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Clinical significance of substantially elevated von Willebrand factor antigen levels in patients with advanced chronic liver disease

  • Katharina Pomej
    Affiliations
    Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
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  • Bernhard Scheiner
    Affiliations
    Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
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  • Lorenz Balcar
    Affiliations
    Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
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  • Rosa Johanna Nussbaumer
    Affiliations
    Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
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  • Johanna Weinzierl
    Affiliations
    Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
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  • Rafael Paternostro
    Affiliations
    Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
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  • Benedikt Simbrunner
    Affiliations
    Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria

    Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
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  • David Bauer
    Affiliations
    Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
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  • David Pereyra
    Affiliations
    Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
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  • Patrick Starlinger
    Affiliations
    Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
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  • Albert Friedrich Stättermayer
    Affiliations
    Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
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  • Matthias Pinter
    Affiliations
    Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
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  • Michael Trauner
    Affiliations
    Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
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  • Peter Quehenberger
    Affiliations
    Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
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  • Thomas Reiberger
    Correspondence
    Corresponding author.
    Affiliations
    Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria

    Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
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  • Mattias Mandorfer
    Affiliations
    Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
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Open AccessPublished:July 21, 2022DOI:https://doi.org/10.1016/j.dld.2022.06.010

      Abstract

      Background

      Von Willebrand factor antigen (VWF) is a non-invasive marker for clinically significant portal hypertension (HVPG≥10 mmHg) and confers HVPG-independent prognostic information. While quantification of increased VWF-levels is not relevant in the context of von Willebrand disease, highly elevated VWF may be of clinical significance in ACLD. Thus, we have modified our analytical approach to quantify very high VWF-levels (i.e.,>420%) and investigated their prognostic value.

      Methods

      Patients undergoing HVPG-measurement at the Vienna Hepatic Hemodynamic Lab with evidence of ACLD and information on VWF were considered. Clinical stages (CS) were defined as follows: Probable compensated ACLD (cACLD): LSM≥10kPa&HVPG<6 mmHg; 0: cACLD&6–9 mmHg; 1: cACLD&HVPG≥10 mmHg; 2: bleeding; 3: non-bleeding decompensation; 4: ≥2 decompensations.

      Results

      124 (16%) of 793 patients had VWF>420%. The proportion of VWF>420% increased with disease severity (probable cACLD-0: 5(4%) vs. 1: 22(10%) vs. 2–4: 97(23%),p ≤ 0.001) as well as across HVPG (<6mmHg: 1(2%) vs. 6–9: 6(6%) vs. 10–15: 17(9%) vs. ≥16: 100(22%),p ≤ 0.001) and MELD (<10: 17(6%) vs. 10–14: 27(10%) vs. ≥15: 79(32%),p ≤ 0.001) strata. In patients with VWF>420%, median VWF was 533 (IQR:466–611)% and VWF was unrelated to HVPG (Spearman's ρ=0.139,p = 0.123), but showed direct correlations of weak/moderate strength with MELD (ρ=0.336,p < 0.001) and CRP (ρ=0.286,p = 0.001). In the subgroup with VWF>420%, VWF was predictive of decompensation/liver-related mortality (VWF per 10%; hazard ratio (HR): 1.02(95% confidence interval (95%CI): 1.01–1.04),p = 0.008, even after adjusting for other factors (VWF per 10%; adjusted HR: 1.02(95%CI: 1.00–1.05),p = 0.031).

      Conclusion

      The proportion of patients with substantially elevated VWF values steadily increases with disease progression. While VWF is not reflective of HVPG in these patients, it is correlated with hepatic dysfunction and systemic inflammation. Importantly, quantification of high values provides prognostic information.

      Keywords

      1. Introduction

      Elevated levels of von Willebrand factor antigen (VWF) are a common haemostatic alteration in patients with advanced chronic liver disease (ACLD) [
      • Ferro D.
      • Quintarelli C.
      • Lattuada A.
      • et al.
      High plasma levels of von Willebrand factor as a marker of endothelial perturbation in cirrhosis: relationship to endotoxemia.
      ,
      • Albornoz L.
      • Alvarez D.
      • Otaso J.C.
      • et al.
      Von Willebrand factor could be an index of endothelial dysfunction in patients with cirrhosis: relationship to degree of liver failure and nitric oxide levels.
      .
      Von Willebrand factor (VWF) is a multimeric adhesive protein, which is released by endothelial cells and is responsible for linking the subendothelium with platelets, if vascular injury has occurred [
      • Randi A.M.
      • Laffan M.A.
      Von Willebrand factor and angiogenesis: basic and applied issues.
      ,
      • Groeneveld D.J.
      • Poole L.G.
      • Luyendyk J.P.
      Targeting von Willebrand factor in liver diseases: a novel therapeutic strategy?.
      . In patients with ACLD, elevated levels of VWF are considered a consequence of endothelial perturbation due to hemodynamic changes and bacterial translocation/systemic inflammation [
      • Ferro D.
      • Quintarelli C.
      • Lattuada A.
      • et al.
      High plasma levels of von Willebrand factor as a marker of endothelial perturbation in cirrhosis: relationship to endotoxemia.
      ,
      • Lisman T.
      • Bongers T.N.
      • Adelmeijer J.
      • et al.
      Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity.
      . VWF is reflective of the presence/severity of portal hypertension and increasingly used as a non-invasive test (NIT) for clinically significant portal hypertension (CSPH, HVPG ≥10 mmHg), i.e., the threshold for the development of complications [
      • Reiberger T.
      • Schwabl P.
      • Trauner M.
      • Peck-Radosavljevic M.
      • Mandorfer M.
      Measurement of the hepatic venous pressure gradient and transjugular liver biopsy.
      ]. Thus, VWF levels predict the development of common complications of ACLD, i.e., ascites and related complications as well as variceal bleeding [
      • Ferlitsch M.
      • Reiberger T.
      • Hoke M.
      • et al.
      von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis.
      ,
      • Scheiner B.
      • Balcar L.
      • Paternostro R.
      • et al.
      Von Willebrand factor for outcome prediction within different clinical stages of advanced chronic liver disease.
      . However, the prognostic relevance of VWF levels seems to extend beyond its association with CSPH, as VWF predicts clinical events in hepatic venous pressure gradient (HVPG)-independent manner [
      • La Mura V.
      • Reverter J.C.
      • Flores-Arroyo A.
      • et al.
      Von Willebrand factor levels predict clinical outcome in patients with cirrhosis and portal hypertension.
      ,
      • Mandorfer M.
      • Schwabl P.
      • Paternostro R.
      • et al.
      Von Willebrand factor indicates bacterial translocation, inflammation, and procoagulant imbalance and predicts complications independently of portal hypertension severity.
      and may reflect non-hemodynamic effects of non-selective betablockers (NSBB).
      Von Willebrand disease – one of the most common inherited bleeding disorders and the main conventional indication for VWF testing – is characterized by low/absent VWF levels. Importantly, quantification of increased levels of VWF has no clinical relevance in this context. However, the situation differs in ACLD patients, in whom substantially elevated levels of VWF (i.e., >420%) are common and may be of prognostic/clinical significance. Thus, we have modified our analytical approach and quantified very high VWF levels in a large cohort of ACLD patients undergoing HVPG measurement to investigate (i) the prognostic value of highly elevated VWF levels and (ii) their correlation with HVPG, markers of hepatic dysfunction, and inflammation.

