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Effect of factor VIII and FVIII/PC ratio on portal vein thrombosis in liver cirrhosis: a systematic review and meta‑analysis

BMC Gastroenterology volume 24, Article number: 320 (2024) Cite this article

Abstract

Background

To date, there is an ongoing debate regarding the ability to predict PVT development using markers of FVIII or FVIII/PC ratio. This study presents evidence-based medical findings on the influence of FVIII activity levels and FVIII/PC values in the formation of PVT in cirrhosis.

Methods

The search for original studies on risk factors for portal vein thrombosis (PVT) associated with cirrhosis was conducted, which primarily focused on comparing circulating FVIII activity levels or FVIII/PC ratio in cirrhotic patients with and without PVT. The quality of evidence from each study was assessed using the Newcastle-Ottawa Scale.

Results

The meta-analysis included a total of 10 original studies. In total, 2250 cirrhotic patients were included, with 414 having PVT and 1836 without PVT. The pooled analysis using a random-effects model showed no significant difference in standardized mean difference (SMD) for FVIII activity levels in cirrhotic patients with or without PVT (SMD = 0.12, 95% CI=-0.46 to 0.70, P = 0.68), but there was significant heterogeneity (I2 = 95.52%, P = 0.00). Meta-regression analysis indicated that differences in mean FVIII activity levels in the PVT group, the number of cases in the non-PVT group, and the study design methods partially contributed to the heterogeneity (P < 0.05). However, compared to the non-PVT group, the PVT group had higher FVIII/PC ratio with a statistically significant difference (SMD = 0.39, 95% CI: 0.15 to 0.63, P = 0.00), and there was no significant heterogeneity (I2 = 28.62%).

Conclusion

In conclusion, the FVIII/PC ratio not only reflects the severity of liver disease, but also can be used as one of the predictors of PVT development.

Peer Review reports

Introduction

The liver plays a crucial role in the synthesis of coagulation factors. In cases of organic or functional liver damage, there is often an abnormality in the number or activity of these coagulation factors. Cirrhosis, an advanced stage of liver disease, is commonly associated with coagulation disorders. This is primarily characterized by an overall imbalance between pro-and anti-coagulant factors, which is barely maintained at a weak balance due to the body’s extreme compensation. However, when triggers such as infection, renal injury, and decompensated events occur, this delicate balance can easily lead to bleeding or thrombosis [1]. Several researchers have discovered that the level of circulating FVIII activity in cirrhosis patients is significantly higher when compared to healthy individuals [2]. Additionally, a study by Praktiknjo et al. confirmed that the level of FVIII activity in the portal vein of cirrhosis patients is much higher than in the systemic circulation, which may contribute to portal vein thrombosis (PVT) in cirrhosis patients [3]. The impact of coagulation compensation in patients with cirrhosis is commonly manifested by elevated FVIII levels and reduced PC levels. PC, which is the most powerful natural anticoagulant substance, experiences the most significant decrease. This ratio of FVIII/PC is considered an important indicator for evaluating the coagulation balance in patients with cirrhosis [4]. On the other hand, the study conducted by the Scheiner team concluded that in patients with acute-on-chronic liver failure, the FVIII/PC ratio could predict liver-related adverse events, regardless of the bleeding and thrombotic status caused by cirrhosis [5]. PVT is a frequently observed complication in patients with liver cirrhosis. The development of PVT is primarily linked to factors such as portal vein blood flow velocity, coagulation disorders, and the degree of portal vein endothelial injury. Scholars widely recognize that a portal vein trunk blood flow velocity of less than 15 cm/s is considered the most reliable predictor of PVT. However, there is ongoing debate among scholars regarding the association between coagulation status and the occurrence of PVT in liver cirrhosis. A meta-analysis conducted in 2013 found no significant impact of PC activity level on the development of PVT [6], but there is insufficient reliable evidence to determine the role of FVIII activity level and its ratio to PC in PVT development among patients with liver cirrhosis. The published views on the explanation of the relationship between FVIII activity level, its ratio to PC, and PVT in liver cirrhosis are inconsistent [2, 7,8,9,10,11,12,13,14,15,16]. To address this gap, we conducted a comprehensive literature search and employed statistical software to analyze and organize the data related to FVIII activity level or FVIII/PC ratio and PVT in liver cirrhosis. Our findings provide valuable insights for a better understanding of the mechanism underlying PVT formation and can guide clinical practice.

