formation of PVST. Some argued that patients with cirrhosis had an increased risk of bleeding due to coagulation disorders [3, 8] and should not be given prophylactic anticoagulation. But some studies [9, 10] showed that both pro- and anticoagulation elements were reduced in cirrhotic patients, which maintain the complex coagulation homeostasis. Thus, anticoagulants can’t increase the risk of bleeding.

Therefore, the aim of this meta-analysis was to verify the safety and efficacy of the anticoagulants for the prevention of PVST in patients with cirrhosis after splenectomy. And then we further explored the optimal time of anticoagulants administration to prevent the occurrence of PVST after splenectomy.

2. Methods

2.1 Literature search

The systematic literature search was conducted by two investigators (Zheng Liao and Zixiang Wang) independently through PubMed, Embase and China Biology Medicine disc (CBM) databases, so as to screen out comparative studies evaluating the efficacy of anticoagulation (with or without anticoagulants) in cirrhotic patients undergoing splenectomy. The search was restricted to comparative studies (prospective or retrospective) written in English or Chinese and published before 31 July 2022. This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement [11].

The search was based on the following search formula: ((("Splenectomy"[Mesh]) OR (splenectomy)) AND ((("Thrombosis"[Mesh]) OR (thrombosis)) OR (thrombus))) AND (("Anticoagulants"[Mesh]) OR (anticoagulant)). The reference list of screened articles was also checked for potential hits.

2.2 Study selection

The eligibility of each study was assessed independently by two investigators. All titles and abstracts had been screened to determine the relevance of each study to this article. Studies meeting the following criteria were included in the meta-analysis: 1. randomized or comparative studies evaluated the effects of anticoagulation (with or without anticoagulants) in preventing PVST in cirrhotic patients undergoing splenectomy, regardless of the numbers of patients in each arm; 2. the dose and timing of post-splenectomy anticoagulation treatment were clearly shown; 3. the information of the incidence of PVST was available.; 4. randomized controlled trials (RCTs) with an evaluation of four or more ‘low risk’ and retrospective non-randomized trials (RTs) with a cumulative quality of literature score ≥7.

Studies were excluded if: 1. without a control group; 2. incomplete raw data for the purpose of this research; 3. only animals or cells included in the research; 4. reviews, study protocols, comments or case reports; 5. studies unrelated to the prevention of PVST after splenectomy.

If the two investigators disagreed with the inclusion or exclusion of an article, a meeting was held to determine its eligibility.

2.3 Data extraction

The two investigators examined the full text, tables and figures of relevant literature to extract data from articles that have been included in this study. The extracted data included: 1. name of the first author, year of publication, operation method, state of postoperative bleeding and detection medium; 2. demographics (sample size in each group and aetiology); 3. use of anticoagulants in each study 4. primary outcome: post-operative incidence of PVST and secondary outcome: the incidence of post-operative bleeding. The controversies were resolved via consensus between the two authors if they disagreed with the data.

2.4 Quality assessment

The methodological quality of RCTs was assessed using the Cochrane Handbook for Systematic Reviews of Interventions [12]. Risk of bias for each eligible RCTs was determined by seven items: 1. random sequence generation; 2. allocation concealment; 3. blinding of participants and personnel; 4. blinding of outcome assessment; 5. incomplete outcome data; 6. selective reporting; 7. other bias. The evaluation results for each item include: ‘low risk’, ‘unclear risk’ and ‘high risk’. An article was considered high quality if it had three or more ‘low risk’ and low quality if it has less than three ‘low risk’. The methodological quality of retrospective non-RTs was assessed using the modified Newcastle–Ottawa scale [13]. It contains three parts: 1. patient selection (0–4 points); 2. Comparability (0–2 points); 3. outcome (0–3 points). Differences in evaluation regarding the bias of studies were resolved through discussion and consensus.

2.5 Statistical analysis

The meta‑analysis was performed using stata12.0.The incidences of postoperative PVST and postoperative bleeding were treated as dichotomous data and pooled odds ratios (OR) with 95% confidence interval (CI) were used to perform analysis. The OR is used to reflect differences in exposure between experiments and controls, thus establishing a link between disease and exposure factors. P<0.05 was considered to indicate a statistically significant difference between the two groups. In terms of the heterogeneity test, when the statistics P > 0.05, I2 < 50%, it can be assumed that there is no significant statistical difference in the included data, so the fixed effect model is adopted. When the statistics P ≤ 0.05 and I2 ≥ 50%, indicating that there are significant statistical differences among the included data. The random effect model is adopted. A funnel plot and Egger’s test were designed to establish the existence of publication bias [14]. The trim-and-fill method was performed to further assess the potential publication bias.

