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Presenter: Lars, Burdorf, Baltimore, United States
Authors: Lars Burdorf1, Tianshu Zhang1, Elana Rybak1, Katleen Broos2, Emily Welty1, Christopher Avon1, Amal Laaris1, Xiangfei Cheng1, David Ayares3, Hans Deckmyn2, Agnes M Azimzadeh1, Richard N Pierson III1
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Combined GPIb and GPIIb/IIIa blockade prevents sequestration of platelets in a pig-to-human lung perfusion model
Lars Burdorf1, Tianshu Zhang1, Elana Rybak1, Katleen Broos2, Emily Welty1, Christopher Avon1, Amal Laaris1, Xiangfei Cheng1, David Ayares3, Hans Deckmyn2, Agnes M Azimzadeh1, Richard N Pierson III1
1Department of Surgery, University of Maryland, Baltimore, MD, United States; 2Laboratory for Thrombosis Research, KU Leuven Campus Kortrijk, Leuven, Belgium; 3Revivicor Inc., Blacksburg, VA, United States
Purpose: Perfusion of GalTKO.hCD46 pig lungs with human blood is associated with the immediate sequestration of circulating platelets. GPIb (to von Willebrand factor (vWF)) and GPIIb/IIIa (by variouscoagulation cascade ligands) receptors mediate binding of platelets to other platelets and to injured vessel wall component, leading to platelet activation, aggregation, and sequestration. Here we evaluate whether the administration of an aGPIb Fab in combination with aGPIIb/IIIa Fab prevents platelet sequestration during a xenogeneic lung perfusion.
Methods: GalTKO.hCD46 transgeneic pig lungs were perfused with heparinized fresh human blood until failure or elective termination at 4h. In 4 pairedexperiments aGPIb (6B4, 10mg/L blood) and aGPIIb/IIIa (ReoPro, 3.5mg/L blood) were administered as single dose to the circulating blood before the perfusion of one lung was started, while the contralateral lung circuit received aGPIIb/IIIa alone. As a reference, 7 GalTKO.hCD46 lung pairs were either untreated or treated with aGPIb.
Results: Platelet sequestration was significantly reduced when aGPIb and aGPIIb/IIIa were added simultaneously to the perfusate (% of initial platelets remaining at 120’: 84±21 vs. aGPIIb/IIIa 60±25, p=0.03: vs. aGPIb 33±15, p=0.006: vs. untreated 37±29, p=0.043). Pulmonary vascular resistance (PVR) tended to be lower in the combined treatment group (58±31 vs. aGPIIb/IIIa 104±51 at 90’; p=0.246). Median survival time and neutrophil sequestration were not significantly altered by combined treatment compared to reference groups.
Conclusion: Administration of aGPIb and aGPIIb/IIIa significantly decreases platelet sequestration during GalTKO.hCD46 pig lung perfusion with human blood, demonstrating that GPIb-vWF and GPIIb/IIIa-ligand interactions mediate this phenomenon. Additional aGPIIb/IIIa attenuates the delayed platelet sequestration seen with aGPIb monotherapy. This observation supports the hypothesis that efficiently inhibiting elaboration of GPIIb/IIIa coagulation cascade ligands by further modifications to the pig may be sufficient to replace aGPIIb/IIIa as the basis for a clinically applicable strategy to prevent platelet sequestration in this model.
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