Methods

The present systematic review and meta-analysis were conducted as per the updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [17].

Information source and search strategy

This meta-analysis aimed to identify published studies on differences in circulating FVIII activity and its ratio to PC between cirrhotic patients with PVT and those without PVT through a systematic literature search. The search was conducted in foreign language databases such as PubMed, Embase, and Cochrane, as well as Chinese databases including China National Knowledge Infrastructure (CNKI) and Wan Fang. The search keywords used were “liver cirrhosis”, “portal vein thrombosis”, and “VIII” (In Supplementary Material-Table 4, we have only provided foreign language database search formulas). In addition to this, we also conducted a manual search and carefully reviewed the references of the corresponding articles to find relevant literature that met the inclusion criteria. If multiple publications reported the same data, we only included studies with more complete data in the meta-analysis.

Eligibility criteria

Inclusion criteria: (1) Study type: this study includes case-control studies or cohort studies that focus on factors associated with PVT formation in cirrhosis. (2) Study subjects: the main objective of the study is to examine the level of FVIII activity and its relationship with PC ratio and PVT formation in cirrhosis. (3) Exposure factors: The study considers FVIII or FVIII/PC levels. (4) Means and standard deviations are reported or can be calculated. (5) There are no language restrictions.

Exclusion criteria: (1) Data of non-cirrhotic patients are excluded. (2) Studies without control case reports or unavailable effect sizes are excluded. (3) Studies that report the same data are excluded. (4) Studies without relevant outcome measures are excluded. (5) Studies without statistical data or full text availability are excluded. (6) Reports, reviews, letters, editorials, conference abstracts, and dissertations are excluded.

Data extraction and quality assessment

Two investigators independently conducted studies selection and data extraction from the identified articles. Initially, duplicate studies were removed. Subsequently, case reports, reviews, letters, editorials and conference abstracts were excluded. The remaining literature was then screened based on the titles or abstracts to remove obviously inconsistent ones. Finally, the full text of the remaining articles was analyzed to determine their inclusion in this study. If necessary, the Corresponding Author was contacted via mail to obtain the required information. Data extraction involved recording the first author, country, year of publication, study type, number of cases, age, sex, mean and standard deviation of FVIII, PC or FVIII/PC, Child-Pugh score, MELD score, and follow-up time. The risk of bias in the literature was assessed by two independent reviewers, who cross-checked their evaluations. Any disagreements were resolved through discussion and consultation. The quality of cohort and case-control studies was evaluated using the Newcastle-Ottawa Scale, which considers three main aspects: study population selection, comparability between groups, and measurement of exposure factors. A maximum score of 9 points could be achieved. Studies with a score of 8 or higher were considered high quality, those with a score between 5 and 7 were considered moderate quality, and those with a score of 4 or lower were considered low quality.

Data synthesis

FVIII activity or FVIII/PC ratio were collected from cirrhotic patients with and without PVT. Mean differences in FVIII activity or FVIII/PC ratio between these groups were calculated. To assess the relationship between FVIII activity levels or FVIII/PC ratio and PVT formation in cirrhotic patients, we calculated the standardized mean difference (SMD) and 95% confidence interval (CI) using Hedges’ g method (Hedges’ g is a way to measure effect size, which gives us an idea of how much two groups differ). Standardized values were employed to account for variations in units and methods across studies. A combined SMD was obtained by pooling the SMDs from each study. A pooled SMD > 0 indicated that an increase in FVIII activity level or FVIII/PC ratio promoted PVT development. Statistical significance was set at P > 50% indicated substantial heterogeneity) and the χ2 test (P < 0.10 indicated statistically significant heterogeneity). The presence of publication bias was evaluated using Egger’s test. Meta-regression and subgroup analyses were conducted to explore sources of heterogeneity. All statistical analyses were performed using STATA 17.0 and R 4.3.0.