3. Results

3.1 Literature search results

According to the preliminary search, the search strategy identified 854 articles, in which 247 articles from the PubMed, 328 from the Embase, 278 from the CBM, and 1 from other sources. Among these, 117 were excluded due to duplication and 557 were excluded after reading the title and abstract, leaving 265 available for further full-text review. After full-text review of the remaining 180 studies, 172 were excluded for reasons shown in Fig 1. Finally, 8 eligible studies [15–22] were finally included in this meta-analysis.

Fig 1. Flow chart of the study selection procedure.

Fig 1

Open in a new tab

3.2 Characteristics of included studies

Two of the eight included studies [15–22] were RCTs, one of which was triple-blinded [17] and the other was single-blinded [16]. The remaining 6 studies [15, 18–22] were retrospective non-RTs. These 8 studies [15–22] contained 592 patients, 320 of whom were treated with Low-molecular weight heparin (LMWH) and warfarin (experimental group) and the remaining 272 patients were not treated with anticoagulants (control group). The years of publication spanned from 2013 to 2022. The characteristics of each study are displayed in Table 1. All of the patients included in the eight studies [15–22] were Chinese, and they were diagnosed with liver cirrhosis with or without portal hypertension and hypersplenism. The aetiologies of cirrhosis included hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol, autoimmunity, schistosomiasis and Idiopathic cirrhosis.

Table 1. Characteristics of the included studies.

Author, Year Country Surgery method Anticoagulation regimen Subjects Bleeding(n) Experiment: Control Etiology NOS
Experiment Control Experiment Control
Li [16] 2022 China Laparoscopic splenectomy pericardial disconnection LMWH,4250U/day POD 1 to 5 warfarin (2.5mg/day) POD 3 to POM 6 aspirin (100mg/day) on the POD3 for 6 months 68 63 1:0 - 7
Zhen [15] 2022 China Splenectomy azygoportal disconnection LMWH,5000U/day POD 1 to 7 warfarin (1.5~3mg/day) POD 7 to POM 6 No prophylactic therapy 56 50 2:5 "HBV; HCV; Alcohol Autoimmunity 7
Bai [17] 2019 China Laparoscopic splenectomy azygoportal disconnection LMWH,4100U/day POD 3 to 8 warfarin (2.5mg/day) POD 3 to POM 12 aspirin (100mg/day) on the POD3 for 1 year 39 39 4:4 HBV; HCV; Alcohol Schistosomiasis Autoimmunity Idiopathic cirrhosis 7
Tang [18] 2018 China Laparoscopic splenectomy LMWH,3000U/day POD 1 to 7 warfarin(3.75mg/day) POD 3 to POM3 aspirin (100mg/day) on the POD3 for 3 months 33 21 - HBV; HCV 7
Huang [19] 2017 China Laparoscopic splenectomy azygoportal disconnection LMWH,4100U/day POD 3 to 8 warfarin (2.5mg/day) POD3 to POM 12 aspirin (100mg/day) on the POD3 for 1 year 31 31 - 7
Jiang [20] 2016 China Laparoscopic splenectomy azygoportal disconnection LMWH,4100U/day POD 3 to 8 warfarin (2.5mg/day) POD 3 to POM 3 aspirin (100mg/day) on the POD3 for 3 months 34 39 0:2 HBV; HCV Schistosomiasis; Alcohol Autoimmunity Idiopathic cirrhosis. 8
Wu [21] 2015 China Splenectomy + pericardial devascularization LMWH,6000U/day POD 1 to 5 warfarin POD 6 to POM 1 No prophylactic therapy 23 19 1:0 HBV; HCV 8
Zou [22] 2013 China Splenectomy LMWH,3000U/day POD 1 to 7 warfarin (3.75mg/day) POD 3 to POM 3 aspirin (100mg/day) from the POD3 for 3 months 36 20 - HBV; HCV 7
Open in a new tab

"-": the data were not available, POD: postoperative day, POM: postoperative month, HBV: hepatitis B virus-induced cirrhosis, HCV: hepatitis C virus-induced cirrhosis

The results of the quality assessment are as follows: two RCTS obtained more than four ‘low risk’, six retrospective non-RTs received a score of more than 7.

3.3 The incidence of PVST

Patients received continuous subcutaneous injections of LMWH for 5 [16, 17, 19–21] or 7 [15, 18, 22] days and warfarin for 1 [21] to 12 [17, 19] months in the experimental group. And the control group received enteric-coated aspirin tablets for 3 [18, 20, 22] to 12 [17, 19] months or no prophylactic therapy [15, 21] (Detailed information is shown in Table 1).

In order to investigate the effect of LMWH and warfarin in preventing PVST formation after splenectomy in patients with cirrhosis, we grouped the patients according to their anticoagulation time after splenectomy so as to analyse the incidence of PVST at different times with the use of anticoagulants. Ultrasound and angiography were used in patients at POD 7, 14 and POM 1, 3, 6, 9 and 12 to detect thrombosis in the main trunk or branches of the portal venous system.

