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ORIGINAL ARTICLE
Year : 2020  |  Volume : 18  |  Issue : 3  |  Page : 158-164

Von-Willebrand factor: A biomarker to predict in-hospital survival in patients with severe and very severe alcoholic hepatitis


1 Department of Hepatology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Transfusion Medicine and Immunohematology, Christian Medical College, Vellore, Tamil Nadu, India
3 Division of GI Sciences, Wellcome Research Unit, Christian Medical College, Vellore, Tamil Nadu, India
4 Department of Haematology, Haemostasis Research Unit, University College London, London, United Kingdom
5 Liver Unit, University Hospitals Birmingham, Birmingham, United Kingdom

Date of Submission28-Apr-2020
Date of Decision22-May-2020
Date of Acceptance04-Jun-2020
Date of Web Publication10-Jul-2020

Correspondence Address:
Dr. C E Eapen
Department of Hepatology, Christian Medical College, Vellore, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmi.cmi_68_20

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  Abstract 


Objectives: The aim of this study is to assess the utility of plasma von-Willebrand factor (VWF) levels in predicting in-hospital survival for patients with severe alcoholic hepatitis. Methods: From a prospectively collected database of acute-on-chronic liver failure (ACLF) patients, we retrospectively selected all severe alcoholic hepatitis (discriminant function [DF] ≥32) patients and correlated baseline plasma VWF (antigen, Ag and collagen-binding activity [CBA]) levels with disease severity. In-hospital survival was classified as discharged alive (or) died/discharged in a terminal condition (poor outcome). Results: Of 34 consecutive severe alcoholic hepatitis patients (age: 40.5, 30–63 years; median, range, hospital stay: 6, 2–15 days) studied, 15 had a poor outcome. Plasma VWF-CBA was higher in patients with poor outcome (736 [396–1157] IU/dL) as compared to patients discharged in stable state (492 [97–986] IU/dL; P = 0.03). VWF-CBA correlated well with VWF-Ag, model for end-stage liver disease (MELD) score, sequential organ failure assessment score and ACLF grades. AUROC to predict composite poor outcome was similar for plasma VWF-CBA (0.72, 0.54–0.89) and MELD score (0.71, 0.53–0.89). Plasma VWF-CBA was higher in 23 “very severe” alcoholic hepatitis (DF >60 or MELD >30) patients. Combining plasma VWF-CBA (>750 IU/dL) and criteria for “very severe” alcoholic hepatitis had a sensitivity of 100% (81%–100%) and negative predictive value of 100% (68%–100%) for predicting poor outcome. Conclusions: Plasma VWF levels are markedly elevated, correlate with organ failure, and predict in-hospital survival in severe alcoholic hepatitis, and also in “very severe” alcoholic hepatitis, patients.

Keywords: Acute-on-chronic liver failure, Endothelium, microangiopathy


How to cite this article:
Tiwari PS, Prasanna K S, Gandhi P B, Nair S C, Amirtharaj G J, Balasubramanian K A, Ramachandran A, Mackie I, Zachariah U, Elias E, Eapen C E, Goel A. Von-Willebrand factor: A biomarker to predict in-hospital survival in patients with severe and very severe alcoholic hepatitis. Curr Med Issues 2020;18:158-64

How to cite this URL:
Tiwari PS, Prasanna K S, Gandhi P B, Nair S C, Amirtharaj G J, Balasubramanian K A, Ramachandran A, Mackie I, Zachariah U, Elias E, Eapen C E, Goel A. Von-Willebrand factor: A biomarker to predict in-hospital survival in patients with severe and very severe alcoholic hepatitis. Curr Med Issues [serial online] 2020 [cited 2020 Sep 26];18:158-64. Available from: http://www.cmijournal.org/text.asp?2020/18/3/158/289423




  Introduction Top


The high short-term mortality in patients with severe alcoholic hepatitis is a challenge in contemporary practice of medicine.[1] National Institute on Alcohol Abuse and Alcoholism Consortium on Alcoholic Hepatitis recently emphasized the need to use standard definitions and to stratify disease severity for implementing clinical trials in alcoholic hepatitis.[2]