Results

Baseline characteristics of the studies and quality assessment

In our literature selection process, the search strategy yielded 360 records, of which 12 studies were included in the final analysis. Figure 1 shows the selection and exclusion process of the study. But two studies were excluded because they used the same data and it was not possible to calculate the mean and standard deviation of FVIII or FVIII/PC ratio (despite attempting to contact the corresponding author three times via email to obtain the original data, no response was received). Therefore, a total of ten original studies were excluded in this article. 10 studies involving 414 cirrhotic patients with PVT and 1836 cirrhotic patients without PVT were eligible in the systematic review and meta-analysis (Table 1). These comprised of three prospective cohort studies, two retrospective cohort studies, and five case-control studies. Baseline characteristics and the mean and standard deviation of FVIII activity or FVIII/PC ratio were summarized in Tables 1 and 2. For studies in patients with cirrhosis, 4 studies were from China and 3 were from Italy, 2 were from Spain and 1was from Iran. Based on the study design, 5 were cohort (including 3 prospective studies) and the remaining 5 were case-control studies. The duration of follow-up varied from 7 days to 48 months. For study in patients with cirrhosis undergoing splenectomy and esophagogastric devascularization, the study was from China [18]. Table 3 summarize the study quality analysis for cohort and case-control studies. The quality evaluation results of the included studies showed that the Newcastle-Ottawa Scale (NOS) scores of all included studies were ≥ 6 points, indicating medium to high quality studies. Mean and standard deviation of FVIII activity and FVIII/PC ratio were not provided in some original literatures. The standard deviation from the study by Lankarani et al. [19] was calculated using the Cochrane officially recommended continuous variable data conversion tool. The mean and standard deviation from three studies [10, 15, 16] were converted using the Tong literature method [20]. FVIII was measured in ng/mL in the study by Han and in µg/mL in the study by PC [18], while the rest of the studies reported FVIII in % active units. Therefore, the standardized mean difference (SMD) was used as the effect size. Data on FVIII/PC were available for only four cohort studies.

Fig. 1
figure 1

Flowchart for study identification, selection and inclusion process

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Table 1 Baseline characteristics of the studies included in the meta-analysis
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Table 2 Means and standard deviations of included literatures
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Table 3 Quality evaluation
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To assess the role of FVIII activity levels in PVT development in cirrhotic patients

Pooled analysis

In Table 1, FVIII activity levels were found to be similar between the PVT and non-PVT groups in five studies [9, 10, 14, 18, 19]. Additionally, FVIII activity levels were shown to differ based on different Child-Pugh classification [7, 9], and were significantly different in four studies with or without PVT [10, 12, 13, 16]. A meta-analysis using a random-effects model, pooling the data, revealed no significant difference in SMD in patients with cirrhosis with or without PVT (0.12, 95% CI = -0.46 to 0.70, P = 0.68). There was significant between-study heterogeneity (I2 = 95.52%, P = 0.00) (Fig. 2). Egger’s test did not suggest evidence of publication bias (z=-0.13, P = 0.8955). However, since the funnel plot showed asymmetry, we proceeded to use the trim and fill method for assessment and the final result remained insignificant (Supplementary Material-Figs. 1 and 2 and Supplementary Material-Table 1).

Fig. 2
figure 2

Forest plot for the association of FVIII activity with PVT with overall analysis

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Subgroup analysis

Subgroup analysis was performed by categorizing the studies into case-control and cohort studies. The combined results indicated that in the cohort study, there was no significant correlation according to the standardized mean difference (SMD = 0.48, 95% CI=-0.63 to 1.59, P = 0.39), but there was a notable heterogeneity among the studies (I2 = 97.18%, P = 0.00) (Fig. 3). Conversely, the pooled SMD in the case-control study exhibited a significant correlation (SMD =-0.26, 95% CI=-0.48 to -0.04, P = 0.002), with a moderate level of heterogeneity among the studies (I2 = 38.1%) (Fig. 4). (Supplementary Material-Table 2).

