Von Willebrand factor processing in patients with advanced chronic liver disease and its relation to portal hypertension and clinical outcome

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Abstract

Background and aims

Endothelial dysfunction and portal hypertension (PH) are reflected by increased von Willebrand factor antigen (VWF-Ag) levels in advanced chronic liver disease (ACLD). This study investigated VWF release and cleavage and their association with PH and clinical outcomes.

Methods

Levels of VWF-Ag, VWF-N (VWF-propeptide), and VWF-A (VWF processed by the main VWF-cleaving protease ADAMTS13) were assessed in 229 patients with clinically stable ACLD (hepatic venous pressure gradient [HVPG] ≥ 6 mmHg; absence of bacterial infections or acute decompensation) undergoing HVPG-measurement. Liver-healthy individuals served as controls (n = 24).

Results

VWF-Ag and VWF-N were similarly accurate for the identification of clinically significant PH (CSPH; HVPG ≥ 10 mmHg) in compensated ACLD (AUROC: VWF-Ag 0.748; VWF-N 0.728). ADAMTS13 activity was similar between patients with ACLD and controls and did not correlate with PH and disease severity, whereas VWF cleavage decreased in patients with CSPH (i.e., VWF-Ag/-A-ratio increased). In vitro VWF activity strongly reflected VWF-Ag levels (Spearman’s r = 0.874, p < 0.001), but decreased (vs. controls) in patients with CSPH when normalized to VWF-Ag levels (VWF-activity/-Ag-ratio). VWF-Act/-Ag ratio correlated negatively with ADAMTS13 activity (r =– 0.256, p < 0.001). ADAMTS13 activity was independently predictive for (i) portal vein thrombosis (PVT) and (ii) hepatic decompensation or liver-related death.

Conclusions

VWF-Ag levels and its propeptide are similarly suitable surrogates of PH in patients with compensated ACLD. ADAMTS13-Act was not linked to disease and PH severity, however, when normalized to VWF-Ag, both VWF cleavage and VWF activity were decreased in patients with CSPH, as compared to liver-healthy individuals. Low ADAMTS13-Act was associated with presumably more procoagulant VWF and adverse outcomes.

Clinical trial number

NCT03267615

Supplementary Information

The online version contains supplementary material available at 10.1007/s12072-023-10577-y.

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Most cited references 48

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BAVENO VII - RENEWING CONSENSUS IN PORTAL HYPERTENSION

Roberto de Franchis, Jaime Bosch, Guadalupe Garcia-Tsao … (2021)

To expand on the work of previous meetings, a virtual Baveno VII workshop was organised for October 2021. Among patients with compensated cirrhosis or compensated advanced chronic liver disease (cACLD - defined at the Baveno VI conference), the presence or absence of clinically significant portal hypertension (CSPH) is associated with differing outcomes, including risk of death, and different diagnostic and therapeutic needs. Accordingly, the Baveno VII workshop was entitled "Personalized Care for Portal Hypertension". The main fields of discussion were the relevance and indications for measuring the hepatic venous pressure gradient as a gold standard, the use of non-invasive tools for the diagnosis of cACLD and CSPH, the impact of aetiological and non-aetiological therapies on the course of cirrhosis, the prevention of the first episode of decompensation, the management of an acute bleeding episode, the prevention of further decompensation, as well as the diagnosis and management of splanchnic vein thrombosis and other vascular disorders of the liver. For each of these 9 topics, a thorough review of the medical literature was performed, and a series of consensus statements/recommendations were discussed and agreed upon. A summary of the most important conclusions/recommendations derived from the workshop is reported here. The statements are classified as unchanged, changed, and new in relation to Baveno VI.

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Liver sinusoidal endothelial cells: Physiology and role in liver diseases.

Richard Moreau, Dominique Valla, Pierre-Emmanuel Rautou … (2017)

Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells representing the interface between blood cells on the one side and hepatocytes and hepatic stellate cells on the other side. LSECs represent a permeable barrier. Indeed, the association of 'fenestrae', absence of diaphragm and lack of basement membrane make them the most permeable endothelial cells of the mammalian body. They also have the highest endocytosis capacity of human cells. In physiological conditions, LSECs regulate hepatic vascular tone contributing to the maintenance of a low portal pressure despite the major changes in hepatic blood flow occurring during digestion. LSECs maintain hepatic stellate cell quiescence, thus inhibiting intrahepatic vasoconstriction and fibrosis development. In pathological conditions, LSECs play a key role in the initiation and progression of chronic liver diseases. Indeed, they become capillarized and lose their protective properties, and they promote angiogenesis and vasoconstriction. LSECs are implicated in liver regeneration following acute liver injury or partial hepatectomy since they renew from LSECs and/or LSEC progenitors, they sense changes in shear stress resulting from surgery, and they interact with platelets and inflammatory cells. LSECs also play a role in hepatocellular carcinoma development and progression, in ageing, and in liver lesions related to inflammation and infection. This review also presents a detailed analysis of the technical aspects relevant for LSEC analysis including the markers these cells express, the available cell lines and the transgenic mouse models. Finally, this review provides an overview of the strategies available for a specific targeting of LSECs.