We plotted a line graph (Fig 2) based on the incidence of PVST at different times after splenectomy and a subgroup analysis (Fig 3) was performed according to the anticoagulation time. The incidence of PVST decreased first and then increased in the early stage (≤1 month). The incidence of PVST at POD 7 was 37.92% and 44.75% in the experimental and control groups, respectively. There was no statistical difference between the two groups (OR = 0.73(0.47~1.14); P = 0.799; I2 = 0.0%). The incidence of PVST decreased significantly in the experimental group at POD 14 after splenectomy; The incidence of PVST was 22.31% in the experimental group and 43.36% in the control group (OR = 0.38(0.22~0.67); P = 0.205; I2 = 37.9%). We found an increase in the incidence of PVST in both groups at 1 month after splenectomy, and the rise in the control group was greater. The incidence of thrombosis in the experimental group was 28.40% and was significantly lower than that in the control group (51.15%) (OR = 0.37(0.25~0.55); P = 0.752; I2 = 0.0%). We speculated that this may be due to the high incidence period of thrombosis from POD 14 to POM 1 after splenectomy.

Fig 2. The line graph of the incidence of PVST.

Fig 2

Open in a new tab

Fig 3. Meta‐analysis of the probability of portal vein system thrombosis following anticoagulants administration after splenectomy.

Fig 3

Open in a new tab

The incidence of PVST was 11.22% and 43.30% in the experimental and control groups at 3 months postoperatively (OR = 0.17(0.11~0.27); P = 0.767; I2 = 0.0%). The difference between the two groups at this time was the most significant of all time points, and the incidence of PVST showed a gradual decrease in both groups from 3 months after splenectomy. The incidence of PVST was 8.51% and 30.80% in experimental and control groups at 6 months postoperatively (OR = 0.21(0.11~0.40); P = 0.714; I2 = 0.0%), the experimental group was significantly lower than the control group. The incidence was 7.69% and 20.51% in the experiment and the control groups at 9 months postoperatively (OR = 0.32(0.08~1.32)), and 3.65% and 6.77% at 12 months postoperatively (OR = 0.52(0.15~1.84); P = 0.948; I2 = 0.0%). At the two time points, the incidence of thrombosis was not significantly higher in the experimental group.

3.4 Incidence of postoperative bleeding

For the safety of anticoagulants, postoperative bleeding was assessed in the five studies [15–17, 20, 21]. There were 8 and 11 patients occurred postoperative bleeding in the experimental and control groups, and the incidence was 2.89% and 3.73%. The most common bleeding manifestation in these patients was gastrointestinal bleeding. The incidence of bleeding was not significantly higher in the experimental group(OR = 0.71 (0.30~1.71); P = 0.580; I2 = 0.0%) (Fig 4).

Fig 4. Meta‐analysis of bleeding after splenectomy with anticoagulants.

Fig 4

Open in a new tab

3.5 Publication bias

The publication bias was evaluated by funnel plot (Fig 5) and Egger’s test. The Egger’s test gave a P-value of 0.039(<0.05) for the incidence of PVST, indicating the potential presence of publication bias. According to the Trim-and-Fill method (Fig 6), the corrected random-effect ORs was- 1.045(95%CI:- 1.252,- 0.838). P-values before and after filling were >0.05, there was no substantial difference between the two results. So, it can be assumed that the original results are plausible.

Fig 5. Funnel plot for the incidence of portal vein system thrombosis.

Fig 5

Open in a new tab

Fig 6. Filled funnel plot of OR for the incidence of portal vein system thrombosis.

Fig 6

Open in a new tab

The Egger’s test gave a P-value of 0.658 for the incidence of postoperative bleeding (Fig 7), indicating no evidence of publication bias.

Fig 7. Funnel plot for incidence of post‐operative bleeding.

Fig 7

Open in a new tab

4. Discussion

The formation of PVST after splenectomy is a complication that should be closely monitored, it can affect the prognosis and even be life-threating. The detailed mechanisms of its formation remain unclear, but it is generally believed to be related to the local hypercoagulable state of the postoperative portal venous system. It may be attributed to the soaring count and augmented aggregation competence of platelets post-surgery. Hemodynamic changes of the portal venous system and the damage of splenic vein may be another important reason for the formation of PVST [23–25]. In addition, the diameter of the splenic and portal veins is thought to be associated with the formation of PVST after splenectomy [26]. Although the prophylaxis of pulmonary embolism and deep vein thrombosis has been relatively well established, but the prophylaxis of PVST after splenectomy remains controversial. Some studies have discussed the risk factors of PVST in patients after splenectomy [23, 24], and indicated anticoagulants could safely and effectively prevent PVST [27–30]. However, these studies didn’t describe how the anticoagulants were used. Also, no further studies have been conducted on the optimal timing of anticoagulants use. Therefore, specific anticoagulants and the duration of drug administration were further analysed in our study.

