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Exposure of von Willebrand Factor on Isolated Hepatocytes Promotes Tethering of Platelets to the Cell Surface

Gustafson, Elisabet MD, PhD1; Hamad, Osama A. PhD2; Deckmyn, Hans PhD3; Barbu, Andreea PhD2; Ekdahl, Kristina N. PhD4; Nilsson, Bo MD, PhD2

doi: 10.1097/TP.0000000000002707
Original Basic Science—Liver

Background. Hepatocyte transplantation (Hctx) is a potentially attractive method for the treatment of acute liver failure and liver-based metabolic disorders. Unfortunately, the procedure is hampered by the instant blood-mediated inflammatory reaction (IBMIR), a thromboinflammatory response elicited by the vascular innate immune system, causing activation of the coagulation and complement systems and clearance of transplanted cells. Observations have also revealed platelets adhered to the surface of the hepatocytes (Hc). To establish Hctx as a clinical treatment, all factors that trigger IBMIR need to be identified and controlled. This work explores the expression of von Willebrand factor (VWF) on isolated Hc resulting in tethering of platelets.

Methods. VWF on Hc was studied by flow cytometry, confocal microscopy, immunoblot, and real-time polymerase chain reaction. Interaction between Hc and platelets was studied in a Chandler loop model. Adhesion of platelets to the hepatocyte surface was demonstrated by flow cytometry and confocal microscopy.

Results. Isolated Hc constitutively express VWF on their cell surface and mRNA for VWF was found in the cells. Hc and platelets, independently of coagulation formed complexes, were shown by antibody blocking studies to be dependent on hepatocyte-associated VWF and platelet-bound glycoprotein Ibα.

Conclusions. VWF on isolated Hc causes, in contact with blood, adhesion of platelets, which thereby forms an ideal surface for coagulation. This phenomenon needs to be considered in hepatocyte-based reconstitution therapy and possibly even in other settings of cell transplantation.

1 Department of Women’s and Children’s Health, Division of Pediatric Surgery, Uppsala University Hospital, Uppsala, Sweden.

2 Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

3 Laboratory for Thrombosis Research, IRF Life Sciences, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium.

4 Linnæus Center of Biomaterials Chemistry, Linnæus University, Kalmar, Sweden.

Received 22 October 2018. Revision received 24 January 2019.

Accepted 14 February 2019.

This study was supported by grants from HRH, the Crown Princess Louise’s Fund for Scientific Research (Sweden).

The authors declare no conflicts of interest.

E.G. participated in research design, writing of the article, performance of the research, and in data analysis. O.A.H. participated in research design, performance of the research, and in data analysis. H.D. contributed with new reagents, analysis of results, and proof-reading of the article. A.B. participated in performance of the research. K.N.E. participated in research design, writing of the article, and in data analysis. B.N. participated in research design, writing of the article, and in data analysis.

Correspondence: Elisabet Gustafson, MD PhD, ORCID: 0000-0003-3416-1841, Division of Pediatric Surgery, Department of Women’s and Children’s Health, Uppsala University Children’s Hospital, SE-751 85 Uppsala, Sweden. (

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