Inhibiting GPIb? Shedding Preserves Post-Transfusion Recovery and Hemostatic Function of Platelets After Prolonged Storage.

ABSTRACT: The platelet storage lesion accelerates platelet clearance after transfusion, but the underlying molecular mechanism remains elusive. Although inhibiting sheddase activity hampers clearance of platelets with storage lesion, the target platelet protein responsible for ectodomain shedding-induced clearance is not definitively identified. Monoclonal antibody 5G6 was developed recently to bind specifically human platelet receptor glycoprotein (GP)Ib? and inhibit its shedding but not shedding of other receptors. Here, the role of GPIb? shedding in platelet clearance after transfusion was addressed.Both human leukoreduced apheresis-derived platelets and transgenic mouse platelets expressing human GPIb? were stored at room temperature in the presence and absence of 5G6 Fab fragment. At various time points, aliquots of stored platelets were analyzed and compared. 5G6 Fab inhibited GPIb? shedding in both platelets during storage and preserved higher level of GPIb? on the platelet surface. Compared with age-matched control platelets, 5G6 Fab-stored platelets exhibited similar levels of platelet activation, degranulation, and agonist-induced aggregation. 5G6 Fab-stored human GPIb? platelets exhibited significantly higher post-transfusion recovery and in vivo hemostatic function in recipient mice than control platelets. Consistently, 5G6 Fab-stored, 8-day-old human platelets produced similar improvement in post-transfusion recovery in immunodeficient mice and in ex vivo thrombus formation over collagen under shear flow.Specific inhibition of GPIb? shedding in the stored platelets improves post-transfusion platelet recovery and hemostatic function, providing clear evidence for GPIb? shedding as a cause of platelet clearance. These results suggest that specific inhibition of GPIb? shedding may be used to optimize platelet storage conditions.

SUBMITTER: Chen W 

PROVIDER: S-EPMC5001887 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature