Purpose: As previously reported, the development of GalTKO pigs with additional expression of hCD46 has contributed to a significantly improved outcome of lungs in an ex vivo xenogenic perfusion setting. However, survival of those lungs varies from a very early failure to an elective termination after 4h of perfusion. Here we evaluate factors that correlate with early GalTKO.hCD46 lung failure.
Methods: 33 transgenic GalTKO.hCD46 pig lungs were perfused with heparinized fresh human blood until failure (by oxygenation or PA flow and pressure criteria) or elective termination at 4 hours. Based on the survival time, experiments were divided into 3 groups (group 1: survival <120; 2: 120<240; 3: 240). Blood samples, collected though out the perfusion, were analyzed for complement – and coagulation cascade activation parameters. In addition, pre-perfusion non-Gal-IgM antibody levels were measured in the blood.
Results: Median survival time was 171 with 11 lungs surviving <120, 12 between 120<240 and 10 lungs surviving to the elective termination. Pre-perfusion non-Gal-IgM levels were the lowest in group 1 (12.5±4.0 vs. (2) 15.9±9.1 vs. (3) 18.5±5.2) There was no difference in C3a-levels between the groups. Platelet activation in early failing grafts was significantly higher at 60 when compared to surviving lungs (ΔBTG: 786±444 vs. 261±157, p=0.0058). Both, group 1 (ΔF1+2 at 60: 12.1±10.8 vs. 2.7±1.6, p=0.0159) and group 2 (at 120: 14.0 ±9.2 vs. 5.9±3.6, p=0.0173) showed a significantly higher Thrombin generation than lungs in group 3. Platelet sequestration tended to be lower in surviving lungs when compared to lungs failing within 2 hours (% of initial platelets remaining at 60: 61±49 vs. 24±13, p=0.057).
Conclusion: Results of this analysis demonstrate that intensity of initial coagulation cascade and platelet activation (but not complement activation or anti-non-Gal IgM level) correlates with the outcome of xenogenic lung perfusion. We conclude that targeting coagulation and platelet activation, rather than complement or antibody, are required to improve survival of xenogenic lungs.
To cite this abstract in AMA style:Burdorf L, Rybak E, Zhang T, Riner A, Braileanu G, Cheng X, Phelps C, Ayares D, Azimzadeh A, Pierson R. Thrombin Generation and Platelet Activation in a Xenogenic Lung Perfusion Model Determine Survival of GalTKO.hCD46 Transgenic Lungs [abstract]. Am J Transplant. 2013; 13 (suppl 5). http://atcmeetingabstracts.com/abstract/thrombin-generation-and-platelet-activation-in-a-xenogenic-lung-perfusion-model-determine-survival-of-galtko-hcd46-transgenic-lungs/. Accessed June 23, 2018.
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