According to the analysis of the eight included articles [15–22], anticoagulants after splenectomy in patients with cirrhosis can effectively prevent PVST. Warfarin works by inhibiting the hepatic synthesis of coagulation factors II, VII, IX and X, which need to wait for the relative depletion of these factors in the body before the anticoagulant effect can be exerted. Therefore, warfarin has a slow onset of action. It should be used in the early days after splenectomy in combination with LMWH to prevent the formation of PVST. Our results showed that the incidence of thrombosis in the experimental group was lower than that in the control group. The incidence in experimental and control groups showed a trend of decreasing, then increasing, and finally continuing to decrease. We speculate that this may be due to the high incidence period of PVST from POD 14 to POM 1. The largest difference in the incidence of PVST between the experimental and control groups was observed at POM 3 and POM 6. When the postoperative time was 9 months or 12 months, there was no statistical difference between the experimental group and the control group. This may be due to anticoagulants are not effective for thrombosis older than 6 months. Moreover, the thrombosis of most cases could occur recanalization within the first 6 months of treatment [31]. So, we concluded that the optimal time for warfarin after splenectomy was 6 months.

PVST, a common life-threatening complication after splenectomy in patients with cirrhosis, can lead to a worsening clinical course [32]. The clinical manifestations of PVST include fever, abdominal pain and nausea. It can even cause liver function damage, increase portal hypertension leading to variceal bleeding and increase the risk of ischemic bowel necrosis [33–36]. Furthermore, PVST also may decrease the possibility of liver transplantation in the future [37, 38] and increase the mortality rates after transplantation [39, 40]. From this point of view, the significance of long-term anticoagulants after splenectomy is particularly important. Continuous application of anticoagulants after splenectomy can effectively reduce the occurrence of PVST from 1 to 6 months after surgery, prevent related complications, and benefit the prognosis of patients.

A previous meta-analysis [29] suggested LMWH could effectively decrease the incidence of PVST in post-splenectomy patients without an increased risk of bleeding. But it didn’t describe how the anticoagulants were used. And there is another RCT [41] reported LMWH was safe and effective for preventing the formation of PVST in patients with cirrhosis. Patients in this study required subcutaneous LMWH at a prophylactic dose (4000 U/day) for 48 weeks. This approach is not only expensive but also requires a high level of patient compliance. Compared to LMWH, warfarin is cheaper and requires only lower compliance for oral administration. In summary, patients with cirrhosis after splenectomy can be treated with warfarin maintenance therapy for 6 months after early postoperative application of LMWH.

Our study had several limitations. First, due to the number of included articles, there is fewer data on long-term warfarin applications in our article, so it is not possible to make a more detailed classification of the duration of warfarin use. Second, the doses of LMWH and warfarin used by patients in the included studies were not identical. Finally, the studies we included were all from China, which may result in a regional bias. Therefore, further studies are needed to overcome these limitations and confirm our findings.

5. Conclusions

Our meta-analysis suggested that combined anticoagulation with LMWH and warfarin can decrease the incidence of PVST in post-splenectomy cirrhotic patients without an increased risk of bleeding. Patients after splenectomy can have short term injections of LMWH followed by long term use of warfarin. And patients were best served with warfarin for 6 months after splenectomy to prevent portal vein thrombosis.

Supporting information

S1 File

(DOCX)

Click here for additional data file. (15.2KB, docx)

Data Availability

All relevant data are within the paper.

Funding Statement

This work was supported by the Hebei Provincial Key Research Project (21377767D).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

