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Blood Transfusion
Anti-HLA antibodies with complementary and synergistic interaction geometries promote classical complement activation on platelets
Ferrata Storti Foundation
Haematologica 2019 Volume 104(2):403-416
Maaike Rijkers,1 David Schmidt,2 Nina Lu,1 Cynthia S.M. Kramer,3
Sebastiaan Heidt,3 Arend Mulder,3 Leendert Porcelijn,4 Frans H.J. Claas,3 Frank W.G. Leebeek,5 A.J. Gerard Jansen,1,5 Ilse Jongerius,6
Sacha S. Zeerleder,6 Gestur Vidarsson,2 Jan Voorberg1,7 and Masja de Haas3,4,8
1Department of Cellular and Molecular Hemostasis, Sanquin Research and Landsteiner Laboratory Amsterdam UMC, University of Amsterdam; 2Department of Experimental Immunohaematology, Sanquin Research and Landsteiner Laboratory Amsterdam UMC, University of Amsterdam; 3Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center; 4Department of Immunohaematology Diagnostics, Sanquin Diagnostic Services, Amsterdam; 5Department of Hematology, Erasmus University Medical Center, Rotterdam; 6Department of Immunopathology, Sanquin Research and Landsteiner Laboratory Amsterdam UMC, University of Amsterdam; 7Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam and 8Center for Clinical Transfusion Research, Sanquin, Leiden, the Netherlands
ABSTRACT
High titers of HLA antibodies are associated with platelet refractori- ness, causing poor platelet increments after transfusions in a sub- set of patients with HLA antibodies. Currently, we do not know the biological mechanisms that explain the variability in clinical respons- es in HLA alloimmunized patients receiving platelet transfusions. Previously we showed that a subset of anti-HLA IgG-antibodies induces FcγRIIa-dependent platelet activation and enhanced phagocytosis. Here, we investigated whether anti-HLA IgG can induce complement activa- tion on platelets. We found that a subset of anti-HLA IgG induced com- plement activation via the classical pathway, causing C4b and C3b dep- osition and formation of the membrane-attack complex. This resulted in permeabilization of platelet membranes and increased calcium influx. Complement activation also caused enhanced α-granule release, as measured by CD62P surface exposure. Blocking studies revealed that platelet activation was caused by FcγRIIa-dependent signaling as well as HLA antibody induced complement activation. Synergistic complement activation employing combinations of monoclonal IgGs suggested that assembly of oligomeric IgG complexes strongly promoted complement activation through binding of IgGs to different antigenic determinants on HLA. In agreement with this, we observed that preventing anti-HLA-IgG hexamer formation using an IgG-Fc:Fc blocking peptide, completely inhibited C3b and C4b deposition. Our results show that HLA antibod- ies can induce complement activation on platelets including membrane attack complex formation, pore formation and calcium influx. We pro- pose that these events can contribute to fast platelet clearance in vivo in patients refractory to platelet transfusions with HLA alloantibodies, who may benefit from functional-platelet matching and treatment with com- plement inhibitors.
Introduction
HLA alloantibodies can develop upon transfusion,1 transplantation2 and during pregnancy.3,4 Leukoreduction of platelet transfusion products reduced HLA immu- nization by more than 50 percent,5 however, 20-30% of patients receiving multiple platelet transfusions still develop HLA alloantibodies.1,3,6 It is known that high titers of HLA antibodies are associated with platelet refractoriness.7 About 12-15% of patients, in need of chronic platelet transfusion support, become refractory to
Correspondence:
m.dehaas@sanquin.nl
Received: July 11, 2018.
Accepted: September 19, 2018. Pre-published: September 27, 2018.
doi:10.3324/haematol.2018.201665
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/2/403
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