      2. Materials and methods

      2.1 Study design and patients

      We retrospectively included patients with evidence of ACLD and information on von Willebrand factor antigen (VWF) levels undergoing hepatic venous pressure gradient (HVPG) measurement at the Vienna Hepatic Hemodynamic Lab between September 2003 and December 2020. Eligible patients were adults (≥18 years). Patients were excluded for the following reasons: history of orthotopic liver transplantation (OLT); presence of porto-sinusoidal venous vascular disease (PSVD)/idiopathic non-cirrhotic portal hypertension (INCPH) or absence of ACLD (i.e., LSM <10 kPa in the absence of an HVPG ≥6 mmHg); hepatocellular carcinoma or any other active malignancy; presence of PVT or anticoagulant or anti-platelet therapy; missing information on C-reactive protein (CRP) or evidence of bacterial infection, HVPG unavailable/unreliable; absence of information on VWF. The remaining patients were included into the prevalence cohort of our analysis. Patients with VWF levels >420% are being referred to as the group of patients with substantially elevated VWF values. For the outcome cohort, patients in whom substantially elevated VWF levels have not been quantified after pre-dilution for logistical/capacity reasons were additionally excluded.

      2.2 Clinical stages of ACLD

      Based on the definition of prognostic/clinical stages proposed by D'Amico et al. [
      • D'Amico G.
      • Morabito A.
      • D'Amico M.
      • et al.
      Clinical states of cirrhosis and competing risks.
      ], patients were classified into compensated ACLD (cACLD), defined by the absence of any decompensation event, and decompensated ACLD (dACLD), as indicated by history of/presence of at least one decompensation event, i.e., ascites/spontaneous bacterial peritonitis (SBP), variceal bleeding, or hepatic encephalopathy (HE). In detail, clinical stages (CS) of patients with cACLD were defined as follows: probable cACLD including patients with liver stiffness measurement (LSM) ≥10 kPa and HVPG <6 mmHg, CS0 including cACLD with subclinical portal hypertension (HVPG 6–9 mmHg) and CS1 with cACLD and CSPH (HVPG ≥10 mmHg). Patients with dACLD were also divided into 3 sub-stages which were defined as: CS2 – patients with a history of acute variceal bleeding; CS3 –those with one non-bleeding decompensation; CS4 – patients with at least two decompensating events.

      2.3 HVPG measurement

      HVPG measurement was performed according to a published protocol [
      • Reiberger T.
      • Schwabl P.
      • Trauner M.
      • Peck-Radosavljevic M.
      • Mandorfer M.
      Measurement of the hepatic venous pressure gradient and transjugular liver biopsy.
      ] in fasting condition and in the absence of non-selective betablocker or nitrate therapy. In brief, an internal jugular vein was punctured under local anesthesia and ultrasound guidance in order to insert a catheter introducer sheath. After cannulation of a large hepatic vein, the free and the wedged hepatic venous pressures were obtained using a specifically designed balloon catheter [
      • Ferlitsch A.
      • Bota S.
      • Paternostro R.
      • et al.
      Evaluation of a new balloon occlusion catheter specifically designed for measurement of hepatic venous pressure gradient.
      ]. The hepatic venous pressure gradient was calculated by subtracting the free from the wedged hepatic venous pressure. The mean of three measurements was recorded and used for further analyses.

      2.4 Assessment of VWF levels

      Blood samples for performing laboratory tests were obtained at the time of HVPG measurement. VWF was measured by an immuno-turbidimetric assay (STA LIATEST VWF:Ag) on a STA-R Evolution (both DIAGNOSTICA STAGO S.A.S., Asnières sur Seine, France) analyzer. As the VWF assay used by our ISO-certified Department for Laboratory Medicine has a measurement range of up to 420%, this value was used as a cut-off for the assignment of patients to the substantially elevated VWF levels group of. In order to quantify values >420%, the respective samples were prediluted 1:20 with Owren-Koller buffer.

      2.5 Statistical analyses

      Statistical analyses were performed using IBM SPSS Statistics 26 (SPSS Inc., Armonk, New York, USA) and GraphPad Prism 8 (GraphPad Software, La Jolla, California, USA). Continuous variables were reported as mean ± standard deviation (SD) or median (interquartile range; IQR), and categorical variables were shown as numbers (n) and proportions (%) of patients. Group comparisons of normally distributed variables were calculated by using Student's t-test, while Mann-Whitney-U-test was used for non-normally distributed variables. Group comparisons of categorical variables were performed using Pearson's Chi-squared test or Fisher's exact test. The Kaplan-Meier method was used for calculation of time-dependent event rates and groups were compared by applying the log-rank test. Cox regression analysis was performed to evaluate parameters associated with the events of interest. The composite endpoint hepatic decompensation/liver-related mortality accounts for the rare occasion that the specific hepatic decompensation event preceding a liver-related death was insufficiently documented or the information could not be retrieved, due to limited access to the medical records of health care providers that are not part of the Vienna Hospital Association. Variables with a p-value <0.1 in univariable analysis were included along with those considered particularly relevant for the outcome of interest based on the previous literature. Spearman's correlation coefficient was used to assess correlations between VWF and markers of liver disease severity/systemic inflammation. A two-sided p-value <0.05 was considered statistically significant.