  • 1.Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. The Lancet. 2014;383(9930):1749–61. doi: 10.1016/S0140-6736(14)60121-5 [DOI] [PubMed] [Google Scholar]
  • 2.Kawanaka H, Akahoshi T, Kinjo N, Konishi K, Yoshida D, Anegawa G, et al. Technical standardization of laparoscopic splenectomy harmonized with hand-assisted laparoscopic surgery for patients with liver cirrhosis and hypersplenism. J Hepatobiliary Pancreat Surg. 2009;16(6):749–57. Epub 2009/07/25. doi: 10.1007/s00534-009-0149-8 . [DOI] [PubMed] [Google Scholar]
  • 3.Buzele R, Barbier L, Sauvanet A, Fantin B. Medical complications following splenectomy. J Visc Surg. 2016;153(4):277–86. Epub 2016/06/13. doi: 10.1016/j.jviscsurg.2016.04.013 . [DOI] [PubMed] [Google Scholar]
  • 4.Parikh S, Shah R, Kapoor P. Portal vein thrombosis. Am J Med. 2010;123(2):111–9. Epub 2010/01/28. doi: 10.1016/j.amjmed.2009.05.023 . [DOI] [PubMed] [Google Scholar]
  • 5.Stamou KM, Toutouzas KG, Kekis PB, Socrates Nakos AG, Manouras A, Krespis E, et al. <Prospective study of the incidence and risk factors of postsplenectomy thrombosis of the portal, mesenteric, and splenic veins.pdf>. 2006. [DOI] [PubMed] [Google Scholar]
  • 6.Ikeda M, Sekimoto M, Takiguchi S, Yasui M, Danno K, Fujie Y, et al. Total splenic vein thrombosis after laparoscopic splenectomy: a possible candidate for treatment. Am J Surg. 2007;193(1):21–5. Epub 2006/12/26. doi: 10.1016/j.amjsurg.2006.06.036 . [DOI] [PubMed] [Google Scholar]
  • 7.Rattner DW, Ellman L, Warshaw AL. <Portal vein thrombosis after elective splenectomy. An underappreciated, potentially lethal syndrome.pdf>. 1993. [DOI] [PubMed] [Google Scholar]
  • 8.Northup PG, Intagliata NM. Anticoagulation in cirrhosis patients: what don’t we know? Liver Int. 2011;31(1):4–6. Epub 2010/11/26. doi: 10.1111/j.1478-3231.2010.02376.x . [DOI] [PubMed] [Google Scholar]
  • 9.Tripodi A, Primignani M, Chantarangkul V, Dell’Era A, Clerici M, de Franchis R, et al. An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis. Gastroenterology. 2009;137(6):2105–11. Epub 2009/08/27. doi: 10.1053/j.gastro.2009.08.045 . [DOI] [PubMed] [Google Scholar]
  • 10.Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. The New England journal of medicine. 2011;365(2):147–56. Epub 2011/07/15. doi: 10.1056/NEJMra1011170 . [DOI] [PubMed] [Google Scholar]
  • 11.Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8(5):336–41. Epub 2010/02/23. doi: 10.1016/j.ijsu.2010.02.007 . [DOI] [PubMed] [Google Scholar]
  • 12.Shuster JJJRSM. Review: Cochrane handbook for systematic reviews for interventions, Version 5.1.0, published 3/2011. Julian P.T. Higgins and Sally Green, Editors. 2011;2:126–30. [Google Scholar]
  • 13.Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. European journal of epidemiology. 2010;25(9):603–5. Epub 2010/07/24. doi: 10.1007/s10654-010-9491-z . [DOI] [PubMed] [Google Scholar]
  • 14.Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ (Clinical research ed). 1997;315(7109):629–34. Epub 1997/10/06. doi: 10.1136/bmj.315.7109.629 ; PubMed Central PMCID: PMC2127453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Zhen Y, Wang B, Du H, Gao X, Wang Z, Xuan J, et al. Efficacy and safety of anticoagulation therapy for PVT after solenectomy in patients with liver cirrhosis. Chinese Hepatology. 2022;27(02):169–73. doi: 10.14000/j.cnki.issn.1008-1704.2022.02.029 [DOI] [Google Scholar]
  • 16.Li Y, Fu X, Li Y, Liu P, Liu S, Pan Y. Early prevention and risk factors analysis of portal vein system thrombosis after laparoscopic splenectomy and pericardial devascularization. Surg Endosc. 2022. Epub 2022/06/29. doi: 10.1007/s00464-022-09340-5 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Bai DS, Xia BL, Zhang C, Ye J, Qian JJ, Jin SJ, et al. Warfarin versus aspirin prevents portal vein thrombosis after laparoscopic splenectomy and azygoportal disconnection: A randomized clinical trial. Int J Surg. 2019;64:16–23. Epub 2019/03/10. doi: 10.1016/j.ijsu.2019.02.018 . [DOI] [PubMed] [Google Scholar]
  • 18.Tang J. Effectiveness of sequential anticoagulation with low molecular heparin and warfarin for portal vein thrombosis after laparoscopic splenectomy. BMU Journal. 2018;41(04):316–8. [Google Scholar]
  • 19.Huang HW. Warfarin and aspirin in the prevention and treatment of portal vein thrombosis after modified laparoscopic splenectpmy combined with cardiac peripheral vascular disconnection. Chinese Journal of Practical Medicine. 2017;44(05):61–4. [Google Scholar]
  • 20.Jiang GQ, Xia BL, Chen P, Qian JJ, Jin SJ, Zuo SQ, et al. Anticoagulation Therapy with Warfarin Versus Low-Dose Aspirin Prevents Portal Vein Thrombosis After Laparoscopic Splenectomy and Azygoportal Disconnection. J Laparoendosc Adv Surg Tech A. 2016;26(7):517–23. Epub 2016/04/12. doi: 10.1089/lap.2016.0012 . [DOI] [PubMed] [Google Scholar]
  • 21.Wu S, Wu Z, Zhang X, Wang R, Bai J. The incidence and risk factors of portal vein system thrombosis after splenectomy and pericardial devascularization. Turk J Gastroenterol. 2015;26(5):423–8. Epub 2015/09/10. doi: 10.5152/tjg.2015.0063 . [DOI] [PubMed] [Google Scholar]
  • 22.Zou W, Huang H, Duan J, Lin J, Wang S, Zeng Z. Early prevention of portal thrombosis after splenectomy for portal hypertension with low molecular weight heparin and warfarin. Chinese Journal of General Surgery. 2013;22(01):121–3. [Google Scholar]
