Hayley R Waterman1, Linda M Kapp1, Adam Munday1, Katherine Odem-Davis1, James C Zimring1,2,3. 1. Bloodworks NW Research Institute, University of Washington School of Medicine, Seattle, Washington. 2. Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington. 3. Department of Medicine, Division of Hematology, University of Washington School of Medicine, Seattle, Washington.
Abstract
BACKGROUND: Platelet (PLT) transfusions can be an essential therapy for patients with thrombocytopenia to maintain hemostasis. However, some patients become alloimmunized to antigens on PLTs (typically HLA), which can prevent efficacy of PLT transfusion due to antibody-mediated clearance. In extreme cases, patients with alloimmunization to multiple HLAs can become "refractory" to PLT transfusion, such that insufficient compatible PLT units can be found to meet transfusion needs. MATERIALS AND METHODS: An in vivo murine model of PLT-induced alloimmunization was refined so as to include both transfusion with allogeneic leukoreduced PLTs and studies of posttransfusion PLT recoveries, allowing assessment of alloimmunization and refractoriness. Basic mechanisms of antibody-mediated PLT clearance were investigated using recipients missing either the C3 complement gene or the common gamma chain for Fc receptors. In addition, the efficacy of using costimulatory blockade as a therapeutic intervention was assessed by testing CTLA4-Ig administration before PLT transfusion. RESULTS: Fcγ receptors (but not complement C3) are required for alloantibody-mediated PLT refractoriness. In addition, levels of anti-MHC predict the extent of refractoriness in a given animal. Finally, costimulatory blockade as a therapeutic modality prevents transfusion-induced PLT refractoriness. CONCLUSIONS: Together these findings introduce new experimental methods, basic mechanistic understanding, and a potential therapeutic intervention for alloimmunization to MHC-based antigens on transfused PLTs.
BACKGROUND: Platelet (PLT) transfusions can be an essential therapy for patients with thrombocytopenia to maintain hemostasis. However, some patients become alloimmunized to antigens on PLTs (typically HLA), which can prevent efficacy of PLT transfusion due to antibody-mediated clearance. In extreme cases, patients with alloimmunization to multiple HLAs can become "refractory" to PLT transfusion, such that insufficient compatible PLT units can be found to meet transfusion needs. MATERIALS AND METHODS: An in vivo murine model of PLT-induced alloimmunization was refined so as to include both transfusion with allogeneic leukoreduced PLTs and studies of posttransfusion PLT recoveries, allowing assessment of alloimmunization and refractoriness. Basic mechanisms of antibody-mediated PLT clearance were investigated using recipients missing either the C3 complement gene or the common gamma chain for Fc receptors. In addition, the efficacy of using costimulatory blockade as a therapeutic intervention was assessed by testing CTLA4-Ig administration before PLT transfusion. RESULTS: Fcγ receptors (but not complement C3) are required for alloantibody-mediated PLT refractoriness. In addition, levels of anti-MHC predict the extent of refractoriness in a given animal. Finally, costimulatory blockade as a therapeutic modality prevents transfusion-induced PLT refractoriness. CONCLUSIONS: Together these findings introduce new experimental methods, basic mechanistic understanding, and a potential therapeutic intervention for alloimmunization to MHC-based antigens on transfused PLTs.
Authors: Pablo Cure; Melania Bembea; Stella Chou; Allan Doctor; Anne Eder; Jeanne Hendrickson; Cassandra D Josephson; Alan E Mast; William Savage; Martha Sola-Visner; Philip Spinella; Simon Stanworth; Marie Steiner; Traci Mondoro; Shimian Zou; Catherine Levy; Myron Waclawiw; Nahed El Kassar; Simone Glynn; Naomi L C Luban Journal: Transfusion Date: 2017-03-28 Impact factor: 3.157
Authors: Jacqueline N Poston; Arijita Jash; Lindsay M Hannan; Ariel M Hay; Chomkan Usaneerungrueng; Heather L Howie; Linda M Kapp; James C Zimring Journal: Transfusion Date: 2020-12-18 Impact factor: 3.337
Authors: Maaike Rijkers; Anno Saris; Sebastiaan Heidt; Arend Mulder; Leendert Porcelijn; Frans H J Claas; Ruben Bierings; Frank W G Leebeek; A J Gerard Jansen; Gestur Vidarsson; Jan Voorberg; Masja de Haas Journal: Haematologica Date: 2018-06-01 Impact factor: 9.941