At present, most scoring systems to stratify the severity of alcoholic hepatitis utilize serum bilirubin, prothrombin time (PT)/international normalized ratio (INR), serum creatinine, or age and combining data from these scores appear to best predict the outcome.[3] Discriminant function (DF) and model for end-stage liver disease (MELD) scores are recommended to stratify the severity of alcoholic hepatitis. Patients with severe alcoholic hepatitis (i.e., with DF ≥32 or MELD score >20) have 20%–50% mortality at 1 month.[2] Disease severity in severe alcoholic hepatitis patients can be further stratified. Patients with “very severe” alcoholic hepatitis (DF >60 or MELD >30) have poorer survival.[2] Severity (grade) of acute-on-chronic liver failure (ACLF) predicts mortality in patients with severe alcoholic hepatitis; thus, ACLF grade is yet another way to stratify by disease severity.[4]

Identifying newer biomarkers/predictors of survival in severe alcoholic hepatitis patients may help better tailor currently available treatments as well as uncover newer pathophysiological mechanisms, which in turn may offer newer therapeutic targets.

The marked inflammatory response typical of severe alcoholic hepatitis may activate the endothelium and lead to the release of endothelial proteins. von-Willebrand factor (VWF) is a multimeric glycoprotein secreted mainly from endothelium. VWF sub-units (multimers) have receptors for binding to platelets or to collagen. VWF has an important role in primary hemostasis. The deficiency of VWF (called von-Willebrand disease) is the most common inherited bleeding disorder worldwide.[5] On the contrary, increased plasma VWF levels are risk factors for thrombotic disorders such as ischemic strokes and myocardial infarction.[6],[7]

In a systematic review of 765 chronic liver disease patients of different etiologies (cirrhosis: 715 patients; ACLF: 50 patients) from six studies, we found raised plasma VWF levels correlated with MELD score and predicted death. In patients with cirrhosis, the optimal cutoff level of plasma VWF antigen was 318% (216%–390%; median, range) to predict survival over 25.6 months (23.6–33 months). In contrast, in ACLF patients, plasma VWF collagen-binding activity (CBA) of 712% predicted survival (sensitivity: 48%; specificity: 86%) over a median follow-up of 7 days. This prognostic value of VWF was independent of the MELD score. Thus, compared to cirrhosis patients, endothelial activation (reflected by raised plasma VWF levels) is more pronounced in ACLF patients and is associated with drastic truncation of survival.[8] Elevated plasma VWF levels are almost equal to MELD scores in predicting survival in patients with cirrhosis,[8] ACLF,[9] and acute liver injury/failure.[10]

To date, the prognostic value of VWF levels has not been studied specifically in patients with severe alcoholic hepatitis. From a cohort of ACLF patients, in whom we reported the predictive value of raised plasma VWF levels,[9] we selected patients with severe alcoholic hepatitis for this study. The aims of the current study of severe alcoholic hepatitis patients were to analyze plasma VWF levels, correlate these with liver disease severity scores and assess its prognostic ability in the entire patient cohort and in patients in different categories of disease severity.


  Methods Top


From a prospectively collected database, we retrospectively analyzed the data of consecutive patients hospitalized in our department from October 1st, 2014 to March 31st, 2015, who fulfilled the criteria of severe alcoholic hepatitis. The study particiants were recruited for the original study after obtaining their informed consent.[9] Patients with hepatocellular carcinoma, portal vein thrombosis were excluded. Pregnant women and children were also excluded.

Diagnosis of alcoholic hepatitis

We used the following criteria to diagnose alcoholic hepatitis: the presence of new-onset/worsening jaundice in a patient with heavy alcohol intake till 2 months before the onset of jaundice, bilirubin >3 mg% and the ratio of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) of >1.5, AST >50 IU/L, with both AST and ALT <400 IU/L. A diagnosis made by these clinical criteria without other confounding etiologies of liver diseases is termed “probable” alcoholic hepatitis, while the presence of confounding etiologies is termed “possible” alcoholic hepatitis. If the liver biopsy shows features of alcoholic hepatitis, it is termed “definite” alcoholic hepatitis.[2]

Plasma von-Willebrand factor assays

Plasma VWF was assayed using CBA (VWF-CBA), and antigen (VWF-Ag) assays in all study patients at admission to hospital. Peripheral blood was collected using 0.109M citrate anticoagulant and centrifuged (2500 g for 15 min, 4°C). Separated plasma was aliquoted and stored frozen at −80°C till assay. Plasma VWF antigen was measured by an ELISA Kit (Zymutest vWF catalog no. RK 030 A Hyphen BioMed, France).[11] The collagen-binding activity of VWF was measured using an ELISA Kit (Zymutest vWF: CBA catalog no. RK 038 A Hyphen BioMed, France) using microwells coated with fibrillar collagen Types I and III.[12] Normal values for both plasma VWF antigen and activity were 50 −150 IU/dL.

