Platelet sequestration and activation during GalTKO.hCD46 pig lung perfusion by human blood is primarily mediated by GPIb, GPIIb/IIIa, and von Willebrand Factor

Background Here, we ask whether platelet GPIb and GPIIb/IIIa receptors modulate platelet sequestration and activation during GalTKO.hCD46 pig lung xenograft perfusion. Methods GalTKO.hCD46 transgenic pig lungs were perfused with heparinized fresh human blood. Results from perfusions in which αGPIb F...

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Published in:Xenotransplantation (Københaven) 2016-05, Vol.23 (3), p.222-236
Main Authors: Burdorf, Lars, Riner, Andrea, Rybak, Elana, Salles, Isabelle I., De Meyer, Simon F., Shah, Aakash, Quinn, Kevin J., Harris, Donald, Zhang, Tianshu, Parsell, Dawn, Ali, Franchesca, Schwartz, Evan, Kang, Elizabeth, Cheng, Xiangfei, Sievert, Evelyn, Zhao, Yuming, Braileanu, Gheorghe, Phelps, Carol J., Ayares, David L., Deckmyn, Hans, Pierson III, Richard N., Azimzadeh, Agnes M.
Format: Article
Language:English
Subjects:
Animals
Animals, Genetically Modified
Blood Platelets - cytology
coagulation
ex-vivo perfusion
Fab
GalTKO.hCD46
Glycoprotein
GPIb
GPIIb/IIIa
Graft Survival - immunology
Heterografts - immunology
Humans
lung
Lung - immunology
Lung - metabolism
Lung Transplantation - methods
platelet activation
Platelet Activation - physiology
Platelet Aggregation - genetics
Platelet Aggregation - immunology
Platelet Glycoprotein GPIb-IX Complex - genetics
Platelet Glycoprotein GPIb-IX Complex - metabolism
Platelet Glycoprotein GPIIb-IIIa Complex - metabolism
Swine
Thrombocytopenia - etiology
Transplantation, Heterologous - methods
von Willebrand Factor - genetics
von Willebrand Factor - metabolism
Xenotransplantation
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Summary:Background Here, we ask whether platelet GPIb and GPIIb/IIIa receptors modulate platelet sequestration and activation during GalTKO.hCD46 pig lung xenograft perfusion. Methods GalTKO.hCD46 transgenic pig lungs were perfused with heparinized fresh human blood. Results from perfusions in which αGPIb Fab (6B4, 10 mg/l blood, n = 6), αGPIIb/IIIa Fab (ReoPro, 3.5 mg/l blood, n = 6), or both drugs (n = 4) were administered to the perfusate were compared to two additional groups in which the donor pig received 1‐desamino‐8‐d‐arginine vasopressin (DDAVP), 3 μg/kg (to pre‐deplete von Willebrand Factor (pVWF), the main GPIb ligand), with or without αGPIb (n = 6 each). Results Platelet sequestration was significantly delayed in αGPIb, αGPIb+DDAVP, and αGPIb+αGPIIb/IIIa groups. Median lung “survival” was significantly longer (>240 vs. 162 min reference, p = 0.016), and platelet activation (as CD62P and βTG) were significantly inhibited, when pigs were pre‐treated with DDAVP, with or without αGPIb Fab treatment. Pulmonary vascular resistance rise was not significantly attenuated in any group, and was associated with residual thromboxane and histamine elaboration. Conclusions The GPIb‐VWF and GPIIb/IIIa axes play important roles in platelet sequestration and coagulation cascade activation during GalTKO.hCD46 lung xenograft injury. GPIb blockade significantly reduces platelet activation and delays platelet sequestration in this xenolung rejection model, an effect amplified by adding αGPIIb/IIIa blockade or depletion of VWF from pig lung.
ISSN:0908-665X
1399-3089
DOI:10.1111/xen.12236