Anti-thrombin III levels in cynomolgus monkey recipients of a life-supporting porcine renal xenograft

Abstract number: P1012

Cozzi^* E., Ancona† E., Boldrin‡ M., Fadin† M., Gavasso† S., Zerbinati† P., Tognin† G., Katopodis‡ A., Bedendo‡ S., Fante‡ F., Lideo‡ L., Baldan‡ N., Busetto‡ R., Girolami† A., Simioni† P.

‡CORIT, Padua, Italy †Department of Medical and Surgical Sciences, Padua University, Italy; ^*Padua General Hospital, Padua, Italy;

Activation of the clotting cascade is a key feature of the rejection process that takes place when a pig organ is transplanted into a primate. In this study the levels of anti-thrombin III (ATIII) were determined before and after xenotransplantation in primate recipients of porcine xenografts, with a view to investigate whether ATIII consumption is an important part of this process and also to determine whether ATIII measurements could be used to monitor the rejection process and predict the outcome of porcine organs transplanted into primates.

Methods  

Five male Cynomolgus monkeys were nephrectomized and received a hDAF pig kidney (Novartis). All recipients received GAS914 (Novartis) and an immunosuppressive regimen consisting of cyclosporine A, cyclophosphamide, mycophenolate sodium, and steroids. ATIII levels were assessed at least three times a week by colorimetric in vitro assay for quantitative ATIII activity determination (Roche Diagnostic) on an automated clinical chemistry analyzer.

Results  

The animals in this study survived between 2 and 37 days; they were euthanized with a rejected xenograft in four cases. Pretransplant ATIII levels were between 107 and 150% of those observed in the human control samples. Immediately after reperfusion, ATIII levels dropped in all five animals to 50–80%. Reduced ATIII levels on the postoperative days 1 and 2 were invariably associated with early poor outcome. Furthermore, ATIII levels returning to normal by day 5 appeared to be a good indicator of prolonged xenograft survival. In the three animals surviving the longest, physiologic or supra-physiologic levels of ATIII were observed from day 4 onwards. Two of these animals were nonetheless sacrificed in the presence of acute humoral xenograft rejection (AHXR).

Conclusion  

These findings suggest that a rapid recovery in ATIII levels following pig-to-primate xenotransplantation appears to be associated with prolonged graft survival. It also suggests, however, that ATIII levels of 100–160% for most of the postoperative period are not sufficient to prevent the activation of the clotting cascade observed in AHXR. It is currently not known whether continuous exposure to supra-physiologic levels (>150%) of ATIII, such as those obtainable with the administration of rhATIII concentrates, can provide protection against rejection of a porcine xenograft transplanted into a primate.