Stratifying liver disease severity

In the study patients, liver disease severity was assessed by the MELD score and grade of ACLF (as per the European Association for the Study of the Liver–Chronic Liver Failure (EASL-CLIF) consortium definition).[13] Patients with DF ≥32 or MELD score >20 were classified as very severe alcoholic hepatitis, and patients with either MELD >30 or DF >60 were classified as very severe alcoholic hepatitis.[2] Organ failure was assessed using the Sequential Organ Failure Assessment (SOFA) score.[14]

Defining in-hospital survival

We categorized survival at the end of the hospital stay into discharged alive (good outcome) and died/underwent liver transplantation/discharged in terminal condition (poor outcome). In India, many patients pay for medical expenses out of their own resources (i.e., they are not funded by the state nor by insurance). Patients managed in our department mainly come from the lower or middle socioeconomic class.[15] In such resource-constrained settings, it is common practice for families/attendants of patients who are becoming worse/moribund despite treatment, to take the patient home in terminal condition for palliative care at a hospital near their home or at home.

Statistical analysis

We analyzed plasma VWF levels in all patients with severe alcoholic hepatitis and in the subset with “very severe” alcoholic hepatitis. Plasma VWF levels were correlated with routine tests of coagulation and parameters of the severity of liver disease and of organ failure. Plasma VWF assays as a predictor of poor outcome were also assessed in the study patients.

Continuous variables were expressed as median with range and discrete variables as numbers and percentages. Continuous variables were compared using Mann–Whitney U-test/Wilcoxon signed-rank and discrete variables by Chi-squared test or Fischer's exact test as relevant. Bivariate correlation was assessed by Pearson's correlation coefficient. Univariate ordinal regression was done to analyze the ability of variables to predict the baseline grade of ACLF. Extended Mantel-Haenszel Chi-square for linear trend was used to assess the combined effect of liver disease severity criteria and VWF in predicting outcome. Multivariate logistic regression was done to assess independent factors affecting survival. The receiver operating characteristic (ROC) curve was used to assess the sensitivity and specificity of plasma VWF as a predictor of composite poor outcome. Statistical Package for the Social Sciences (IBM Corp. Released 2018. IBM SPSS, Version 25.0.0.0, Armonk, NY, USA) was used for the statistical analysis. A two-sided P < 0.05 was considered significant.

The study was approved by the institutional review board and ethics committee.


  Results Top


Demographics and baseline laboratory data [Table 1]
Table 1: Baseline laboratory data and disease severity scores in patients with severe alcoholic hepatitis

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Of the 34 patients with severe alcoholic hepatitis (all male; age: 40.5 years, 30–63 years; median, range) studied, 29 patients had “probable” alcoholic hepatitis and 5 patients had “possible” alcoholic hepatitis (the latter 5 patients had exposure to alternative medication: 2 patients, chronic hepatitis B: 1; acute hepatitis E: 1 and swine flu: 1; modest elevation of serum AST : 90 U/L, 83–227 U/L, serum ALT : 26 U/L, 10–55 U/L and the ratio of serum AST: ALT of >1.5 suggesting alcoholic hepatitis as the predominant insult). No patient had liver biopsy. All study patients had DF ≥32.

In the 29 patients with “probable” severe alcoholic hepatitis, baseline MELD score, VWF-CBA, VWF-Ag and DF were 29 (19–49), 611 (97–1157) IU/dL, 742 (311–1347) IU/dL, and 69 (32–143) respectively.

All 34 severe alcoholic hepatitis patients had standard medical treatment. In addition, one patient received steroids; none received N acetylcysteine, and seven received pentoxifylline. No patient underwent liver transplantation. The length of hospital stay in these 34 patients was 6 days (2–15 days).

