Platelet sequestration and activation during GalTKO.hCD46 pig lung perfusion by human blood is primarily mediated by GPIb, GPIIb/IIIa, and VWF
| Autor: | L, Burdorf, A, Riner, E, Rybak, I I, Salles, S F, De Meyer, A, Shah, K J, Quinn, D, Harris, T, Zhang, D, Parsell, F, Ali, E, Schwartz, E, Kang, X, Cheng, E, Sievert, Y, Zhao, G, Braileanu, C J, Phelps, D L, Ayares, H, Deckmyn, R N, Pierson, A M, Azimzadeh, Amy, Dandro, Kasinath, Karavi |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Blood Platelets
0301 basic medicine Vasopressin Platelet Aggregation Swine Thromboxane Transplantation Heterologous Immunology Platelet Glycoprotein GPIIb-IIIa Complex 030230 surgery Pharmacology Article Animals Genetically Modified 03 medical and health sciences 0302 clinical medicine Von Willebrand factor von Willebrand Factor medicine Animals Humans Platelet Platelet activation Lung Transplantation biology Chemistry Graft Survival Platelet Activation Thrombocytopenia 030104 developmental biology medicine.anatomical_structure Platelet Glycoprotein GPIb-IX Complex Coagulation Vascular resistance biology.protein Heterografts Perfusion Lung Transplantation |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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