Fig. 3
figure 3

Forest plot for the association of FVIII activity with PVT in cohort studies

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Fig. 4
figure 4

Forest plot for the association of FVIII activity with PVT in case control studies

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Meta-regression

Meta-regression was conducted to investigate the source of heterogeneity. The results indicated that heterogeneity was not associated with age, gender ratio, year of publication, total number of cases, the ratio of PVT case number to non-PVT case number, and liver function (Child-Pugh class A + B/C) (P > 0.05). However, it was significantly correlated with the difference of mean FVIII activity level in the PVT group and the number of cases in the non-PVT group across studies (P < 0.05) (Supplementary Material-Table 3).

Sensitivity analysis

Sensitivity analysis demonstrated good robustness, with the study by Lopez-Gomez et al. having the greatest impact on the results when removed, but still not statistically significant (Supplementary Material-Table 4).

Effect of FVIII/PC ratio on PVT development in cirrhotic patients

FVIII/PC ratio was measured from 4 studies [13,14,15, 18], which included 72 cirrhotic patients of PVT and 960 without PVT, overall prevalence of PVT 7.0%. The pooled results of the correlation between FVIII to PC ratio and PVT formation in cirrhotic patients showed a significant difference in SMD (0.38, 95% CI = 0.13 to 0.63, P = 0.00). The heterogeneity test results indicated I2 = 28.62%, P = 0.20 (Fig. 5).

Fig. 5
figure 5

Forest plot for the association of FVIII/PC with PVT with overall analysis

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Discussion

PVT is a frequent and severe complication in patients with cirrhosis. The prevalence of PVT varies depending on the stage of liver disease, with rates ranging from approximately 10–26% in different patient populations [21]. When PVT occurs, it leads to increased pressure in the portal vein, because collateral circulation is present in patients with cirrhosis, symptoms may not be evident, and the damage caused by PVT may be continuously progressive. Therefore, it is important to identify the risk factors associated with PVT development in cirrhotic patients in order to detect and manage it early. To date, there is ongoing debate regarding the association between FVIII activity levels and the development of PVT. This study is the first to conduct a systematic review and meta-analysis to assess the impact of FVIII activity level and FVIII/PC ratio on PVT formation in cirrhotic patients. The findings of this study indicate that FVIII activity levels were similar in cirrhotic patients with and without PVT. In non-cirrhotic patients, a study demonstrated that FVIII activity levels can serve as predictive markers for PVT. Both their training and validation cohorts showed that FVIII levels ≥ 150% pose the highest risk for recurrent thrombosis [22]. In cirrhotic patients, the synthesis, secretion, and mechanism of action of FVIII are significantly complex due to impaired coagulation factor synthesis. Pradhan et al. systematically examined the role of FVIII in chronic liver disease and highlighted its involvement in portal hypertension, liver fibrosis, and the development of cirrhosis, in addition to its procoagulant effect [23]. Tang et al. [9] found no significant difference in FVIII activity levels among patients with varying liver function classes (Child-Pugh class A/B/C). Similarly, Lewis et al. confirmed that FVIII activity levels did not differ significantly between Child-Pugh class A and B patients, but were significantly higher in Child-Pugh class C patients [24]. This suggests that FVIII may not be an ideal indicator for early liver disease changes. Fimognari et al. observed that FVIII activity levels were similar between Child-Pugh class A/B patients with or without PVT, while in Child-Pugh class C patients, FVIII activity levels were significantly lower in the PVT group compared to non-PVT patients (70 ± 39.9 vs. 128.6 ± 68.3)7. Overall, three studies indicated that FVIII activity levels were lower in the PVT group than in the non-PVT group, although statistical significance was not reached [7, 9, 24]. This may suggest that development of PVT may lead to the consumption of FVIII. However, there is currently no definitive evidence for the development of PVT. Our meta-analysis provides evidence-based medical support for this claim. Specifically, quantitative analysis revealed that FVIII is not a risk factor for PVT in patients with cirrhosis. Turon et al. demonstrated through a univariate competing risk model that FVIII activity levels were lower in the PVT group compared to the non-PVT group, with a sHR of 0.981 (95% CI = 0.96–0.99, P = 0.036). However, multivariate analysis showed that FVIII was not an independent predictive marker of PVT [13]. This finding is consistent with the studies conducted by Georgios N et al. and Chen et al. [8, 11] which also support our meta-analysis results.