  • 23.Kawanaka H, Akahoshi T, Itoh S, Iguchi T, Harimoto N, Uchiyama H, et al. Optimizing risk stratification in portal vein thrombosis after splenectomy and its primary prophylaxis with antithrombin III concentrates and danaparoid sodium in liver cirrhosis with portal hypertension. Journal of the American College of Surgeons. 2014;219(5):865–74. Epub 2014/09/27. doi: 10.1016/j.jamcollsurg.2014.07.939 . [DOI] [PubMed] [Google Scholar]
  • 24.Iida H, Aihara T, Ikuta S, Yamanaka N. Predictive factors of portal vein thrombus following splenectomy in patients with severe cirrhosis. Hepato-gastroenterology. 2014;61(134):1552–5. Epub 2014/12/02. . [PubMed] [Google Scholar]
  • 25.Francoz C, Valla D, Durand F. Portal vein thrombosis, cirrhosis, and liver transplantation. Journal of hepatology. 2012;57(1):203–12. Epub 2012/03/27. doi: 10.1016/j.jhep.2011.12.034 . [DOI] [PubMed] [Google Scholar]
  • 26.Danno K, Ikeda M, Sekimoto M, Sugimoto T, Takemasa I, Yamamoto H, et al. Diameter of splenic vein is a risk factor for portal or splenic vein thrombosis after laparoscopic splenectomy. Surgery. 2009;145(5):457–64; discussion 65–6. Epub 2009/04/21. doi: 10.1016/j.surg.2008.06.030 . [DOI] [PubMed] [Google Scholar]
  • 27.Gong C, Qin X, Yang J, Guo T. The Best Anticoagulation Strategy for Cirrhotic Patients who Underwent Splenectomy: A Network Meta-Analysis. Gastroenterol Res Pract. 2017;2017:9216172. Epub 2017/07/06. doi: 10.1155/2017/9216172 ; PubMed Central PMCID: PMC5476877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Qi X, Bai M, Guo X, Fan D. Pharmacologic prophylaxis of portal venous system thrombosis after splenectomy: a meta-analysis. Gastroenterol Res Pract. 2014;2014:292689. Epub 2014/09/23. doi: 10.1155/2014/292689 ; PubMed Central PMCID: PMC4163290. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Yang M, Liu J. Low-molecular weight heparin prevents portal vein system thrombosis after splenectomy: a systematic review and meta-analysis. ANZ journal of surgery. 2020;90(12):2420–4. Epub 2020/04/28. doi: 10.1111/ans.15865 ; PubMed Central PMCID: PMC7818250. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Zhang N, Yao Y, Xue W, Wu S. Early prophylactic anticoagulation for portal vein system thrombosis after splenectomy: A systematic review and meta-analysis. Biomedical Reports. 2016;5(4):483–90. Epub 2016/10/05. doi: 10.3892/br.2016.755 ; PubMed Central PMCID: PMC5038582. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Rodriguez-Castro KI, Vitale A, Fadin M, Shalaby S, Zerbinati P, Sartori MT, et al. A prediction model for successful anticoagulation in cirrhotic portal vein thrombosis. European journal of gastroenterology & hepatology. 2019;31(1):34–42. Epub 2018/09/07. doi: 10.1097/MEG.0000000000001237 . [DOI] [PubMed] [Google Scholar]
  • 32.Garcia-Pagan JC, Valla DC. Portal vein thrombosis: a predictable milestone in cirrhosis? Journal of hepatology. 2009;51(4):632–4. Epub 2009/08/08. doi: 10.1016/j.jhep.2009.06.009 . [DOI] [PubMed] [Google Scholar]
  • 33.Hashizume M, Tomikawa M, Akahoshi T, Tanoue K, Gotoh N, Konishi K, et al. Laparoscopic splenectomy for portal hypertension. Hepato-gastroenterology. 2002;49(45):847–52. Epub 2002/06/18. . [PubMed] [Google Scholar]
  • 34.Janssen HL, Wijnhoud A, Haagsma EB, van Uum SH, van Nieuwkerk CM, Adang RP, et al. Extrahepatic portal vein thrombosis: aetiology and determinants of survival. Gut. 2001;49(5):720–4. Epub 2001/10/16. doi: 10.1136/gut.49.5.720 ; PubMed Central PMCID: PMC1728504. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Condat B, Pessione F, Hillaire S, Denninger MH, Guillin MC, Poliquin M, et al. Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy. Gastroenterology. 2001;120(2):490–7. Epub 2001/02/13. doi: 10.1053/gast.2001.21209 . [DOI] [PubMed] [Google Scholar]
  • 36.Pagliaro L D ’Amico G, Luca A, Pasta L, Politi F, Aragona E, et al. Portal hypertension: diagnosis and treatment. Journal of hepatology. 1995;23 Suppl 1:36–44. Epub 1995/01/01. . [PubMed] [Google Scholar]
  • 37.Yerdel MA, Gunson B, Mirza D, Karayalçin K, Olliff S, Buckels J, et al. Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome. Transplantation. 2000;69(9):1873–81. Epub 2000/06/01. doi: 10.1097/00007890-200005150-00023 . [DOI] [PubMed] [Google Scholar]
  • 38.Winslow ER, Brunt LM, Drebin JA, Soper NJ, Klingensmith ME. Portal vein thrombosis after splenectomy. American journal of surgery. 2002;184(6):631–5; discussion 5–6. Epub 2002/12/19. doi: 10.1016/s0002-9610(02)01095-4 . [DOI] [PubMed] [Google Scholar]
  • 39.Fimognari FL, Violi F. Portal vein thrombosis in liver cirrhosis. Internal and emergency medicine. 2008;3(3):213–8. Epub 2008/02/16. doi: 10.1007/s11739-008-0128-0 . [DOI] [PubMed] [Google Scholar]
  • 40.Englesbe MJ, Kubus J, Muhammad W, Sonnenday CJ, Welling T, Punch JD, et al. Portal vein thrombosis and survival in patients with cirrhosis. Liver transplantation: official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2010;16(1):83–90. Epub 2009/12/26. doi: 10.1002/lt.21941 . [DOI] [PubMed] [Google Scholar]
  • 41.Villa E, Cammà C, Marietta M, Luongo M, Critelli R, Colopi S, et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology. 2012;143(5):1253–60.e4. Epub 2012/07/24. doi: 10.1053/j.gastro.2012.07.018 . [DOI] [PubMed] [Google Scholar]

