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Recombinant human antithrombin prevents xenogenic activation of hemostasis in a model of pig‐to‐human kidney transplantation
Author(s) -
Ramackers Wolf,
Friedrich Lars,
Klose Johannes,
Vondran Florian,
Bergmann Sabine,
Schüttler Wolfgang,
Johanning Kai,
Werwitzke Sonja,
Trummer Arne,
Bröcker Verena,
Klempnauer Jürgen,
Winkler Michael,
Tiede Andreas
Publication year - 2014
Publication title -
xenotransplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.052
H-Index - 61
eISSN - 1399-3089
pISSN - 0908-665X
DOI - 10.1111/xen.12104
Subject(s) - ex vivo , antithrombin , xenotransplantation , hemostasis , transplantation , thrombotic microangiopathy , platelet activation , platelet , immunology , heparin , medicine , kidney , in vivo , biology , microbiology and biotechnology , disease
Background Xenogenic activation of hemostasis ( XAH ) represents a major hurdle for the transplantation of discordant animal organs into humans as it results in thrombotic microangiopathy ( TMA ). We have previously shown that recombinant human‐activated protein C (rh APC ) mitigates XAH and TMA in an ex vivo model of pig‐to‐human kidney transplantation. However, the use of rh APC may not be feasible in a perioperative setting due to possible bleeding complications. Methods Here, we explored the effects of another natural inhibitor of coagulation, human recombinant antithrombin (rh AT ), in comparison with rh APC . Unmodified porcine kidneys (n = 25) were perfused ex vivo with porcine blood, human blood, or human blood supplemented with rh APC or rh AT . Surrogate parameters of organ survival, markers of XAH (D‐ Dimer, thrombin‐antithrombin complex [ TAT ], fibrinogen, antithrombin activity, plasminogen), endothelial cell and platelet activation (E‐selectin, P‐selectin), platelet function tests and histological signs of TMA were evaluated. Results Perfusion was feasible for > 240 min in all experiments with autologous porcine blood, but limited to 126 ± 78 min with human blood due to increased vascular resistance. Addition of rh AT protected from TMA and allowed for perfusion times > 240 min. In addition, there were less signs of XAH with reduced release of P‐selectin and overexpression of E‐selectin, whereas the progressive loss of platelet function, observed during discordant perfusion, was prevented. The effect of rh AT was dose‐dependent with maximum protection obtained at 3 IU/ml. Conclusion In conclusion, in this ex vivo model of discordant xenotransplantation, rh AT reduced XAH and prevented TMA in doses that appear feasible for use in clinical or preclinical transplantation settings.