Assay of Plasma Antihemophilic Activity in Normal, Heterozygous (Hemophilia) and Prothrombinopenic Dogs.

Graham, John B.; Collins, Dana; Godwin, IR; Brinkhous, K. M.

doi:10.3181/00379727-77-18755

Cited by 27 publications

(7 citation statements)

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“…The fact that antihaemophilic globulin is not diminished in parallel with the fall in other plasma factors indicates that this factor is syn-thesized elsewhere than in the liver. It is interesting to note that Graham, Collins, Godwin, and Brinkhous (1951) have shown that in severe liver damage in dogs the antihaemophilic globulin level remains normal although other plasma coagulation factors are deficient. Cause of Bleeding in Patients.-It was noticed that, even when plasma coagulation factors were markedly reduced, bleeding did not always occur.…”

Section: Discussionmentioning

confidence: 99%

Coagulation Defects in Liver Disease

Cowling¹

1956

Journal of Clinical Pathology

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Section: Discussionmentioning

confidence: 99%

Coagulation Defects in Liver Disease

Cowling¹

1956

Journal of Clinical Pathology

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“…[1][2][3][4] Factor VIII messenger RNA (mRNA) is present in nearly every tissue examined, including liver, spleen, lymph node, heart, brain, lung, kidney, testes, muscle, and placenta. [5][6][7] The liver clearly is an important site of synthesis because liver transplantation cures human and canine hemophilia A.…”

Section: Introductionmentioning

confidence: 99%

Factor VIII expression in azoxymethane-induced murine fulminant hepatic failure

Doering

Josephson

Craddock

et al. 2002

Blood

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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 g/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 synthe- IntroductionDespite more than 50 years of investigation, the nature of factor VIII biosynthesis in vivo remains poorly understood. [1][2][3][4] Factor VIII messenger RNA (mRNA) is present in nearly every tissue examined, including liver, spleen, lymph node, heart, brain, lung, kidney, testes, muscle, and placenta. [5][6][7] The liver clearly is an important site of synthesis because liver transplantation cures human and canine hemophilia A. [8][9][10] However, the relative contribution of hepatocytes and liver sinusoidal endothelial cells remains uncertain. 7,[11][12][13][14][15] Furthermore, the contribution of extrahepatic biosynthesis of factor VIII in health and disease states is not known.Paradoxically, there usually is a significant rise in plasma factor VIII activity in human fulminant hepatic failure (FHF). [16][17][18][19] This increase can be more than 14 times normal levels and occurs simultaneously with profound decreases in the circulating levels of vitamin K-dependent and fibrinolytic plasma proteins. 16,20,21 The analysis of this phenomenon has been hindered by the lack of a reproducible animal model of FHF. However, a murine model of FHF recently was developed using the hepatotoxin azoxymethane (AOM), which is found in cycad palm nuts on the island of Guam. 22 AOM-treated mice develop hepatocellular necrosis, elevated liver transaminase and ammonia levels in blood and hepatic encephalopathy. They die within days, with death related to the dose of AOM. In this study, we examined the expression of factor VIII and several other hemostatic factors, including factors V, VII, and IX, and von Willebrand factor (VWF) in AOM-induced murine FHF. Materials and methods MaterialsMale C57BL/6 mice (22-30 g body weight) were purchased from Charles River Laboratory (Wilmington, MA). AOM and TriReagent were purchased from Sigma (St Lou...

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“…This means biochemically either that a single normal allele at the Stuart locus does not furnish enough enzymatic activity or substrate at some point in the synthetic metabolic pathway to maintain the level of the factor at that of "wild type," or that the mutant gene inhibits some step (21). The normal allele at this locus is therefore, in its overall effect, like that for Factor V in some pedigrees (18,19), some pedigrees of Christmas disease (22,23), and some pedigrees of mild hemophilia (24), and unlike the allele for classic hemophilia (22,23,25 …”

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confidence: 99%