      3. Results

      3.1 Patient selection

      In total, 2550 patients underwent HVPG measurement at the Vienna Hepatic Hemodynamic Lab in the defined study period. Patient selection after application of in- and exclusion criteria is shown in Fig. 1A. Seven hundred and ninety-three patients were included in the prevalence cohort, while the outcome cohort comprised 772 patients.
      Fig 1
      Fig. 1(A) Patient flowchart and (B) number of patients within different CS. Abbreviations: AC, anticoagulation; ACLD, advanced chronic liver disease; anti-PLT, anti-platelet; cACLD, compensated advanced chronic liver disease; CRP, C-reactive protein; CS, clinical stage; CTP, Child-Turcotte-Pugh; dALCD, decompensated advanced chronic liver disease; HIV, human immunodeficiency virus; HVPG, hepatic venous pressure gradient; INCPH, idiopathic non-cirrhotic portal hypertension; LSM, liver stiffness measurement; OLT, orthotopic liver transplantation; PSVD, porto-sinusoidal venous disease; PVT, portal vein thrombosis; VWF, von Willebrand factor antigen.

      3.2 Prevalence of substantially elevated VWF levels (VWF >420%) and associated characteristics (prevalence cohort)

      In total, 124 out of 793 (16%) patients had VWF levels >420% with a median VWF of 533% (IQR: 466–611) (Table 1). In the subgroup of patients with substantially elevated VWF levels, the majority of patients had decompensated ACLD (97 (78%) vs. 334 (50%) among patients with VWF <420%, p < 0.001). Furthermore, patients with VWF >420% had more advanced liver disease as assessed by Child-Turcotte-Pugh (CTP) score (9 (IQR: 7–10) vs. 6 (IQR: 5–8), p < 0.001) and MELD (17 (IQR: 11–22) vs. 10 (8–14) points, p < 0.001), as well as more pronounced portal hypertension as indicated by HVPG (20 ± 6 vs. 16 ± 7 mmHg, p < 0.001), compared to the other patients included in our study. Accordingly, the proportion of patients with VWF >420% increased steadily with liver disease severity (probable cACLD: 1 (2%) vs. CS0: 4 (5%) vs. CS1: 22 (10%) vs. CS2: 6 (13%) vs. CS3: 36 (19%) vs. CS4: 55 (29%), p < 0.001) and across HVPG (<6 mmHg: 1 (2%) vs. 6–9: 6 (6%) vs. 10–15: 17 (9%) vs. ≥16: 100 (22%), p < 0.001) and MELD (<10 points: 17 (6%) vs. 10–14: 27 (10%) vs. ≥15: 79 (32%), p < 0.001) strata (Table 2, Fig. 2). Moreover, patients with VWF >420% showed increased levels of CRP (0.9 (IQR: 0.4–1.5) vs. 0.2 (0.1–0.6) mg/dL, p < 0.001) as a marker of systemic inflammation. Detailed patient characteristics are displayed in Table 1.
      Table 1Patient characteristics at the time of HVPG measurement and comparison between patients with low (<420%) and high (>420%) VWF levels in the prevalence cohort.
      Patient characteristics

      prevalence cohort
      All patients, n=793Patients with VWF <420%,

      n=669
      Patients with VWF >420%,

      n=124
      p-value
      N (%) and median (IQR) / mean ± SD
      Age, years53.2 ± 11.552.8 ± 11.655.2 ± 10.70.028
      Sex0.913
       Male521 (66%)439 (66%)82 (66%)
       Female272 (34%)230 (34%)42 (34%)
      Etiology<0.001
       ALD296 (37%)228 (34%)68 (55%)
       NAFLD77 (10%)69 (10%)8 (6%)
       Viral305 (38%)268 (40%)37 (30%)
       Other115 (15%)104 (16%)11 (9%)
      Varices463 (58%)371 (55%)92 (74%)0.004
      cACLD362 (46%)335 (50%)27 (22%)<0.001
      dACLD431 (54%)334 (50%)97 (78%)
      History of variceal bleeding139 (18%)108 (16%)31 (25%)0.018
      Ascites<0.001
       None448 (56%)410 (61%)38 (31%)
       Mild251 (32%)194 (29%)57 (46%)
       Severe94 (12%)65 (10%)29 (23%)
      History of/current overt hepatic encephalopathy181 (23%)134 (20%)47 (38%)<0.001
      ACLF35 (4%)22 (3%)13 (10%)<0.001
      CTP score, points6 (5-8)6 (5-8)9 (7-10)
       A406 (51%)381 (57%)25 (20%)<0.001
       B284 (36%)229 (34%)55 (44%)
       C103 (13%)59 (9%)44 (36%)
      MELD, points11 (9-16)10 (8-14)17 (11-22)<0.001
      HVPG, mmHg16 ± 716 ± 720 ± 6<0.001
      Platelet count, G x L –1104 (69-148)105 (71-157)98 (63-130)0.021
      Albumin, g x L –135.1 ± 6.235.8 ± 6.030.9 ± 6.0<0.001
      Bilirubin, mg x dL –11.2 (0.8-2.2)1.1 (0.8-1.8)2.5 (1.2-4.4)<0.001
      INR1.3 (1.2-1.5)1.3 (1.1-1.5)1.4 (1.3-1.7)<0.001
      CRP, mg x dL –10.3 (0.1-0.8)0.2 (0.1-0.6)0.9 (0.4-1.5)<0.001
      VWF, %302 (224-399)276 (210-352)533 (466-611)<0.001
      Abbreviations: ACLF, acute-on-chronic liver failure; ALD, alcoholic liver disease; cACLD, compensated advanced chronic liver disease; CRP, C-reactive protein; CS, clinical stage; CTP score, Child-Turcotte-Pugh score; dACLD, decompensated advanced chronic liver disease; HVPG, hepatic venous pressure gradient; INR, international normalized ratio; MELD, Model for end-stage liver disease; NAFLD, non-alcoholic fatty liver disease; VWF, von Willebrand factor antigen.
      Table 2Comparison of disease severity between patients with low (<420%) and high (>420%) VWF levels in the prevalence cohort.
      Patient characteristics

