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PLoS One. 2017 Aug 24;12(8):e0183590. doi: 10.1371/journal.pone.0183590. eCollection 2017.

Mice deficient in the anti-haemophilic coagulation factor VIII show increased von Willebrand factor plasma levels.

Author information

1
Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany.
2
German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Mainz, Germany.
3
Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany.
4
Department of Anesthesiology, University Medical Center Mainz, Mainz, Germany.

Abstract

Von Willebrand factor (VWF) is the carrier protein of the anti-haemophilic Factor VIII (FVIII) in plasma. It has been reported that the infusion of FVIII concentrate in haemophilia A patients results in lowered VWF plasma levels. However, the impact of F8-deficiency on VWF plasma levels in F8-/y mice is unresolved. In order to avoid confounding variables, we back-crossed F8-deficient mice onto a pure C57BL/6J background and analysed VWF plasma concentrations relative to C57BL/6J WT (F8+/y) littermate controls. F8-/y mice showed strongly elevated VWF plasma concentrations and signs of hepatic inflammation, as indicated by increased TNF-α, CD45, and TLR4 transcripts and by elevated macrophage counts in the liver. Furthermore, immunohistochemistry showed that expression of VWF antigen was significantly enhanced in the hepatic endothelium of F8-/y mice, most likely resulting from increased macrophage recruitment. There were no signs of liver damage, as judged by glutamate-pyruvate-transaminase (GPT) and glutamate-oxalacetate-transaminase (GOT) in the plasma and no signs of systemic inflammation, as white blood cell subsets were unchanged. As expected, impaired haemostasis was reflected by joint bleeding, prolonged in vitro clotting time and decreased platelet-dependent thrombin generation. Our results point towards a novel role of FVIII, synthesized by the liver endothelium, in the control of hepatic low-grade inflammation and VWF plasma levels.

PMID:
28837614
PMCID:
PMC5570278
DOI:
10.1371/journal.pone.0183590
[Indexed for MEDLINE]
Free PMC Article

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