Twenty-six (77%) patients had hepatic encephalopathy, all had raised PT (INR ≥1.5), and serum creatinine was raised (>1.4 mg/dl) in 19 (56%) patients at presentation. Nineteen patients (56%) were discharged in a stable condition (hospital stay 8 days, 4–21 days; median, range), while 15 (44%) had poor outcome (8 patients died after hospital stay of 6.5, 3–12 days; 7 patients were discharged in terminal condition after hospital stay of 5, 2–11 days). [Table 1] compares various disease severity parameters in patients with or without favorable outcome.

Ratio of VWF-CBA: VWF-Ag in 34 study patients was 0.78 (0.15–1.47). VWF-CBA: VWF-Ag ratio was concordant (i.e., ratio ranging from 0.7 to 1.2) in 24 patients and discordant in 10 patients (this ratio was <0.7 in 9 patients and >1.2 in 1 patient).

Correlation of baseline plasma von-Willebrand factor collagen-binding activity level with von-Willebrand factor antigen level, routine coagulation parameters, organ failure (sequential organ failure assessment score) and liver disease severity (model for end-stage liver disease, discriminant function, acute-on-chronic liver failure grade) scores

Plasma VWF-CBA showed excellent correlation with plasma VWF-Ag level (r = 0.73; P < 0.001). There was no significant correlation of plasma VWF-CBA with routine coagulation parameters (platelets, INR, and APTT-data not shown), or with DF score (r = 0.16, P = 0.38).

There was a moderate but significant positive correlation of baseline plasma VWF-CBA with SOFA score (r = 0.43; P = 0.01) and with MELD score (r = 0.33; P = 0.06).

Of the 34 severe alcoholic hepatitis patients, at baseline, 9 patients fulfilled criteria for ACLF Grade 1, 7 for ACLF grade 2 and 6 for ACLF Grade 3. Twelve patients were classified as Grade 0 as per EASL-CLIF definition. Coagulation parameters worsened, and plasma VWF levels increased with an increase in grade of ACLF [Table 2].
Table 2: Plasma von Willebrand factor levels and routine coagulation tests in different grades of acute-on-chronic liver failure severity in patients with severe alcoholic hepatitis

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Baseline plasma von-Willebrand factor level in severe alcoholic hepatitis patients with good outcome compared to those with poor outcome

Baseline plasma VWF-CBA was significantly higher in patients with poor outcome (736 (396–1157) IU/dL, median (range)) compared to those discharged in stable condition (492 (97–986) IU/dL; P = 0.02) [Table 1]. Plasma VWF-Ag, although higher in patients with poor outcome (742 (516–1347) IU/dL compared to those discharged in stable condition (740 [311–1082] IU/dL; P = 0.15), did not reach statistical significance.

Baseline plasma von-Willebrand factor level as predictor of in-hospital survival in 34 severe alcoholic hepatitis patients

On multivariate logistic regression analysis, adjusting for the MELD score, baseline plasma VWF-CBA showed a trend toward predicting the poor outcome (adjusted hazard ratio 1.003; 95% confidence interval [CI]: 1–1.006; P = 0.08).

AUROC for plasma VWF assays showed good accuracy for predicting poor outcome. As predictor of in-hospital survival, plasma VWF assays were much better than PT (INR), APTT and platelets and were similar to MELD score [Figure 1]. Plasma VWF-CBA of 500 IU/dL had sensitivity of 80% (95% CI: 58%–94%) and specificity of 53% (36%–64%) in predicting poor outcome. The specificity was 100% (88%–100%) at VWF-CBA of 1000 IU/dL, although with a lower sensitivity of 27% (11%–27%). Optimal cutoff for plasma VWF-CBA to predict poor outcome was 750 IU/dL (sensitivity: 40%, 21%–49% and specificity: 90%, 74%–98%).
Figure 1: Receiver operating curve depicting utility of plasma VWF assays, as compared to MELD score, DF and routine tests of coagulation in predicting poor outcome in patients with severe alcoholic hepatitis. VWF: Von Willebrand factor, aPTT: Activated partial thromboplastin time, DF: Discriminant function, MELD: Model for end-stage liver disease, PT-INR: Prothrombin time-international normalized ratio, VWF-Ag: Von Willebrand factor antigen, VWF-CBA: Von Willebrand factor collagen binding activity.

