An unbalance between von Willebrand factor and ADAMTS13 in acute liver failure: Implications for hemostasis and clinical outcome

Authors

  • Greg C. G. Hugenholtz,

    1. Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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  • Jelle Adelmeijer,

    1. Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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  • Joost C. M. Meijers,

    1. Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
    2. Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
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  • Robert J. Porte,

    1. Departments of Experimental Vascular Medicine, Amsterdam, The Netherlands
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  • R. Todd Stravitz,

    1. Section of Hepatology and Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, VA
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    • These authors contributed equally to this work.

  • Ton Lisman

    Corresponding author
    1. Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
    2. Departments of Experimental Vascular Medicine, Amsterdam, The Netherlands
    • Address reprint requests to: Ton Lisman, Ph.D., Department of Surgery, BA44, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, the Netherlands. E-mail: j.a.lisman@umcg.nl; fax: +31−50-363-2796.

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    • These authors contributed equally to this work.


  • Potential conflict of interest: Nothing to report.

  • This study was supported in part by a grant from the Stichting Tekke Huizinga Fonds.

  • This work was an ancillary study of the Acute Liver Failure Study Group (National Institute of Diabetes and Digestive and Kidney Diseases (grant U01 DK58369; William M. Lee, M.D., Principal Investigator).

Abstract

Emerging evidence supports the concept of a rebalanced hemostatic state in liver disease as a result of a commensurate decline in prohemostatic and antihemostatic drivers. In the present study, we assessed levels and functionality of the platelet-adhesive protein von Willebrand factor (VWF) and its cleaving protease ADAMTS13 in the plasma of patients with acute liver injury and acute liver failure (ALI/ALF). Furthermore, we explored possible associations between VWF, ADAMTS13, and disease outcome. We analyzed the plasma of 50 patients taken on the day of admission for ALI/ALF. The plasma of 40 healthy volunteers served as controls. VWF antigen levels were highly elevated in patients with ALI/ALF. In contrast, the collagen-binding activity and the ratio of the VWF ristocetin cofactor activity and VWF antigen was significantly decreased when compared with healthy controls. Also, the proportion of high molecular weight VWF multimers was reduced, despite severely decreased ADAMTS13 levels. In spite of these functional defects, platelet adhesion and aggregation were better supported by plasma of patients with ALI/ALF when compared with control plasma. Low ADAMTS13 activity, but not high VWF antigen, was associated with poor outcome in patients with ALI/ALF as evidenced by higher grades of encephalopathy, higher transplantation rates, and lower survival. VWF or ADAMTS13 levels were not associated with bleeding or thrombotic complications. Conclusion: Highly elevated levels of VWF in plasma of patients with ALI/ALF support platelet adhesion, despite a relative loss of function of the molecule. Furthermore, low ADAMTS13 activity is associated with progressive liver failure in the patient cohort, which might be attributed to platelet-induced microthrombus formation in the diseased liver resulting from a substantially unbalanced VWF/ADAMTS13 ratio. (Hepatology 2013;58:752–761)

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