      prevalence cohort
      All patients, n=793Patients with VWF <420%,

      n=669
      Patients with VWF >420%,

      n=124
      p-value
      MELD, points<0.001
       <10280 (35%)263 (39%)17 (14%)
       10-14266 (34%)239 (36%)27 (22%)
       ≥15246 (31%)167 (25%)79 (64%)
      HVPG, mmHg<0.001
       HVPG <658 (7%)57 (8%)1 (1%)
       HVPG 6-996 (12%)90 (14%)6 (5%)
       HVPG 10-15183 (23%)166 (25%)17 (14%)
       HVPG ≥16456 (58%)356 (53%)100 (81%)
      Clinical stages<0.001
       Probable cACLD58 (7%)57 (8%)1 (1%)
       CS082 (10%)78 (12%)4 (3%)
       CS1222 (28%)200 (30%)22 (18%)
       CS245 (6%)39 (6%)6 (5%)
       CS3194 (25%)158 (24%)36 (29%)
       CS4192 (24%)137 (20%)55 (44%)
      Abbreviations: ACLF, acute-on-chronic liver failure; cACLD, compensated advanced chronic liver disease; CS, clinical stage; CTP score, Child-Turcotte-Pugh score; dACLD, decompensated advanced chronic liver disease; HVPG, hepatic venous pressure gradient; MELD, Model for end-stage liver disease; pcACLD, probable compensated advanced chronic liver disease; VWF, von Willebrand factor antigen.
      Fig 2
      Fig. 2Proportions of patients with VWF >420% according to (A) HVPG and (B) MELD strata and across different CS (C) (prevalence cohort). Abbreviations: CS, clinical stage; HVPG, hepatic venous pressure gradient; MELD, model for end-stage liver disease; pcACLD, probable compensated advanced chronic liver disease; VWF, von Willebrand factor antigen.

      3.3 Patient characteristics (outcome cohort)

      Mean age was 53 ± 11.5 years and the majority of patients were male (n = 509, 66%) (Supplementary Table 1). Viral hepatitis (n = 302, 39%) and alcoholic liver disease (ALD) (n = 281, 36%) were the most common etiologies of ACLD. At baseline, almost half of patients (n = 358, 46%) had compensated disease, including 58 (16%) patients with probable cACLD, 82 (23%) patients with CS0, and 218 (61%) patients with CS1. In contrast, 414 (54%) patients were characterized as decompensated ACLD (dACLD), including 45 (11%) patients with CS2 and 184 (44%) patients with CS3, and 185 (45%) with CS4. Thirty-four (4%) patients had a history of acute-on-chronic liver failure (ACLF) at baseline. Median MELD score was 11 (9–16), mean HVPG was 16 ± 7 mmHg and median VWF was 299 (IQR: 222–391)%.

      3.4 Correlation of VWF with portal hypertension, hepatic dysfunction, and systemic inflammation among patients with substantially elevated values (outcome cohort)

      Next, we assessed the association of numerical VWF values with markers of liver disease severity and inflammation in the subgroup of patients with substantially increased VWF levels. While there was a positive correlation of moderate strength with HVPG (Spearman's ρ=0.481, p < 0.001) in the whole cohort, VWF levels were unrelated to HVPG (ρ=0.139, p = 0.123) in the subgroup of patients with VWF >420%. In the latter subgroup, VWF levels showed positive correlations of weak/moderate strength with MELD (ρ=0.336, p < 0.001) and CRP (ρ=0.286, p = 0.001).

      3.5 Follow-up events (outcome cohort)

      The median time of follow-up in the outcome cohort was 24.4 (IQR: 7.1–56.0) months. The following decompensating events occurred: ascites (n = 129, 16.7%) and SBP (n = 5, 0.6%), HE (n = 58, 7.5%), and variceal bleeding (n = 33, 4.3%). 183 (23.7%) and 58 (7.5%) patients died of liver- and non-liver-related causes, respectively.

      3.6 Impact of substantially elevated VWF levels on hepatic decompensation and liver-related mortality (outcome cohort)

      Assessing the impact of substantially elevated VWF levels on hepatic decompensation and liver-related mortality in the whole cohort, patients with VWF >420% had a significantly shorter median time to hepatic decompensation or liver-related mortality when compared to those with lower values (23.4 (95%CI: 12.6–34.3) vs. 113.7 (95%CI: not evaluable) months, p < 0.001), which was confirmed when analyzing further decompensation/liver-related mortality in the subgroup of patients with decompensated ACLD (i.e., CS ≥2) (10.8 (95% CI: 4.3–17.4) vs. 25.0 (95% CI: 18.8–31.3) months, p = 0.002), hepatic decompensation/liver-related mortality in those with pronounced portal hypertension (i.e., HVPG ≥16 mmHg) (23.4 (95% CI: 7.4–39.4) vs. 34.2 (95% CI: 25.4–42.9) months, p = 0.004), and hepatic decompensation/liver-related mortality in those with advanced hepatic dysfunction (i.e., MELD ≥15 points) (10.1 (95% CI: 4.2–15.9) vs. 17.1 (95% CI: 8.1–26.1) months, p = 0.005) (Fig. 3).
      Fig 3
      Fig. 3Comparison of (A) hepatic decompensation/liver-related mortality between patients with VWF <420% and VWF >420% in the overall cohort, (B) further decompensation/liver-related mortality in dACLD patients (i.e., patients with ≥CS 2), (C) patients with HVPG ≥16 mmHg and (D) patients with MELD ≥15 points (outcome cohort). Abbreviations: CS, clinical stage; dACLD, decompensated advanced chronic liver disease; HVPG, hepatic venous pressure gradient; MELD, model for end-stage liver disease; VWF, von Willebrand factor antigen.

