Outcome of orthotopic liver transplantation in patients with haemophilia

Abstract

Background-Many patients with haemophilia have developed cirrhosis or hepatocellular carcinoma due to transfusion acquired chronic viral hepatitis. Aims-To assess the long term outcome of all haemophilic patients reported to have undergone orthotopic liver transplantation. Methods-Transplant centres of patients identified by medical database search were contacted and survival data assessed by Kaplan-Meier analysis. Results-Twenty six haemophilic men (median age 46 years, range 5-63 years) underwent orthotopic liver transplantation in 16 centres between 1982 and 1996. Indications for transplantation were hepatitis C cirrhosis (69%), hepatitis B with or without C cirrhosis (15%), viral hepatitis related hepatocellular carcinoma (12%), and biliary atresia (4%). Six patients (23%) were infected with human immunodeficiency virus (HIV). Postoperatively, the median time to normal clotting factor levels was 24 hours (range 0-48 hours) and exogenous clotting factors were stopped at a median of 24 hours (range 0-480 hours). Four patients (15%) had bleeding complications. The one and three year survival of HIV positive recipients (67% and 23%) was significantly poorer (p=0.0003) than that of HIV negative recipients (90% and 83%). Coagulopathy was cured in all patients surviving more than 12 days post-transplant. Six of the 20 patients (30%) with hepatitis C cirrhosis pretransplant had evidence of disease recurrence at a mean of nine months post-transplant. Conclusions-Hepatitis C cirrhosis is the most common indication for orthotopic liver transplantation in patients with haemophilia. Transplantation results in long term cure of haemophilia but may be complicated by the eVects of HIV infection or recurrent viral hepatitis. (Gut 1998;42:744-749)

Murine coagulation factor VIII is synthesized in endothelial cells

“…[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.…”

“…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.…”

“…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.…”

Orthotopic liver transplantation in patients with human immunodeficiency virus and end-stage liver disease

“…29,30 It is important to recognize that not all patients with HIV and liver failure may be acceptable candidates for OLT. Patients with profound immunosuppression attributable to advanced AIDS or with a detectable viral load caused by HAART therapy from multiple drug resistance may not be good candidates for transplantation at this time.…”

Correction of hemophilia as a proof of concept for treatment of monogenic diseases by fetal spleen transplantation

“…Hepatocytes and liver sinusoidal endothelial cells, but not Kupffer cells, produce factor VIII in the mouse liver (5). The role of the liver in factor VIII synthesis has been supported by liver transplantation studies in both hemophilic animals and humans, after which increasing factor VIII levels were detected (6)(7)(8)(9)(10). Early transplantation studies in the canine model (11,12) led, in the early 1960s, to the first human spleen transplants in four patients with malignancies and one with agammaglobulinemia (13).…”