Recombinant human antithrombin prevents xenogenic activation of hemostasis in a model of pig-to-human kidney transplantation.

Abstract

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 (rhAPC) mitigates XAH and TMA in an ex vivo model of pig-to-human kidney transplantation. However, the use of rhAPC 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 (rhAT), in comparison with rhAPC. Unmodified porcine kidneys (n = 25) were perfused ex vivo with porcine blood, human blood, or human blood supplemented with rhAPC or rhAT. 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 rhAT 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 rhAT was dose-dependent with maximum protection obtained at 3 IU/ml.

CONCLUSION:

In conclusion, in this ex vivo model of discordant xenotransplantation, rhAT reduced XAH and prevented TMA in doses that appear feasible for use in clinical or preclinical transplantation settings.

• Authors: Wolf Ramackers, Lars Friedrich, Johannes Klose, Florian Vondran, Sabine Bergmann, Wolfgang Schüttler, Kai Johanning, Sonja Werwitzke, Arne Trummer, Verena Bröcker, Jürgen Klempnauer, Michael Winkler, Andreas Tiede
• Journal: Xenotransplantation (Xenotransplantation) 2014 Jul-Aug Vol. 21 Issue 4 Pg. 367-75 ISSN: 1399-3089 [Electronic] Denmark
• PMID: 24807299 (Publication Type: Journal Article)
• Copyright: © 2014 John Wiley & Sons A/S Published by John Wiley & Sons Ltd.

Chemical References

• Antithrombin Proteins
• E-Selectin
• Protein C
• Recombinant Proteins

Topics

• Animals
• Antithrombin Proteins (administration & dosage)
• Blood Coagulation (drug effects)
• Dose-Response Relationship, Drug
• E-Selectin (genetics, metabolism)
• Hemostasis (drug effects)
• Humans
• Kidney (blood supply, pathology)
• Kidney Transplantation (adverse effects, methods)
• Male
• Models, Biological
• Perfusion
• Platelet Activation (drug effects)
• Protein C (administration & dosage)
• Recombinant Proteins (administration & dosage)
• Sus scrofa
• Thrombotic Microangiopathies (blood, etiology, prevention & control)
• Transplantation, Heterologous (adverse effects, methods)
• Vascular Resistance (drug effects)