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Platelet sequestration and activation during GalTKO.hCD46 pig lung perfusion by human blood is primarily mediated by GPIb, GPIIb/IIIa, and von Willebrand Factor
Author(s) -
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 Richard N.,
Azimzadeh Agnes M.
Publication year - 2016
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.12236
Subject(s) - platelet , von willebrand factor , platelet activation , chemistry , thromboxane a2 , medicine , immunology , bleeding time , pharmacology , platelet aggregation
Abstract Background Here, we ask whether platelet GPI b and GPII b/ III a receptors modulate platelet sequestration and activation during Gal TKO . hCD 46 pig lung xenograft perfusion. Methods Gal TKO . hCD 46 transgenic pig lungs were perfused with heparinized fresh human blood. Results from perfusions in which α GPI b Fab (6B4, 10 mg/l blood, n = 6), α GPII b/ III a 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 μ g/kg (to pre‐deplete von Willebrand Factor ( pVWF ), the main GPI b ligand), with or without α GPI b (n = 6 each). Results Platelet sequestration was significantly delayed in α GPI b, α GPI b+ DDAVP , and α GPI b+α GPII b/ III a groups. Median lung “survival” was significantly longer (>240 vs. 162 min reference, p = 0.016), and platelet activation (as CD 62P and β TG ) were significantly inhibited, when pigs were pre‐treated with DDAVP , with or without α GPI b Fab treatment. Pulmonary vascular resistance rise was not significantly attenuated in any group, and was associated with residual thromboxane and histamine elaboration. Conclusions The GPI b‐ VWF and GPII b/ III a axes play important roles in platelet sequestration and coagulation cascade activation during Gal TKO . hCD 46 lung xenograft injury. GPI b blockade significantly reduces platelet activation and delays platelet sequestration in this xenolung rejection model, an effect amplified by adding α GPII b/ III a blockade or depletion of VWF from pig lung.