2011 - CTS-IXA


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Parallel Session 15- Coagulation and Thrombosis I (Xeno Track)

32.398 - Alterations in the coagulation profile of primate recipients of a life-supporting renal xenograft from a α1,3-galactosyltransferase gene-knockout (GTKO) pig

Presenter: Massimo, Boldrin, Padua, Italy
Authors: Massimo Boldrin1, Luca Spiezia2, Marta Vadori1, Nicola Baldan3, Massimo Castagnaro4, Roberto Busetto5, Federica Besenzon1, Diana Bertini1, Fiorella Calabrese6, Sabrina Gavasso2, Emanuele Cozzi1,7, Paolo Simioni2

398

Alterations in the coagulation profile of primate recipients of a life-supporting renal xenograft from a α1,3-galactosyltransferase gene-knockout (GTKO) pig

Massimo Boldrin1, Luca Spiezia2, Marta Vadori1, Nicola Baldan3, Massimo Castagnaro4, Roberto Busetto5, Federica Besenzon1, Diana Bertini1, Fiorella Calabrese6, Sabrina Gavasso2, Emanuele Cozzi1,7, Paolo Simioni2

1Consortium for Research in Organ Transplantation (CORIT); 2Department of Medical and Surgical Sciences, University of Padua Medical School; 3Department of Medical and Surgical Sciences, Padua General Hospital; 4Department of Public Health, Comparative Pathology and Veterinary Hygiene, University of Padua; 5Department of Clinical Veterinary Sciences, University of Padua; 6Department of Pathological Anatomy, University of Padua; 7Direzione Sanitaria, Padua General Hospital; Padua, Italy

Introduction: Activation of the clotting cascade is central in acute humoral xenograft rejection (AHXR) that occurs when pig organs are transplanted into primates. Recently, α1,3-galactosyltransferase gene-knockout (GTKO) pigs expressing multiple transgenes involved in the regulation of the coagulation and complement cascade have been developed. The present study aimed to evaluate the alterations in the coagulation profile following renal pig-to-monkey xenotransplantation.

Materials and Methods: Nine bilaterally nephrectomized cynomolgus monkeys were included in this study. Seven received a kidney from GTKO pigs transgenic for human CD46, CD55, CD59, CD39 and fucosyltransferase (HTF), and were treated at induction with rituximab (Group A). Two monkeys (Group B) received a xenograft from GTKO pigs transgenic for human CD55 and an induction regimen with cyclophosphamide (up to 4 doses). All recipients also received Cyclosporin A, Mycophenolate Sodium and steroids. In a preliminary evaluation, conventional clotting parameters were considered (i.e. Platelet counts, prothrombin time, activated partial thromboplastin time, fibrinogen, and antithrombin).

Results: Mean survival times were 11.2 ± 4.5 days (Group A) and 8 days (Group B). Seven out of nine animals were euthanized due to renal failure, one due to lung hemorrhage, one due to abdominal bleeding. In all cases, histology showed different degrees of AHXR ranging from I to III. Interestingly, in all nine animals the coagulation profile showed a dramatic drop of platelet counts and fibrinogen from day 4 onwards, in the presence of overall stable levels of clotting inhibitors, including antithrombin.

Conclusions: This study shows that, in pig-to-primate xenotransplantation using kidneys from GTKO pigs, AHXR is associated with a severe selective consumption of fibrinogen and platelets which predicted a bad graft outcome. In contrast, levels of clotting inhibitors do not seem to be affected by the coagulopathy observed in these GTKO-based models.


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