Factor VIII expression in liver disease

Martine J. Hollestelle; Hendrika G. M. Geertzen; Irene H. Straatsburg; Thomas M. van Gulik; Jan A. van Mourik

doi:10.1160/TH03-05-0310

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 91(02): 267-275
DOI: 10.1160/TH03-05-0310

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Factor VIII expression in liver disease

Martine J. Hollestelle

¹Department of Plasma Proteins, Amsterdam, The Netherlands

,

Hendrika G. M. Geertzen

³Department of Immunopathology, Sanquin Research at CLB, Amsterdam, The Netherlands

,

Irene H. Straatsburg

⁴Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands

,

Thomas M. van Gulik

⁴Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands

,

Jan A. van Mourik

¹Department of Plasma Proteins, Amsterdam, The Netherlands

²Department of Blood Coagulation, Amsterdam, The Netherlands

› Author Affiliations

Abstract

Summary

Liver disease is associated with markedly elevated plasma factor VIII (FVIII) levels, whereas the synthesis of many other coagulation factors and proteins is reduced. In order to define the mechanism of FVIII increase, we have determined the expression levels of FVIII, both at mRNA and protein level, in patients with liver disease who underwent partial liver resection. In addition, the expression of von Willebrand factor (VWF) and low density lipoprotein receptor-related protein (LRP), proteins known for their ability to modulate FVIII plasma levels, were examined. Tissue samples for RNA extraction were obtained from 4 patients with cirrhosis, 9 patients with liver failure without cirrhosis and 6 patients with liver metastasis of a colon or rectum carcinoma (control group). In patients with liver cirrhosis hepatic FVIII and LRP mRNA levels were significantly lower than controls (p ≤ 0.010), while VWF mRNA was significantly higher (p ≤ 0.050). Immunohistochemical analysis revealed that cellular VWF protein distribution was also increased in cirrhotic livers compared to liver tissue from patients with non-cirrhotic liver disease. In cirrhotic tissue enlarged portal veins appeared to overgrow FVIII producing sinusoidal endothelial cells. Similarly, the number of LRP-producing cells appeared to be lower in cirrhotic tissue than in controls. The plasma concentration of both FVIII and VWF was significantly higher in patients with cirrhosis than control subjects (p = 0.038 and 0.010 respectively). These results demonstrate that elevated plasma FVIII levels in liver cirrhosis are associated with increased hepatic biosynthesis of VWF and decreased expression of LRP, rather than increased FVIII synthesis.

Keywords

Factor VIII - liver cirrhosis - low density lipoprotein receptor-related protein - von Willebrand factor

Full Text

References

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