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
1   Department of Plasma Proteins, Amsterdam, The Netherlands
,
Hendrika G. M. Geertzen
3   Department of Immunopathology, Sanquin Research at CLB, Amsterdam, The Netherlands
,
Irene H. Straatsburg
4   Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
,
Thomas M. van Gulik
4   Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
,
Jan A. van Mourik
1   Department of Plasma Proteins, Amsterdam, The Netherlands
2   Department of Blood Coagulation, Amsterdam, The Netherlands
› Institutsangaben
Grant support: This work was supported by the Dutch Thrombosis Research Foundation grant # 20003.
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Publikationsverlauf

Received 22. Mai 2003

Accepted after revision 30. Oktober 2003

Publikationsdatum:
01. Dezember 2017 (online)

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.

 
  • References

  • 1 Kelly DA, Summerfield JA. Hemostasis in liver disease. Semin Liver Dis 1987; 07: 182-91.
  • 2 Joist JH, George JN. Hemostatic abnormalities in liver and renal disease. In: Hemostasis and thrombosis; Basic principles & clinical practice. Lippincott Williams & Wilkins; 2001: 955-73.
  • 3 Wion KL, Kelly D, Summerfield JA. et al.. Distribution of factor VIII mRNA and antigen in human liver and other tissues. Nature 1985; 317: 726-9.
  • 4 Hollestelle MJ, Thinnes T, Crain K. et al.. Tissue distribution of factor VIII gene expression in vivo-a closer look. Thromb Haemost 2001; 86: 855-61.
  • 5 Do H, Healey JF, Waller EK. et al.. Expression of factor VIII by murine liver sinusoidal endothelial cells. J Biol Chem 1999; 274: 19587-92.
  • 6 Langley PG, Hughes RD, Williams R. Increased factor VIII complex in fulminant hepatic failure. Thromb Haemost 1985; 54: 693-6.
  • 7 Lombardi R, Mannucci PM, Seghatchian MJ. et al.. Alterations of factor VIII von Willebrand factor in clinical conditions associated with an increase in its plasma concentration. Br J Haematol 1981; 49: 61-8.
  • 8 Ferro D, Quintarelli C, Lattuada A. et al.. High plasma levels of von Willebrand factor as a marker of endothelial perturbation in cirrhosis: relationship to endotoxemia. Hepatology 1996; 23: 1377-83.
  • 9 Lenting PJ, van Mourik JA, Mertens K. The life cycle of coagulation factor VIII in view of its structure and function. Blood 1998; 92: 3983-96.
  • 10 Yamamoto K, de Waard V, Fearns C. et al.. Tissue distribution and regulation of murine von Willebrand factor gene expression in vivo . Blood 1998; 92: 2791-801.
  • 11 Fukuda Y, Nagura H, Imoto M. et al.. Immunohistochemical studies on structural changes of the hepatic lobules in chronic liver diseases. Am J Gastroenterol 1986; 81: 1149-55.
  • 12 Hattori M, Fukuda Y, Imoto M. et al.. Histochemical properties of vascular and sinusoidal endothelial cells in liver diseases. Gastroenterol Jpn 1991; 26: 336-43.
  • 13 Lenting PJ, Neels JG, van den Berg BM. et al.. The light chain of factor VIII comprises a binding site for low density lipoprotein receptor-related protein. J Biol Chem 1999; 274: 23734-9.
  • 14 Saenko EL, Yakhyaev AV, Mikhailenko I. et al.. Role of the low density lipoprotein-related protein receptor in mediation of factor VIII catabolism. J Biol Chem 1999; 274: 37685-92.
  • 15 Schwarz HP, Lenting PJ, Binder B. et al.. Involvement of low-density lipoprotein receptor-related protein (LRP) in the clearance of factor VIII in von Willebrand factor-deficient mice. Blood 2000; 95: 1703-8.
  • 16 Moestrup SK, Gliemann J, Pallesen G. Distribution of the alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein in human tissues. Cell Tissue Res 1992; 269: 375-82.
  • 17 Pugh RN, Murray-Lyon IM, Dawson JL. et al.. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60: 646-9.
  • 18 Ishikawa T, Ichida T, Matsuda Y. et al.. Reduced expression of thrombopoietin is involved in thrombocytopenia in human and rat liver cirrhosis. J Gastroenterol Hepatol 1998; 13: 907-13.
  • 19 Lenting PJ, Donath MJ, van Mourik JA. et al.. Identification of a binding site for blood coagulation factor IXa on the light chain of human factor VIII. J Biol Chem 1994; 269: 7150-5.
  • 20 Borchiellini A, Fijnvandraat K, ten Cate JW. et al.. Quantitative analysis of von Willebrand factor propeptide release in vivo: effect of experimental endotoxemia and administration of 1-deamino-8-D-arginine vasopressin in humans. Blood 1996; 88: 2951-8.
  • 21 Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987; 162: 156-9.
  • 22 Toole JJ, Knopf JL, Wozney JM. et al.. Molecular cloning of a cDNA encoding human antihaemophilic factor. Nature 1984; 312: 342-7.
  • 23 Jenny RJ, Pittman DD, Toole JJ. et al.. Complete cDNA and derived amino acid sequence of human factor V. Proc Natl Acad Sci U S A 1987; 84: 4846-50.
  • 24 Ginsburg D, Handin RI, Bonthron DT. et al.. Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization. Science 1985; 228: 1401-6.
  • 25 Foca C, Moses EK, Quinn MA. et al.. Differential expression of the alpha(2)-macroglobulin receptor and the receptor associated protein in normal human endometrium and endometrial carcinoma. Mol Hum Reprod 2000; 06: 921-7.
  • 26 Bock SC, Marrinan JA, Radziejewska E. Antithrombin III Utah: proline-407 to leucine mutation in a highly conserved region near the inhibitor reactive site. Biochemistry 1988; 27: 6171-8.
  • 27 Martini G, Toniolo D, Vulliamy T. et al.. Structural analysis of the X-linked gene encoding human glucose 6-phosphate dehydrogenase. EMBO J 1986; 05: 1849-55.
  • 28 Kaufman RJ, Pipe SW, Tagliavacca L. et al.. Biosynthesis, assembly and secretion of coagulation factor VIII. Blood Coagul Fibrinolysis 1997; 8 (Suppl. 02) S3-14. S3-14.
  • 29 Saenko EL, Ananyeva NM, Tuddenham EG. et al.. Factor VIII novel insights into form and function. Br J Haematol 2002; 119: 323-31.
  • 30 Noe DA. A mathematical model of coagulation factor VIII kinetics. Haemostasis 1996; 26: 289-303.
  • 31 Fijnvandraat K, Peters M, ten Cate JW. Interindividual variation in half-life of infused recombinant factor VIII is related to pre-infusion von Willebrand factor antigen levels. Br J Haematol 1995; 91: 474-6.
  • 32 Thompson SG, Kienast J, Pyke SD. et al.. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med 1995; 332: 635-41.
  • 33 Bovenschen N, Herz J, Grimbergen JM. et al.. Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor-related protein deficiency. Blood 2003; 101: 3933-9.