The FVIII/PC ratio was significantly higher in cirrhotic patients with PVT compared to those without PVT, indicating a potential association between this ratio and PVT development. It is worth noting that PC, a natural anticoagulant, is significantly decreased in cirrhotic patients compared to healthy controls [25]. The increased FVIII activity levels and decreased PC levels were once considered hypercoagulable in cirrhotic patients [3]. Recent study has associated FVIII/PC ratio with the clinical stage of liver disease and hepatic venous pressure gradient (P < 0.001) and have identified it as an independent risk factor for hepatic decompensation/liver-related death (aHR = 1.11; 95%CI = 1.08–1.13; P < 0.001) [5]. Similarly, Kalambokis GN et al. [26] demonstrated that FVIII/PC ratio could predict new-onset ascites (aHR = 2.944; 95%CI = 1.095–7.914; P = 0.003) or variceal bleeding (aHR = 1.575; 95%CI = 0.990–2.504; P = 0.01). These two studies confirmed the predictive value of FVIII/PC in terms of liver disease severity, and further, it has been demonstrated that liver disease severity is positively associated with the risk of PVT. Therefore, our study is consistent with this, and by quantitative analysis, FVIII/PC ratio was confirmed as a PVT predictor (SMD = 0.38, 95%CI = 0.13 to 0.63, P = 0.00).

This study does not provide strong evidence for the association between FVIII activity levels and the development of PVT in cirrhosis. It is important to interpret these findings cautiously due to the presence of coagulation disorders, complex mechanisms in cirrhotic patients. The strengths of our study include being the first systematic review to explore the association between FVIII and its ratio to PC in cirrhosis with PVT. Additionally, all analyses used both fixed and random effects models, with random effects models being used when significant heterogeneity was observed. This approach makes the results more reliable and conservative, with wider confidence intervals. Certainly, there are some limitations to consider. The original studies included in our review did not provide specific cut-off values for FVIII or FVIII/PC. In some studies, the mean and standard deviation of FVIII or FVIII/PC were estimated using statistical methods, which may introduce errors and affect the results. Heterogeneity was also observed due to differences in experimental design methods, included populations, and disease severity among the original studies. Although we performed heterogeneity source analysis, there may still be other factors affecting heterogeneity that were not considered.

Conclusion

In conclusion, the FVIII/PC ratio not only reflects the severity of liver disease, but also can be used as one of the predictors of PVT development.

Data availability

The datasets supporting the conclusions of this article are included in the article.

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Acknowledgements

We are grateful for the useful comments and suggestions from anonymous referees.

Funding

This study was supported by Natural Science Foundation of Hebei province (Grant No. H2023206042).

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  1. Department of Infectious Diseases, the Hebei Medical University Third Hospital, Shijiazhuang, 050051, China

    Zhinian Wu, Ying Xiao, Zeqiang Qi, Tingyu Guo, Hua Tong & Yadong Wang

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Contributions

All authors meet the ICMJE authorship criteria. Zhinian Wu and Ying Xiao accessed the literature and wrote the article. Zeqiang Qi and Tingyu Guo is responsible for reviewing the screened literatures. Hua Tong was responsible for performing statistical calculations on the data. Yadong Wang is the corresponding author and critically reviewed and revised the manuscript. All authors wrote the manuscript and approved this version of the submitted manuscript.

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Wu, Z., Xiao, Y., Qi, Z. et al. Effect of factor VIII and FVIII/PC ratio on portal vein thrombosis in liver cirrhosis: a systematic review and meta‑analysis. BMC Gastroenterol 24, 320 (2024). https://doi.org/10.1186/s12876-024-03399-1

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