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
References
1
Kelly DA,
Summerfield JA.
Hemostasis in liver disease. Semin Liver Dis 1987; 07: 182-91.
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.
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.
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.
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.
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.
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.