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Predictive ability of plasma von-Willebrand factor levels in 23 patients with “very severe” alcoholic hepatitis [Table 3]
Table 3: Plasma von-Willebrand factor levels and routine coagulation tests in different grades of the severity of alcoholic hepatitis

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23/34 patients (age: 40, 30–58 years) with “very severe” alcoholic hepatitis had baseline MELD score, SOFA score, DF score, VWF-CBA, and VWF-Ag-34 (25–49), 8 (5–14), 83 (44–143), 680 (116–1157) IU/dL, and 740 (369–1347) IU/dL, respectively. Thirteen patients (57%) with “very severe” alcoholic hepatitis as compared to 2/11 (18%) patients with severe alcoholic hepatitis (not “very severe”) had poor outcome (P = 0.06). To predict in-hospital survival, criteria for “very severe” alcoholic hepatitis had sensitivity of 87% (66%–98%), specificity of 47% (31%–56%), negative predictive value of 82% (53%–97%), and positive predictive value of 57% (43%–64%).

[Table 3] depicts baseline severity parameters in “very severe” alcoholic hepatitis and the other severe alcoholic hepatitis (not “very severe”) patients. Plasma VWF assays, MELD score, and DF did not predict poor outcome in these patients (data not shown). SOFA score had an AUROC of 0.78 (95% CI: 0.56–1) in predicting poor outcome in “very severe” alcoholic hepatitis patients.

All 9 patients, with both plasma VWF-CBA <750 IU/dL and severe alcoholic hepatitis (not “very severe”), were discharged in stable state. Of the 19 patients with either plasma VWF-CBA >750 IU/dL or “very severe” alcoholic hepatitis, 11 (58%) had poor outcome. 4/6 patients with both plasma VWF-CBA >750 IU/dL and “very severe” alcoholic hepatitis had poor outcome [P = 0.01, [Figure 2].
Figure 2: Graph showing proportion of patients with poor outcome in severity groups based on combination of plasma VWF-CBA (>750 IU/dL) and very severe alcoholic hepatitis criteria. VWF-CBA: Von Willebrand factor collagen-binding activity.

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Thus, 15/25 (60%) patients with at least one of these two unfavorable parameters (plasma VWF-CBA >750 IU/dL and criteria for “very severe” alcoholic hepatitis), had a poor outcome. To predict outcome, combining plasma VWF-CBA >750 IU/dL and criteria for “very severe” alcoholic hepatitis had a sensitivity of 100% (81%–100%), specificity of 47% (32%–47%), negative predictive value of 100% (68%–100%), and positive predictive value of 60% (48%–60%).


  Discussion Top


The key finding of this study is the identification of a new biomarker to predict prognosis in severe alcoholic hepatitis patients. This new biomarker (plasma VWF) is not included in the currently used scoring systems to stratify disease severity and predict survival in severe alcoholic hepatitis patients. We found plasma VWF-CBA to be as accurate as MELD scores and better than DF score in predicting in-hospital survival in these patients.

Median plasma VWF CBA level was four-fold raised above ULN in the 34 severe alcoholic hepatitis patients studied [Table 1]. Plasma VWF-CBA levels had excellent correlation with plasma VWF-Ag levels (r = 0.73) and had moderate correlation with MELD (r = 0.33) and SOFA scores (r = 0.43) in these patients. Increasing plasma VWF levels were seen in severe alcoholic hepatitis patients with increasing disease severity [Table 2] and [Table 3]. Median plasma VWF-CBA level was approximately 4.5-fold raised above ULN in “very severe” alcoholic hepatitis patients compared to three-fold raised above ULN in patients without “very severe” alcoholic hepatitis.

Of the various static scores to predict short-term survival in patients with alcoholic hepatitis,[16] DF ≥of 32 is conventionally utilized to diagnose severe alcoholic hepatitis.[2] Of the patients with severe alcoholic hepatitis, the 1-month mortality differs widely: 13%–19% in STOPAH trial from West,[17] to 20%–50% in studies from the Indian subcontinent.[18],[19],[20] Relatively later presentation and greater degree of malnutrition in patients from India may explain these differences in survival. To further homogenize the risk estimate, “very severe” alcoholic hepatitis was proposed.[2] In the current study, we noted significantly less in-hospital survival in patients with “very severe” alcoholic hepatitis compared to severe (but not “very severe”) alcoholic hepatitis patients.