      3.7 Quantification of substantially elevated VWF levels and their association with hepatic decompensation and liver-related mortality (outcome cohort)

      Importantly, median time to hepatic decompensation/liver-related mortality was significantly shorter when comparing VWF tertiles in the subgroup of patients with substantially increased VWF levels (3rd tertile (578–1020%): 4.8 (95%CI: 0–14.0) vs. 2nd tertile (497–577%) 25.7 (95%CI: 12.4–39.1) vs. 1st tertile (421–496%): 48.1 (95%CI: 22.4–73.8) months, p = 0.005) (Fig. 4).
      Fig 4
      Fig. 4Hepatic decompensation/liver-related mortality in patients with VWF >420% according to VWF tertiles (1st tertile: 421–496%, 2nd tertile: 497–577%, 3rd tertile: 578–1020%) (outcome cohort). Abbreviations: VWF, von Willebrand factor antigen.
      Finally, we evaluated parameters associated with hepatic decompensation/liver-related mortality by performing a uni- and multivariable Cox regression analysis in the cohort of patients with VWF >420%. Not only did VWF increase the risks for hepatic decompensation/liver-related mortality (VWF per 10%: HR 1.02 (95% CI: 1.01–1.04), p = 0.008) in univariable analysis, it also proved to be independently associated with outcome of interest in multivariable analysis (VWF per 10%: HR 1.02 (95% CI: 1.00–1.05), p = 0.031), after adjusting for established prognostic indicators, i.e., age, etiology of liver disease, HVPG, CTP score, creatinine, and CRP (Table 3).
      Table 3Uni- and multivariable Cox regression analysis of prognostic factors for decompensation and liver-related transplant-free mortality in patients with high (>420%) VWF (outcome cohort).
      UnivariableMultivariable
      HR95% CIp-valueHR95% CIp-value
      Age, years1.021.00–1.050.0301.041.01–1.060.003
      Etiology
       ALD11
       NAFLD0.490.19–1.240.1313.211.03–10.10.045
       Viral0.320.18–0.60<0.0010.990.50–1.930.966
       Other1.130.53–2.410.7472.100.90–4.900.086
      HVPG, mmHg1.061.02–1.110.0031.071.02–1.130.004
      MELD, points1.091.05–1.14<0.001
      CTP score, points1.281.17–1.41<0.0011.391.21–1.59<0.001
      Clinical stages
       Probable cACLD1
       CS00.330.02–5.350.435
       CS10.450.05–3.820.467
       CS21.520.16–14.120.713
       CS31.840.24–14.220.559
       CS42.870.38–21.660.306
      Creatinine, mg x dL−11.461.19–1.80<0.0011.631.29–2.05<0.001
      Albumin, g x L  10.920.88–0.96<0.001
      CRP, mg x dL−11.901.38–2.60<0.0011.380.94–2.030.098
      VWF, per 10%1.021.01–1.040.0081.021.00–1.050.031
      Abbreviations: ALD, alcoholic liver disease; cACLD, compensated advanced chronic liver disease; CRP, C-reactive protein; CS, clinical stage; CTP, Child-Turcotte-Pugh; HR, hazard ratio; HVPG, hepatic venous pressure gradient; MELD, model for end-stage liver disease; NAFLD, non-alcoholic fatty liver disease; VWF, von Willebrand factor antigen; 95%CI, 95% confidence interval.

