Clinical Cure of Haemophilia a by Liver Transplantation

Scharrer, I.; Encke, A.; Hottenrott, C

doi:10.1016/s0140-6736(88)92456-7

Cited by 25 publications

(20 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These results account for the successful reversal of hemophilia A by liver transplantation and presumably also by lung and spleen transplantation. [5][6][7]13,14 These results are also consistent with the maintenance of normal FVIII levels in patients with parenchymal liver disease in whom the endothelium may still be intact. [42][43][44] The variable levels of endothelial cell mRNA enrichment across tissues likely reflects differences in mRNA expression profiles and the relative ratio of endothelial to parenchymal cells in different vascular beds.…”

Section: Discussionsupporting

confidence: 69%

“…[2][3][4][5][6][7][8]10,11,13,14,[16][17][18][19][20][21] We took advantage of the dependence of efficient FV and FVIII secretion on LMAN1 to examine the cellular biosynthetic source of each protein in vivo. Although both the human For personal use only.…”

Section: Discussionmentioning

confidence: 99%

“…49 In addition, FVIII activity levels were found to be 10-to 100-fold higher in human LSECs than in hepatocytes separated by flow-cytometry cell sorting. 50 Nonetheless, other studies have detected FVIII in human hepatocytes, [5][6][7][8]51 and differences in the pathway for FVIII production between humans and mice cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

“…1 Dozens of conflicting reports have implicated numerous cell and tissue types as the source of FVIII, though the majority of evidence points to either an endothelial and/or hepatocyte origin of FVIII synthesis. [2][3][4] Multiple curative organ transplantation studies in hemophilia A patients and experimental dog models have shown that the liver contributes significantly to FVIII biosynthesis, [5][6][7][8] though the failure of FVIII levels in hemophilia A liver transplant recipients to respond to desmopressin suggested FVIII localization to a different compartment than VWF. 9 As early as 1971, Webster et al demonstrated extrahepatic FVIII synthesis by showing that FVIII synthesis was maintained after replacing the livers of normal dog recipients with hemophilic livers.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Murine coagulation factor VIII is synthesized in endothelial cells

Everett

Cleuren

Khoriaty³

et al. 2014

Blood

160

145

View full text Add to dashboard Cite

• Lman1 tissue-specific knockout mice reveal that endothelial cells, not hepatocytes, are the primary source of FVIII biosynthesis.• F8 gene expression is heterogeneous among endothelial cell populations in different tissues.The primary cellular source of factor VIII (FVIII) biosynthesis is controversial, with contradictory evidence supporting an endothelial or hepatocyte origin. LMAN1 is a cargo receptor in the early secretory pathway that is responsible for the efficient secretion of factor V (FV) and FVIII to the plasma. Lman1 mutations result in combined deficiency of FV and FVIII, with levels of both factors reduced to ∼10% to 15% of normal in human patients. We generated Lman1 conditional knockout mice to characterize the FVIII secretion profiles of endothelial cells and hepatocytes. We demonstrate that endothelial cells are the primary biosynthetic source of murine FVIII and that hepatocytes make no significant contribution to the plasma FVIII pool. Utilizing RiboTag mice and polyribosome immunoprecipitation, we performed endothelial cell-specific messenger RNA isolation and quantitative polymerase chain reaction analyses to confirm that endothelial cells highly express F8 and to explore the heterogeneity of F8 expression in different vascular beds. We demonstrate that endothelial cells from multiple, but not all, tissues contribute to the plasma FVIII pool in the mouse. (Blood. 2014;123(24):3697-3705)

show abstract

Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Murine coagulation factor VIII is synthesized in endothelial cells

Everett

Cleuren

Khoriaty³

et al. 2014

Blood

160

145

View full text Add to dashboard Cite

show abstract

“…3,4 Additionally, liver is the only tissue that has been shown conclusively to produce fVIII when transplanted into fVIII-deficient (hemophilia A) canines or humans, as evident by alleviation of the bleeding phenotype. [5][6][7] However, during the course of fulminant hepatic failure (FHF) induced by acetaminophen or viral hepatitis, plasma fVIII activity can increase to more than 10 times normal levels. 8,9 The cellular source of this superphysiologic fVIII activity is currently unknown.…”

Section: Introductionmentioning

confidence: 99%

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

Doering

Parker

Nichols

et al. 2003

Blood

View full text Add to dashboard Cite

Preclinical experiment of auxiliary partial orthotopic liver transplantation as a curative treatment for hemophilia

Tanaka

Kanehiro

et al. 2005

Liver Transpl

View full text Add to dashboard Cite

The cause of hemophilia is deficiency of coagulation factor VIII production in the liver, which can be cured by liver transplantation. Because the hepatic function of hemophilia patients is quite normal except for production of factor VIII, auxiliary partial orthotopic liver transplantation (APOLT) is beneficial in that patient survival is secured by preserving native liver even in the event of graft loss. However, it is not known whether the graft of APOLT would be enough to cure hemophilia. We evaluated the efficacy and feasibility of APOLT for hemophilia in a canine hemophilia A model that we established. Partial left liver graft was taken from the normal donor (blood factor VIII activity > 60%). The graft was transplanted to the hemophilia beagle dog (blood factor VIII activity < 5%) after resection of the left lobe preserving native right lobe. Changes in time of blood factor VIII activity and liver function parameters were observed after APOLT. APOLT and perioperative hemostatic management were successfully performed. The blood factor VIII activity increased to 30% after APOLT, and was sustained at least 6 weeks throughout the observation period without symptoms of bleeding. The result demonstrated sustained production of factor VIII in the hemophilia recipient after APOLT. Transplantation of approximately one third of whole liver resulted in cure of hemophilia. In conclusion, it is suggested that APOLT would be feasible as a curative treatment of hemophilia A to improve quality of life of the patients. (Liver Transpl 2005;11:579-584.)

show abstract

Clinical Cure of Haemophilia a by Liver Transplantation

Cited by 25 publications

References 2 publications

Murine coagulation factor VIII is synthesized in endothelial cells

Murine coagulation factor VIII is synthesized in endothelial cells

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

Preclinical experiment of auxiliary partial orthotopic liver transplantation as a curative treatment for hemophilia

Contact Info

Product

Resources

About