Decision Letter 0

Redoy Ranjan

15 Jun 2023

PONE-D-23-13885

The role of anticoagulation in the prevention of portal vein thrombosis after splenectomy in patients with cirrhosis: A systematic review and meta-analysis

PLOS ONE

Dear Dr. Liu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jul 29 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Redoy Ranjan, MBBS, MRCSEd, Ch.M., MS (CV&TS), FACS

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and 

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please note that funding information should not appear in any section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript.

   "This work was supported by the Hebei Provincial Key Research Project (21377767D)."

3. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability.

"Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.

Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

4. Please remove your figures from within your manuscript file, leaving only the individual TIFF/EPS image files, uploaded separately. These will be automatically included in the reviewers’ PDF.

5. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In this study, the authors aimed to assess the effectiveness and safety of anticoagulants in preventing portal vein system thrombosis (PVST) in patients with cirrhosis following splenectomy. Additionally, the study aimed to determine the optimal timing for administering anticoagulants. A comprehensive search of literature databases including PubMed, Embase, and China Biology Medicine disc (CBM) was conducted to achieve this. The search aimed to identify relevant studies that compared the outcomes of cirrhotic post-splenectomy patients who received anticoagulants to those who did not. The parameters analyzed encompassed the occurrence of PVST and postoperative bleeding.

The topic is interesting and falls under the scope of the journal. The article is well organized and well structured. However, the authors need to address the following comments.

Major Comments:

1. Provide the syntax codes of STATA 12.0 in the appendix.

2. Revise section 2.5 and interpret different statistical tools used in this study for the convenience of the readers such as confidence interval, Chi-square test, Egger’s test, etc.

Minor comments:

1. The title is too long for the reader; it should be precise.

2. Table 1 font is too small; readjust to make it more visible.

3. Page 2, line 15, write as “explore the optimal time of anticoagulant administration”.

4. Page 10, line 40, write, “Cirrhosis can increase portal vein pressure and lead to hypersplenism”.

5. The two investigators examined the full text, tables, and figures of relevant literature to extract data from articles that had been included in this study.

6. There are some grammatical mistakes in the article please revise the article thoroughly and remove all the errors.

7. Conclusions are not clearly specified.

8. Some of the references need revision such as reference 7 and 19.

Reviewer #2: The objectives of the study are fully met on behalf of the test results/estimates supported by relevant dataset and statistical analysis. In the light of these findings, I recommend accepting and publishing the article in PLOS ONE.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Attachment

Submitted filename: Review Report (PONE-D-23-13885).docx

Click here for additional data file. (17.3KB, docx)
PLoS One. 2023 Aug 15;18(8):e0290164. doi: 10.1371/journal.pone.0290164.r002

Author response to Decision Letter 0

22 Jul 2023

Dear reviewers,

Thank you very much for your comments and professional advice. Based on your suggestion and request we have made corrected modifications on the revised manuscript. We hope that our work can be improved again. The details as follows:

Reviewer #1

Major Comments:

1. Provide the syntax codes of STATA 12.0 in the appendix.

The author’s answer: We uploaded my syntax code of Stata 12.0 as supporting information.