      4. Discussion

      In patients with cirrhosis, liver sinusoidal endothelial cell (LSEC) dysfunction increases intrahepatic resistance, and thus, initiates portal hypertension and promotes liver disease progression [
      • Poisson J.
      • Lemoinne S.
      • Boulanger C.
      • et al.
      Liver sinusoidal endothelial cells: physiology and role in liver diseases.
      ]. Elevated levels of VWF are common in patients with ACLD and indicate endothelial perturbation in the splanchnic, hepatic, and/or systemic vasculature [
      • Ferro D.
      • Quintarelli C.
      • Lattuada A.
      • et al.
      High plasma levels of von Willebrand factor as a marker of endothelial perturbation in cirrhosis: relationship to endotoxemia.
      ,
      • Albornoz L.
      • Alvarez D.
      • Otaso J.C.
      • et al.
      Von Willebrand factor could be an index of endothelial dysfunction in patients with cirrhosis: relationship to degree of liver failure and nitric oxide levels.
      ,
      • Lisman T.
      • Bongers T.N.
      • Adelmeijer J.
      • et al.
      Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity.
      . In contrast to invasive and resource-intensive HVPG measurement – the gold-standard procedure for the determination of portal hypertension severity [
      • Reiberger T.
      • Schwabl P.
      • Trauner M.
      • Peck-Radosavljevic M.
      • Mandorfer M.
      Measurement of the hepatic venous pressure gradient and transjugular liver biopsy.
      ] – VWF is a non-invasive, simple and broadly accessible NIT for portal hypertension. However, VWF levels also indicate systemic inflammation [
      • Mandorfer M.
      • Schwabl P.
      • Paternostro R.
      • et al.
      Von Willebrand factor indicates bacterial translocation, inflammation, and procoagulant imbalance and predicts complications independently of portal hypertension severity.
      ,
      • Starlinger P.
      • Ahn J.C.
      • Mullan A.
      • et al.
      The addition of C-reactive protein and Von Willebrand factor to MELD-Na improves prediction of waitlist mortality.
      , another main pathophysiological mechanism driving disease progression from compensated to stable/unstable decompensated cirrhosis, pre-acute-on-chronic liver failure (ACLF), and ACLF [
      • Trebicka J.
      • Fernandez J.
      • Papp M.
      • et al.
      The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.
      ,
      • Balcar L.
      • Semmler G.
      • Pomej K.
      • et al.
      Patterns of acute decompensation in hospitalized patients with cirrhosis and course of acute-on-chronic liver failure.
      ,
      • Enomoto M.
      • Takaya H.
      • Namisaki T.
      • et al.
      Ratio of von Willebrand factor antigen to ADAMTS13 activity is a useful biomarker for acute-on-chronic liver failure development and prognosis in patients with liver cirrhosis.
      ]. Of note, substantially elevated VWF values may be of particular relevance in this context.
      Previous studies using different assays defined various VWF cut-offs for identifying patients at increased risk for portal hypertension-related complications or transplant-free (liver-related) death. In a study by La Mura et al. [
      • La Mura V.
      • Reverter J.C.
      • Flores-Arroyo A.
      • et al.
      Von Willebrand factor levels predict clinical outcome in patients with cirrhosis and portal hypertension.
      ], a VWF cut-off value of 216 U x dL−1 stratified patients into groups at low vs. high of survival free of complications of portal hypertension and liver transplantation. Ferlitsch and colleagues [
      • Ferlitsch M.
      • Reiberger T.
      • Hoke M.
      • et al.
      von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis.
      ] determined a VWF cut-off value of 315%. In their work, VWF was equal to MELD in mortality prediction and VWF levels >315% were associated with increased risk of hepatic decompensation or mortality in patients with compensated cirrhosis, as indicated by median times to decompensation/death of 59 vs. 32 months in patients with VWF <315% and VWF >315%, respectively. In another study from our center [
      • Mandorfer M.
      • Schwabl P.
      • Paternostro R.
      • et al.
      Von Willebrand factor indicates bacterial translocation, inflammation, and procoagulant imbalance and predicts complications independently of portal hypertension severity.
      ], VWF >367% (together with CRP >6.5 mg x L  1) discriminated between CSPH patients with distinct long-term risks of transplant-free mortality. Moreover, VWF was predictive of variceal bleeding, requirement of paracentesis, bacterial infections including SBP (the latter on a trend-wise level), even after adjusting for HVPG. More recently, Györi et al. [
      • Györi G.P.
      • Pereyra D.
      • Rumpf B.
      • et al.
      The von Willebrand factor facilitates model for end-stage liver disease-independent risk stratification on the waiting list for liver transplantation.
      ] found that incorporation of VWF into the MELD-Na score significantly increased its predictive ability for 3-month mortality in patients on the liver transplant waitlist (i.e., mostly patients with decompensated cirrhosis), thereby possibly improving organ allocation. The median VWF level in the latter study was 419% (i.e., about half of patients had substantially elevated VWF levels) and the proposed cut-off for predicting death on the waiting list was 413%. Of note, all publications from our institution [
      • Ferlitsch M.
      • Reiberger T.
      • Hoke M.
      • et al.
      von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis.
      ,
      • Mandorfer M.
      • Schwabl P.
      • Paternostro R.
      • et al.
      Von Willebrand factor indicates bacterial translocation, inflammation, and procoagulant imbalance and predicts complications independently of portal hypertension severity.
      ,
      • Starlinger P.
      • Ahn J.C.
      • Mullan A.
      • et al.
      The addition of C-reactive protein and Von Willebrand factor to MELD-Na improves prediction of waitlist mortality.
      ,
      • Györi G.P.
      • Pereyra D.
      • Rumpf B.
      • et al.
      The von Willebrand factor facilitates model for end-stage liver disease-independent risk stratification on the waiting list for liver transplantation.
      relied on the similar immuno-turbidimetric assay, while La Mura et al. [
      • La Mura V.
      • Reverter J.C.
      • Flores-Arroyo A.
      • et al.
      Von Willebrand factor levels predict clinical outcome in patients with cirrhosis and portal hypertension.
      ] used an ELISA assay, which limits their comparability. Importantly, none of these studies have directly assessed, whether very high values provide clinically meaningful information and all identified cut-offs for risk stratification were <420%.
      In a recent analysis of patients with decompensated cirrhosis undergoing paired assessments of VWF before and under NSBB therapy found that a decrease in VWF exceeding 5% (which defined ‘VWF-response’) was accompanied by anti-inflammatory changes and less pronounced adverse effects on systemic hemodynamics [
      • Jachs M.
      • Hartl L.
      • Simbrunner B.
      • et al.
      Decreasing von Willebrand factor levels upon nonselective beta blocker therapy indicate a decreased risk of further decompensation, acute-on-chronic liver failure, and death.
      ]. VWF-response translated into substantially decreased risks of further decompensation, ACLF, and liver-related death, thereby discriminating between decompensated patients who benefit from NSBB-treatment and have a favorable prognosis vs. patients with poor outcomes. Median pre-treatment VWF was 350% in this study and approximately one fourth of patients had substantially elevated VWF levels. This indicates the need for quantifying VWF >420% in a considerable proportion of decompensated patients, if applying the concept of VWF-response. Moreover, the studies by Györi et al. [
      • Györi G.P.
      • Pereyra D.
      • Rumpf B.
      • et al.
      The von Willebrand factor facilitates model for end-stage liver disease-independent risk stratification on the waiting list for liver transplantation.
      ] and Starlinger et al. [
      • Starlinger P.
      • Ahn J.C.
      • Mullan A.
      • et al.
      The addition of C-reactive protein and Von Willebrand factor to MELD-Na improves prediction of waitlist mortality.
      ] also emphasized the need for quantifying substantially elevated VWF values, as numerical VWF values were incorporated into the modified MELD-Na equation to improve its prognostic performance.
      The assay for assessing VWF for its use as a prognostic indicator/surrogate of treatment efficacy in patients with ACLD has not been standardized yet. Therefore, both VWF values and ranges of quantification differ depending on the assay, a problem that has also been discussed in regard to the interlaboratory variability of components of the MELD score, specifically INR, before [
      • Porte R.J.
      • Lisman T.
      • Tripodi A.
      • Caldwell S.H.
      • Trotter J.F.
      The International Normalized Ratio (INR) in the MELD score: problems and solutions.
      ]. The immuno-turbidimetric assay used by our ISO-certified Department of Laboratory Medicine has a measurement range of 50–420%. We have recently shown that even at a value of 330%, the VWF assay applied in our studies shows a reasonable precision with a CV of 3%, as determined by 10 consecutive measurements of the same sample [
      • Jachs M.
      • Hartl L.
      • Simbrunner B.
      • et al.
      Decreasing von Willebrand factor levels upon nonselective beta blocker therapy indicate a decreased risk of further decompensation, acute-on-chronic liver failure, and death.
      ]. Values exceeding the upper limit cannot be quantified and are displayed as >420%, which prompted us to modify our analytical approach. Samples with VWF >420% were further pre-diluted to obtain quantitative measurements. While this approach has not been approved by the manufacturer, we were able to obtain reproducible results.
      Indeed, in our large cohort of 793 ACLD patients undergoing HVPG measurement, 16% (n = 124) of patients had substantially elevated VWF levels. When only considering patients with VWF >420%, the median VWF was 533% and values ranged from 421% to 1020%. Thus, the VWF range in patients with ACLD is very wide, which is in line with a previous study also using an immuno-turbidimetric assay (other manufacturer) [
      • Reuken P.A.
      • Kussmann A.
      • Kiehntopf M.
      • et al.
      Imbalance of von Willebrand factor and its cleaving protease ADAMTS13 during systemic inflammation superimposed on advanced cirrhosis.
      ]. The proportion of patients with VWF >420% increased steadily with liver disease and portal hypertension severity and was particularly high in patients with severe portal hypertension (HVPG ≥16 mmHg; 22%), MELD ≥15 points (32%), or CS4 (29%).
      Even at high values, VWF correlated with hepatic dysfunction and systemic inflammation as assessed by MELD and CRP. In contrast, it was unrelated to HVPG in the group of patients with VWF >420%. Previous studies found that VWF values are particularly high in patients with cirrhosis and intercurrent conditions such as systemic inflammatory response syndrome/sepsis or ACLF [
      • Reuken P.A.
      • Kussmann A.
      • Kiehntopf M.
      • et al.
      Imbalance of von Willebrand factor and its cleaving protease ADAMTS13 during systemic inflammation superimposed on advanced cirrhosis.
      ] and that the majority of these patients had VWF values >420%. However, patients with bacterial infection were excluded from our study and the overall prevalence of ACLF was only 4%, indicating that similarly high values may also occur in clinically stable patients.
      Importantly, even at these substantially elevated values, increasing VWF was still paralleled by an increased risk of hepatic decompensation or liver-related mortality in multivariable analysis, despite adjustment for liver dysfunction, portal hypertension and inflammation. Accordingly, in clinically stable patients with cirrhosis, quantification of VWF >420% provides meaningful prognostic information on long-term outcomes.
      Our study has several limitations. First, HVPG measurements are rarely performed in inpatients at our institution, as intercurrent conditions may lead to short-term increases in HVPG [
      • Ruiz-del-Arbol L.
      • Urman J.
      • Fernández J.
      • et al.
      Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis.
      ,
      • Mehta G.
      • Mookerjee R.P.
      • Sharma V.
      • Jalan R.
      Systemic inflammation is associated with increased intrahepatic resistance and mortality in alcohol-related acute-on-chronic liver failure.
      , thereby impeding its prognostic value on the long-term or HVPG-response-guided therapy. Accordingly, the findings of our study regarding the prognostic impact of substantially elevated VWF levels should not be extrapolated to inpatients with acute decompensation (AD)/ACLF in whom short-term outcomes are of particular interest. Second, due to the retrospective design of our study, we cannot rule-out that information on some events may have been missed. However, we have performed a thorough review of city- and nation-wide electronic health records to increase coverage. Additionally, we have searched the liver transplant database of our institution, which is the only transplant center in eastern Austria and queried the nation-wide death registry. Third, some levels >420% could not be further diluted and subsequentially measured for logistical/capacity reasons in 21 patients, which is why we have excluded these patients from the outcome cohort. However, these patients were still included in the prevalence cohort in order to provide unbiased results.
      In conclusion, our study demonstrates that the proportion of patients with substantially elevated VWF values (i.e., >420%) steadily increases with ACLD progression and is particularly high in patients with profound portal hypertension or decompensated cirrhosis. Quantification of substantially elevated VWF levels provides prognostic information on long-term outcomes in patients with ACLD, independently of established factors. Moreover, it is instrumental for the potential clinical application of novel concepts, such as incorporation of VWF into the MELD score or the assessment of VWF-response to NSBB therapy. Accordingly, modifications of the analytical approach allowing the quantification of substantially elevated VWF may be necessary to maximize the prognostic ability/versatility of this NIT in patients with ACLD.

