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Impaired Hemostatic Activity of Healthy Transfused Platelets in Select Inherited Platelet Disorders: Mechanisms and Implications
ISTH Academy. Lee R. Jul 10, 2019; 274106; OC 72.2
Robert Lee
Robert Lee
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OC 72.2

Impaired Hemostatic Activity of Healthy Transfused Platelets in Select Inherited Platelet Disorders: Mechanisms and Implications

R. Lee1, R. Piatt1, J. Rivera2, W. Bergmeier1
1University of North Carolina at Chapel Hill, Chapel Hill, United States, 2Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, CB15/00055-CIBERER, Murcia, Spain

Main Topic: Platelet Disorders
Category: Platelet Disorders, Hereditary

Background: Platelet transfusions often fail to prevent bleeding in patients with select congenital platelet disorders, including patients with mutations in RASGRP2, the gene encoding the critical platelet signaling protein CalDAG-GEFI.
Aims: To investigate whether dysfunctional platelets can interfere with the hemostatic function of healthy platelets in the context of platelet transfusion.
Methods: We performed real-time epifluorescence and spinning disk confocal (SDC) imaging of hemostatic plug formation in the saphenous vein of mice following laser ablation. Wild-type (WT) and mutant platelets were differentially labeled for visualization, and bleeding time and platelet adhesion were quantified.
Results: Rasgrp2-/- mice were refractory to WT platelet transfusion, unless the ratio between mutant and WT platelets was below 3 to 1. Thrombocytopenic recipient mice (IL4R/GPIb-Tg) then received transfusions of labeled WT and Rasgrp2-/- platelets. Surprisingly, both mutant and WT platelets incorporated effectively into the hemostatic plug, but the presence of mutant platelets significantly delayed the adhesion of WT platelets. SDC Z-stacks of hemostatic plugs demonstrated sequestration of WT platelets into distinct regions, while mutant platelets loosely filled the remaining areas. Real-time SDC revealed that plugs containing both mutant and WT platelets were loosely packed, continuously shedding single platelets. Transfusion studies in murine models for Glanzmann's Thrombasthenia (GT) and Bernard-Soulier Syndrome further demonstrated that dysfunctional platelets reduce access of WT platelets to von Willebrand factor exposed at sites of injury. Human GT platelets also interfered with the function of healthy platelets using the Impact-R assay. Finally, plugs containing WT and 'dual anti-platelet therapy' platelets (aspirin-treated P2y12-/- platelets) formed quickly but destabilized in the center, leading to re-bleeding.
Conclusions: These studies suggest that the post-transfusion ratio of donor versus endogenous platelets can predict the success of platelet transfusions in the treatment of select inherited and acquired platelet function disorders. Our findings may also have clinical implications in patients receiving anti-platelet drugs.

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