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Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity.

Ton Lisman, Tamara N Bongers, Jelle Adelmeijer … (2006)

Cirrhosis of the liver is frequently accompanied by complex alterations in the hemostatic system, resulting in a bleeding tendency. Although many hemostatic changes in liver disease promote bleeding, compensatory mechanisms also are found, including high levels of the platelet adhesive protein von Willebrand Factor (VWF). However, conflicting reports on the functional properties of VWF in cirrhosis have appeared in literature. We have measured a panel of VWF parameters in plasma from patients with cirrhosis of varying severity and causes. Furthermore, we assessed the contribution of VWF to platelet adhesion, by measuring the ability of plasma from patients with cirrhosis to support adhesion of normal or patient platelets under flow conditions. VWF antigen levels were strongly increased in patients with cirrhosis. In contrast, the relative collagen binding activity, as well as the relative ristocetin cofactor activity, was significantly lower in patients as compared with controls, indicating loss of function. Accordingly, patients had a reduced fraction of high-molecular-weight VWF multimers. Both strongly elevated and reduced activity and antigen levels of the VWF cleaving protease ADAMTS13 were found in individual patients. Adhesion of either normal or patient platelets to a collagen surface was substantially increased when these platelets were resuspended in plasma of patients with cirrhosis, as compared with control plasma. In conclusion, highly elevated levels of VWF in patients with cirrhosis contribute to the induction of primary hemostasis despite reduced functional properties of the molecule. This phenomenon might compensate for defects in platelet number and function in patients with cirrhosis.

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Author and article information

Contributors

Mattias Mandorfer:

ORCID: http://orcid.org/0000-0003-2330-0017

mattias.mandorfer@meduniwien.ac.at

Journal

Journal ID (nlm-ta): Hepatol Int

Journal ID (iso-abbrev): Hepatol Int

Title: Hepatology International

Publisher: Springer India (New Delhi )

ISSN (Print): 1936-0533

ISSN (Electronic): 1936-0541

Publication date (Electronic): 21 August 2023

Publication date PMC-release: 21 August 2023

Publication date Collection: December 2023

Volume: 17

Issue: 6

Pages: 1532-1544

Affiliations

[1 ]Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, ( https://ror.org/05n3x4p02) Waehringer Guertel 18-20, 1090 Vienna, Austria

[2 ]GRID grid.22937.3d, ISNI 0000 0000 9259 8492, Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, , Medical University of Vienna, ; Vienna, Austria

[3 ]GRID grid.22937.3d, ISNI 0000 0000 9259 8492, Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, , Medical University of Vienna, ; Vienna, Austria

[4 ]Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), ( https://ror.org/03hgkg910) Vienna, Austria

[5 ]GRID grid.418729.1, ISNI 0000 0004 0392 6802, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, ; Vienna, Austria

[6 ]Nordic Bioscience, ( https://ror.org/03nr54n68) Herlev, Denmark

[7 ]University of Copenhagen, ( https://ror.org/035b05819) Copenhagen, Denmark

[8 ]Department of Laboratory Medicine, Medical University of Vienna, ( https://ror.org/05n3x4p02) Vienna, Austria

[9 ]GRID grid.4494.d, ISNI 0000 0000 9558 4598, Surgical Research Laboratory, Department of Surgery, , University of Groningen, University Medical Centre Groningen, ; Groningen, The Netherlands

Author information

Benedikt Simbrunner http://orcid.org/0000-0001-8181-9146

Mattias Mandorfer http://orcid.org/0000-0003-2330-0017

Article

Publisher ID: 10577

DOI: 10.1007/s12072-023-10577-y

PMC ID: 10661794

PubMed ID: 37605068

SO-VID: 0e105b68-8795-4c79-bcb5-9f850ae58914

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 5 May 2023

Date accepted : 27 July 2023

Funding

Funded by: Medical Scientific Fund of the Major of the City of Vienna

Award ID: No. 21047

Award Recipient : Mattias Mandorfer

Funded by: Medical University of Vienna

Open Access :

Open access funding provided by Medical University of Vienna.

Custom metadata

ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: cirrhosis,csph,vwf,propeptide,adamts13,endothelial dysfunction

Data availability:

ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: cirrhosis, csph, vwf, propeptide, adamts13, endothelial dysfunction

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Von Willebrand factor processing in patients with advanced chronic liver disease and its relation to portal hypertension and clinical outcome

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Abstract

Background and aims

Methods

Results

Conclusions

Clinical trial number

Supplementary Information

Related collections

Karger: Gastroenterology

Most cited references 48

BAVENO VII - RENEWING CONSENSUS IN PORTAL HYPERTENSION

Liver sinusoidal endothelial cells: Physiology and role in liver diseases.

Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity.

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Cited by 3

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