      Author's contribution and authorship statement

      Concept of the study (K.P., B.S., and M.M.), extraction of data (K.P., B.S., L.B., RJ.N., and J.W.), drafting of the manuscript (K.P., B.S., and M.M.), writing of the manuscript (K.P. and M.M.), revision for important intellectual content (all authors). M.M. acts as supervisor of the article and all authors approved the final version of the manuscript.

      Funding

      The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

      Ethics

      The study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the local ethics committee (No. 1627/2015 and No. 1262/2017). All patients were consented for HVPG measurement and, if applicable, participation in the VIenna CIrrhosis Study (VICIS; NCT03267615).

      Plant reducibility

      Not applicable.

      Data availability

      The data that support the findings of this study are available upon reasonable request from the authors.

      Declaration of Competing Interest

      K.P., L.B., R.J.N., J.W., R.P., D.P., P.S., A.F.S., and P.Q. have nothing to declare.

      Acknowledgements

      B.Sc. received travel support from AbbVie, Gilead, and Ipsen. B.Si. received travel support from AbbVie and Gilead. D.B. received travel support from AbbVie and Gilead as well as speaker fees from AbbVie. M.P. served as a speaker and/or consultant and/or advisory board member for Bayer, Bristol-Myers Squibb, Ipsen, Eisai, Lilly, MSD, and Roche and received travel support from and Bristol-Myers Squibb. M.T. served as a speaker and/or consultant and/or advisory board member for Albireo, Boehringer Ingelheim, Bristol-Myers Squibb, Falk, Genfit, Gilead, Intercept, MSD, Novartis, Phenex, Regulus, and Shire, received travel support from AbbVie, Falk, Gilead, and Intercept as well as grants/research support from Albireo, Cymabay, Falk, Gilead, Intercept, MSD, and Takeda. He is also co-inventor of patents on the medical use of 24-norursodeoxycholic acid. T.R. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bayer, Boehringer Ingelheim, Gilead, Intercept, MSD, Roche, Siemens, and W. L. Gore & Associates and received grants/research support from AbbVie, Boehringer Ingelheim, Gilead, MSD, Philips, and W. L. Gore & Associates as well as travel support from Boehringer and Gilead. M.M. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol-Myers Squibb, Gilead, Collective Acumen, and W. L. Gore & Associates and received travel support from AbbVie, Bristol-Myers Squibb, and Gilead.

