title: Impact of thrombocytopenia on survival of baboons with genetically modified pig liver transplants: clinical relevance.
abstract: A lack of deceased human donor livers leads to a significant mortality in patients with acute-on-chronic or acute (fulminant) liver failure or with primary nonfunction of an allograft. Genetically engineered pigs could provide livers that might bridge the patient to allotransplantation. Orthotopic liver transplantation in baboons using livers from alpha1,3-galactosyltransferase gene-knockout (GTKO) pigs (n = 2) or from GTKO pigs transgenic for CD46 (n = 8) were carried out with a clinically acceptable immunosuppressive regimen. Six of 10 baboons survived for 4-7 days. In all cases, liver function was adequate, as evidenced by tests of detoxification, protein synthesis, complement activity and coagulation parameters. The major problem that prevented more prolonged survival beyond 7 days was a profound thrombocytopenia that developed within 1 h after reperfusion, ultimately resulting in spontaneous hemorrhage at various sites. We postulate that this is associated with the expression of tissue factor on platelets after contact with pig endothelium, resulting in platelet and platelet-peripheral blood mononuclear cell(s) aggregation and deposition of aggregates in the liver graft, though we were unable to confirm this conclusively. If this problem can be resolved, we would anticipate that a pig liver could provide a period during which a patient in liver failure could be successfully bridged to allotransplantation.
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Ekser
authors.forename: C
authors.initials: C
authors.lastname: Long
authors.forename: G J
authors.initials: GJ
authors.lastname: Echeverri
authors.forename: H
authors.initials: H
authors.lastname: Hara
authors.forename: M
authors.initials: M
authors.lastname: Ezzelarab
authors.forename: C C
authors.initials: CC
authors.lastname: Lin
authors.forename: M E
authors.initials: ME
authors.lastname: de Vera
authors.forename: R
authors.initials: R
authors.lastname: Wagner
authors.forename: E
authors.initials: E
authors.lastname: Klein
authors.forename: R F
authors.initials: RF
authors.lastname: Wolf
authors.forename: D
authors.initials: D
authors.lastname: Ayares
authors.forename: D K C
authors.initials: DK
authors.lastname: Cooper
authors.forename: B
authors.initials: B
authors.lastname: Gridelli
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001777:Blood Coagulation / Q000276:immunology; D005260:Female; D005700:Galactosyltransferases / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000276:immunology; D008099:Liver / Q000276:immunology; D017093:Liver Failure / Q000276:immunology; D016031:Liver Transplantation / Q000276:immunology*; D008297:Male; D010215:Papio; D034421:Sus scrofa; D013921:Thrombocytopenia / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; D005700:Galactosyltransferases; C047006:N-acetyllactosaminide alpha-1,3-galactosyltransferase