Decreased factor VIII levels during acetaminophen-induced murine fulminant hepatic failure

Abstract During human fulminant hepatic failure (FHF) circulating levels of most hemostatic proteins fall dramatically. Concurrently, factor VIII (fVIII) procoagulant activity rises despite destruction of the hepatocytes considered responsible for fVIII synthesis. This observation suggests a role for cells other than hepatocytes in fVIII biosynthesis during FHF. We have attempted to identify nonhepatocytic sites of fVIII biosynthesis by inducing FHF in mice using acetaminophen overdose, a common cause of human FHF. Acetaminophen-treated mice consistently displayed signs characteristic of FHF, including elevated plasma aminotransferase activity. However, acetaminophen-treated mice demonstrated markedly reduced fVIII activity, contrary to the observation in human FHF. von Willebrand factor antigen levels were only mildly reduced, suggesting that the decrease in fVIII is not secondary to loss of von Willebrand factor. These results imply that there are fundamental differences in the regulation of plasma fVIII levels between humans and mice.

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Factor VIII expression in azoxymethane-induced murine fulminant hepatic failure

Blood ◽

10.1182/blood.v100.1.143 ◽

2002 ◽

Vol 100 (1) ◽

pp. 143-147 ◽

Cited By ~ 19

Author(s):

Christopher B. Doering ◽

Cassandra D. Josephson ◽

Heather N. Craddock ◽

Pete Lollar

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Fulminant Hepatic Failure ◽

Hepatic Failure ◽

Messenger Rna ◽

Coagulation Factor ◽

Cellular Damage ◽

Mrna Levels ◽

Von Willebrand ◽

Willebrand Factor

Abstract Fulminant hepatic failure (FHF) in humans produces a bleeding diathesis due in large part to a reduction in the biosynthesis of liver-derived coagulation factors. Remarkably, factor VIII procoagulant activity is elevated in most of these patients despite widespread liver cell death. FHF can be modeled in mice by administration of azoxymethane, the active ingredient found in cycad palm nuts. We compared the expression of factor VIII to other hepatic hemostatic factors in azoxymethane-induced murine FHF. Mice displayed dose-dependent decreases in all coagulation factor activities measured, including factors V, VII, VIII, and IX. At the highest dose of azoxymethane (50 μg/g body weight), factor VIII activity in plasma decreased by 98% within 36 hours after treatment, which was associated with an 80% reduction in hepatic factor VIII messenger RNA (mRNA). In contrast, factor VIII mRNA levels in spleen, kidney, and lung tissue of azoxymethane-treated mice were unchanged. Cellular damage in these mice appeared to be limited to hepatocytes as evident by histologic examination. This finding is supported by 2 observations. First, hepatic mRNA levels of von Willebrand factor, which is synthesized by liver sinusoidal endothelial cells but not hepatocytes, were unchanged. Second, von Willebrand factor was detected antigenically in liver sections of azoxymethane-treated mice by immunofluorescence. These results indicate that the contribution of the liver to factor VIII biosynthesis is not replaced or significantly supplemented by other tissues in this model of FHF.

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Comparative Study of Intranasal, Subcutaneous and Intravenous Administration of Desamino-D-Arginine Vasopressin (DDAVP)

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661458 ◽

1986 ◽

Vol 55 (01) ◽

pp. 108-111 ◽

Cited By ~ 55

Author(s):

M Köhler ◽

P Hellstern ◽

C Miyashita ◽

G von Blohn ◽

E Wenzel

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Factor Xii ◽

Additional Advantage ◽

Mean Values ◽

Routes Of Administration ◽

The Mean ◽

Von Willebrand ◽

Willebrand Factor ◽

Factor Antigen

SummaryThis study was performed to evaluate the influence of different routes of administration on the efficacy of DDAVP treatment. Ten healthy volunteers received DDAVP intranasally (i.n.), subcutaneously (s.c.) and intravenously (i.v.) in a randomized cross-over trial. Factor XII and high molecular weight (HMW)-kininogen levels increased only slightly after DDAVP administration. The mean increase of factor VIII: C was 3.1 (i. v.), 2.3 (s. c.), and 1.3 (i.n.) - fold over baseline. Ristocetin cofactor (von Willebrand factor antigen) increased 3.1 (2.5), 2.0 (2.3) and 1.2 (1.2) - fold over baseline mean values after i.v., s.c. and i.n. DDAVP, respectively. The half-disappearance time of factor VIII and von Willebrand factor (vWF) after DDAVP ranged from five (factor VIII: C) to eight hours (vWF). The mean increase of fibrinolytic activity was more pronounced after i.v. DDAVP. The antidiuretic effect was moderate with no apparent differences between the routes of application. This study provides further evidence that both i.v. and s.c. DDAVP administration result in an appropriate and reliable stimulation of haemostasis. An additional advantage of s. c. administration is its suitability for home treatment.

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The mutation Arg (53)----Trp causes von Willebrand disease Normandy by abolishing binding to factor VIII. Studies with recombinant von Willebrand factor

Blood ◽

10.1182/blood.v79.3.563.563 ◽

1992 ◽

Vol 79 (3) ◽

pp. 563-567 ◽

Cited By ~ 30

Author(s):

S Jorieux ◽

EA Tuley ◽

C Gaucher ◽

C Mazurier ◽

JE Sadler

Keyword(s):

Amino Acid ◽

Factor Viii ◽

Von Willebrand Factor ◽

Protein Complex ◽

Von Willebrand Disease ◽

Cho Cell ◽

Fviii Activity ◽

New Variant ◽

Von Willebrand ◽

Willebrand Factor

Abstract von Willebrand factor (vWF) and factor VIII (FVIII) circulate in plasma as a noncovalently linked protein complex. The FVIII/vWF interaction is required for the stabilization of procoagulant FVIII activity. Recently, we reported a new variant of von Willebrand disease (vWD) tentatively named “Normandy,” characterized by plasma vWF that appears to be structurally and functionally normal except that it does not bind FVIII. Three patients from one family were found to be homozygous for a C----T transition at codon 816 converting Arg 53 to Trp in the mature vWF subunit. To firmly establish a causal relationship between this missense mutation and vWD Normandy phenotype, we have characterized the corresponding recombinant mutant vWF(R53W). Expressed in COS-7 cells or CHO cell lines, normal vWF and vWF(R53W) were processed and formed multimers with equal efficiency. However, vWF(R53W) exhibited the same defect in FVIII binding as did plasma vWF from patients with vWD Normandy, confirming that this mutation is responsible for the vWD Normandy phenotype. These results illustrate the importance of Arg 53 of the mature vWF subunit for the binding of FVIII to vWF, and identify an amino acid residue within a disulfide loop not previously known to be involved in this interaction.

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