2. Revise section 2.5 and interpret different statistical tools used in this study for the convenience of the readers such as confidence interval, Chi-square test, Egger’s test, etc.

The author’s answer: We have revised the section in the article. The details as follows: “The meta‑analysis was performed using stata12.0 .The incidences of postoperative PVST and postoperative bleeding were treated as dichotomous data and pooled odds ratios (OR) with 95% confidence interval (CI) were used to perform analysis. The OR is used to reflect differences in exposure between experiments and controls, thus establishing a link between disease and exposure factors. P<0.05 was considered to indicate a statistically significant difference between the two groups. In terms of the heterogeneity test, when the statistics P > 0.05, I2 < 50%, it can be assumed that there is no significant statistical difference in the included data, so the fixed effect model is adopted. When the statistics P ≤ 0.05 and I2 ≥ 50%, indicating that there are significant statistical differences among the included data. The random effect model is adopted. A funnel plot and Egger’s test were designed to establish the existence of publication bias. The trim-and-fill method was performed to further assess the potential publication bias. ”

Minor comments:

1. The title is too long for the reader; it should be precise.

The author’s answer: We have streamlined the title. The details as follows: “Long term prophylactic anticoagulation for portal vein thrombosis after splenectomy: A systematic review and meta-analysis”.

2. Table 1 font is too small; readjust to make it more visible.

The author’s answer: We have enlarged the font in the table.

3. Page 2, line 15, write as “explore the optimal time of anticoagulant administration”.

The author’s answer: We have revised the sentence. The details as follows: “The aim of this study was to evaluate the efficacy and safety of the anticoagulants for the prevention of portal vein system thrombosis (PVST) in patients with cirrhosis after splenectomy and explore the optimal time of anticoagulant administration.”

4. Page 10, line 40, write, “Cirrhosis can increase portal vein pressure and lead to hypersplenism”.

The author’s answer: We have revised the sentence. The details as follows: “Cirrhosis can increase portal vein pressure and lead to hypersplenism, and splenectomy is often used to treat patients with portal hypertension and hypersplenism.”

5. The two investigators examined the full text, tables, and figures of relevant literature to extract data from articles that had been included in this study.

The author’s answer: We have revised the sentence. The details as follows: “The two investigators examined the full text, tables and figures of relevant literature to extract data from articles that have been included in this study. ”

6. There are some grammatical mistakes in the article please revise the article thoroughly and remove all the errors.

The author’s answer: We have checked the article and fixed some grammatical mistakes.

7. Conclusions are not clearly specified.

The author’s answer: We have revised the conclusions. The details as follows: “Our meta-analysis suggested that combined anticoagulation with LMWH and warfarin can decrease the incidence of PVST in post-splenectomy cirrhotic patients without an increased risk of bleeding. Patients after splenectomy can have short term injections of LMWH followed by long term use of warfarin. And patients were best served with warfarin for 6 months after splenectomy to prevent portal vein thrombosis.”

8. Some of the references need revision such as reference 7 and 19.

The author’s answer: We have revised the references according to the requirements of plos one.

Thank you for your attention and time.

Yours sincerely,

Zheng Liao

Corresponding author:

Name: Jinlong Liu

E-mail: liujl800813@163.com

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file. (19.1KB, docx)

Decision Letter 1

Redoy Ranjan

3 Aug 2023

Long term prophylactic anticoagulation for portal vein thrombosis after splenectomy: A systematic review and meta-analysis

PONE-D-23-13885R1

Dear Dr. Liu,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Redoy Ranjan, MBBS, MRCSEd, Ch.M., MS (CV&TS), FACS

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The authors have addressed all the concerns raised. So I recommend accepting the paper in its present form.

Reviewer #3: I think some comments the reviewer suggested were adequately addressed. The manuscript should be accepted.

Acceptance letter

Redoy Ranjan

7 Aug 2023

PONE-D-23-13885R1

Long term prophylactic anticoagulation for portal vein thrombosis after splenectomy: A systematic review and meta-analysis

Dear Dr. Liu:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Redoy Ranjan

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 File

    (DOCX)

    Click here for additional data file. (15.2KB, docx)
    Attachment

    Submitted filename: Review Report (PONE-D-23-13885).docx

    Click here for additional data file. (17.3KB, docx)
    Attachment

    Submitted filename: Response to Reviewers.docx

    Click here for additional data file. (19.1KB, docx)

    Data Availability Statement

    All relevant data are within the paper.

    Articles from PLOS ONE are provided here courtesy of PLOS

    RESOURCES