Elevated baseline plasma VWF-CBA (>750 IU/dL) and fulfillment of criteria for “very severe” alcoholic hepatitis had an additive role in the prediction of in-hospital survival in patients with severe alcoholic hepatitis [Figure 2]. No patient with both parameters (plasma VWF-CBA and criteria for “very severe” alcoholic hepatitis) favorable had an adverse outcome, compared to 67% of patients with both these parameters being unfavorable. 15/15 (100%) patients with composite poor outcome had at-least one of these two parameters unfavorable. The addition of plasma VWF-CBA (>750 IU/dL) to criteria for “very severe” alcoholic hepatitis increased its sensitivity and negative predictive value, without compromising the specificity and positive predictive value.

On day 1 of hospital stay, plasma VWF-CBA level was as accurate as the MELD score to predict in-hospital survival in the 34 severe alcoholic hepatitis patients. Routine coagulation tests (platelets, PT/INR, APTT) neither correlate with plasma VWF level nor predict in-hospital survival in severe alcoholic hepatitis patients. On multivariate logistic regression analysis, plasma VWF-CBA tended to predict composite poor outcome, independent of the MELD score.

The hemostatic activity of VWF protein, probably through its ability to bind platelets and to bind (sub-endothelial) collagen, is determined by VWF multimer size. VWF protein in circulation is in different molecular weights– low-molecular-weight multimers (1–5 units, 500–2500 kDa in size), intermediate-sized multimers (6–10 units, 3000–5000 kDa) and high molecular weight multimers (11–20 units, 5500–10,000 kDa). Of the VWF multimers in circulation in the physiological state, high-molecular-weight multimers have the highest hemostatic activity.[21]

The multiple assays to measure plasma VWF levels have different sensitivities to detect the different VWF forms– VWF-Ag detects all the different sizes of VWF multimers, while VWF-CBA reflects the presence of high-molecular-weight VWF multimers.[22] The main use of these different assays at present is to diagnose and classify deficiency of VWF (i.e., von-Willebrand disease). For example, VWF-CBA to VWF-Ag ratio in plasma is the best test to diagnose functional defect of VWF protein leading von-Willebrand disease Type 2A.[23],[24] It is unclear whether discordance between levels of plasma VWF-CBA and VWF-Ag reflects high-molecular-weight VWF multimers in situ ations of raised plasma VWF levels, as in some of our patients with severe alcoholic hepatitis, and needs to be studied further.

Why is the four-fold increase in plasma VWF levels associated with marked truncation of short-term survival in these severe alcoholic hepatitis patients? We speculate that in patients with severe alcoholic hepatitis, the adhesive property of VWF protein (to platelet and to sub-endothelial collagen), which increases with VWF multimer size, may predispose to microcirculatory occlusion in the liver and other vital organs, may decrease perfusion of affected vital organs, predispose to worsening liver failure, multi-organ failure, and eventual death.[25],[26] The role of VWF in the progression of liver failure and potential VWF lowering treatments in these difficult to treat patients needs to be further studied. Plasma exchange and other VWF lowering treatments are being explored in patients with acute liver injury/failure and ACLF.[10],[27]

This study is limited in the number of patients, short follow-up duration, and lack of serial plasma VWF measurements. In this exploratory study, we demonstrate plasma VWF as a useful static predictor of short-term survival in patients with severe alcoholic hepatitis and also “very severe” alcoholic hepatitis. Further studies are required to confirm this role and also explore plasma VWF as marker of prognosis in other etiologies of liver failure.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Research quality and ethics statement

The authors of this manuscript declare that this scientific work complies with reporting quality, formatting, and reproducibility guidelines set forth by the EQUATOR Network. The authors also attest that this clinical investigation was determined to require Institutional Review Board/Ethics Committee review, and the corresponding protocol/approval number is IRB Min No: 9146 dated November 12, 2014. We also certify that we have not plagiarized the contents in this submission and have done a Plagiarism Check.



 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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