      Appendix. Supplementary materials

      References

        • Ferro D.
        • Quintarelli C.
        • Lattuada A.
        • et al.
        High plasma levels of von Willebrand factor as a marker of endothelial perturbation in cirrhosis: relationship to endotoxemia.
        Hepatology. 1996; 23: 1377-1383https://doi.org/10.1002/hep.510230613
        • Albornoz L.
        • Alvarez D.
        • Otaso J.C.
        • et al.
        Von Willebrand factor could be an index of endothelial dysfunction in patients with cirrhosis: relationship to degree of liver failure and nitric oxide levels.
        J. Hepatol. Mar 1999; 30: 451-455
        • Randi A.M.
        • Laffan M.A.
        Von Willebrand factor and angiogenesis: basic and applied issues.
        J Thromb Haemost: JTH. Jan 2017; 15: 13-20https://doi.org/10.1111/jth.13551
        • Groeneveld D.J.
        • Poole L.G.
        • Luyendyk J.P.
        Targeting von Willebrand factor in liver diseases: a novel therapeutic strategy?.
        J Thromb Haemost: JTH. Jun 2021; 19: 1390-1408https://doi.org/10.1111/jth.15312
        • Lisman T.
        • Bongers T.N.
        • Adelmeijer J.
        • et al.
        Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity.
        Hepatology. Jul 2006; 44: 53-61https://doi.org/10.1002/hep.21231
        • Reiberger T.
        • Schwabl P.
        • Trauner M.
        • Peck-Radosavljevic M.
        • Mandorfer M.
        Measurement of the hepatic venous pressure gradient and transjugular liver biopsy.
        J Vis Exp. Jun 18 2020; https://doi.org/10.3791/58819
        • Ferlitsch M.
        • Reiberger T.
        • Hoke M.
        • et al.
        von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis.
        Hepatology. Oct 2012; 56: 1439-1447https://doi.org/10.1002/hep.25806
        • Scheiner B.
        • Balcar L.
        • Paternostro R.
        • et al.
        Von Willebrand factor for outcome prediction within different clinical stages of advanced chronic liver disease.
        J Hepatol. 2021; 75: S205-S293https://doi.org/10.1016/S0168-8278(21)01842-0
        • La Mura V.
        • Reverter J.C.
        • Flores-Arroyo A.
        • et al.
        Von Willebrand factor levels predict clinical outcome in patients with cirrhosis and portal hypertension.
        Gut. Aug 2011; 60: 1133-1138https://doi.org/10.1136/gut.2010.235689
        • Mandorfer M.
        • Schwabl P.
        • Paternostro R.
        • et al.
        Von Willebrand factor indicates bacterial translocation, inflammation, and procoagulant imbalance and predicts complications independently of portal hypertension severity.
        Aliment Pharmacol Ther. Apr 2018; 47: 980-988https://doi.org/10.1111/apt.14522
        • D'Amico G.
        • Morabito A.
        • D'Amico M.
        • et al.
        Clinical states of cirrhosis and competing risks.
        J Hepatol. Mar 2018; 68: 563-576https://doi.org/10.1016/j.jhep.2017.10.020
        • Ferlitsch A.
        • Bota S.
        • Paternostro R.
        • et al.
        Evaluation of a new balloon occlusion catheter specifically designed for measurement of hepatic venous pressure gradient.
        Liver Int: Off J Int Assoc Study Liver. Sep 2015; 35: 2115-2120https://doi.org/10.1111/liv.12783
        • Poisson J.
        • Lemoinne S.
        • Boulanger C.
        • et al.
        Liver sinusoidal endothelial cells: physiology and role in liver diseases.
        J Hepatol. Jan 2017; 66: 212-227https://doi.org/10.1016/j.jhep.2016.07.009
        • Starlinger P.
        • Ahn J.C.
        • Mullan A.
        • et al.
        The addition of C-reactive protein and Von Willebrand factor to MELD-Na improves prediction of waitlist mortality.
        Hepatology (Baltimore, Md). Mar 31 2021; https://doi.org/10.1002/hep.31838
        • Trebicka J.
        • Fernandez J.
        • Papp M.
        • et al.
        The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.
        J Hepatol. Oct 2020; 73: 842-854https://doi.org/10.1016/j.jhep.2020.06.013
        • Balcar L.
        • Semmler G.
        • Pomej K.
        • et al.
        Patterns of acute decompensation in hospitalized patients with cirrhosis and course of acute-on-chronic liver failure.
        United Eur Gastroenterol J. May 2021; 9: 427-437https://doi.org/10.1002/ueg2.12089
        • Enomoto M.
        • Takaya H.
        • Namisaki T.
        • et al.
        Ratio of von Willebrand factor antigen to ADAMTS13 activity is a useful biomarker for acute-on-chronic liver failure development and prognosis in patients with liver cirrhosis.
        Hepatol Res: Off J Jpn Soc Hepatol. Apr 2022; 52: 390-400https://doi.org/10.1111/hepr.13743
        • Györi G.P.
        • Pereyra D.
        • Rumpf B.
        • et al.
        The von Willebrand factor facilitates model for end-stage liver disease-independent risk stratification on the waiting list for liver transplantation.
        Hepatology. Aug 2020; 72: 584-594https://doi.org/10.1002/hep.31047
        • Jachs M.
        • Hartl L.
        • Simbrunner B.
        • et al.
        Decreasing von Willebrand factor levels upon nonselective beta blocker therapy indicate a decreased risk of further decompensation, acute-on-chronic liver failure, and death.
        Clin Gastroenterol Hepatol. Jul 10 2021; https://doi.org/10.1016/j.cgh.2021.07.012
        • Porte R.J.
        • Lisman T.
        • Tripodi A.
        • Caldwell S.H.
        • Trotter J.F.
        The International Normalized Ratio (INR) in the MELD score: problems and solutions.
        Am J Transplant: Off Je Am Soc Transplant Am Soc Transpl Surg. Jun 2010; 10: 1349-1353https://doi.org/10.1111/j.1600-6143.2010.03064.x
        • Reuken P.A.
        • Kussmann A.
        • Kiehntopf M.
        • et al.
        Imbalance of von Willebrand factor and its cleaving protease ADAMTS13 during systemic inflammation superimposed on advanced cirrhosis.
        Liver Int: Off J Int Assoc Study Liver. Jan 2015; 35: 37-45https://doi.org/10.1111/liv.12657
        • Ruiz-del-Arbol L.
        • Urman J.
        • Fernández J.
        • et al.
        Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis.
        Hepatology (Baltimore, Md). Nov 2003; 38: 1210-1218https://doi.org/10.1053/jhep.2003.50447
        • Mehta G.
        • Mookerjee R.P.
        • Sharma V.
        • Jalan R.
        Systemic inflammation is associated with increased intrahepatic resistance and mortality in alcohol-related acute-on-chronic liver failure.
        Liver Int: Off J Int Assoc Study Liver. Mar 2015; 35: 724-734https://doi.org/10.1111/liv.12559

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