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

Abstract

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.)

Auxiliary Partial Orthotopic Liver Transplantation as a Treatment for Hemophilia A: A Case Report

“…This result is similar to that of a case report on use of a total liver graft [12]. A nonhuman animal model of APOLT for hemophilia also showed a similar level of factor VIII (w40%), which was observed for 7 weeks [13].…”

In vivo models of haemophilia – status on current knowledge of clinical phenotypes and therapeutic interventions

“…Ko et al. [92] performed a study in a haemophilic dog with a FVIII activity <5% (The Queens University colony) in which they by auxiliary partial orthotopic liver transplantation (APOLT) were able to cure haemophilia. By transplantation of a liver lobe graft from a normal dog (FVIII activity >60%), the FVIII activity in the haemophilic dog was increased to 30% and sustained for an observation period of 6 weeks.…”

Progress and challenges in the development of a cell‐based therapy for hemophilia A

“…Early transplant studies in these dogs showed that liver transplantation could correct the bleeder phenotype but that transplant of spleen or kidney did not have consistent or lasting positive effects . Beagles can also suffer from hemophilia A and have been used to show the efficacy of auxiliary partial orthotopic liver transplantation to treat hemophilia A . With the identification of the liver as the major source of FVIII, efforts focused on which cells in this organ were responsible for FVIII production.…”