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Blood transfusion
A subset of anti-HLA antibodies induces FcγRIIa-dependent platelet activation
Ferrata Storti Foundation
Maaike Rijkers,1 Anno Saris,2 Sebastiaan Heidt,3 Arend Mulder,3 Leendert Porcelijn,4 Frans H.J. Claas,3 Ruben Bierings,1 Frank W.G. Leebeek,5
A.J. Gerard Jansen,1,5 Gestur Vidarsson,6 Jan Voorberg1,7 and Masja de Haas3,4,8
1Department of Plasma Proteins, Sanquin-AMC Landsteiner Laboratory, Amsterdam; 2Department of Immunopathology, Sanquin-AMC Landsteiner Laboratory, 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 Experimental Immunohematology, Sanquin-AMC Landsteiner Laboratory, Amsterdam; 7Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam and 8Center for Clinical Transfusion Research, Sanquin, Leiden, the Netherlands
Haematologica 2018 Volume 103(10):1741-1752
ABSTRACT
HLA antibodies are associated with refractoriness to platelet trans- fusion, leading to rapid platelet clearance, sometimes coinciding with clinical side effects such as fever and chills. The presence of HLA antibodies is not always manifested by clinical symptoms. It is cur- rently unclear why refractoriness to platelet transfusion is only observed in a subset of patients. Here, we utilized the availability of a unique panel of human monoclonal antibodies to study whether these were capable of activating platelets. Three out of eight human HLA-specific monoclonal antibodies induced activation of HLA-matched platelets from healthy donors as evidenced by enhanced α-granule release, aggregation, and αIIbb3 activation. The propensity of HLA monoclonal antibodies to acti- vate platelets was independent of the HLA subtype to which they were directed, but was dependent on the recognized epitope. Activation was fully inhibited either by blocking FcγRIIa, or by blocking FcγRIIa-depen- dent signaling with Syk inhibitor IV. Furthermore, activation required the presence of the IgG-Fc part, as F(ab’)2 fragments of HLA monoclonal anti- bodies were unable to induce platelet activation. Mixing experiments revealed that activation of platelets occurred in an intra-platelet depend- ent manner. Accordingly, a proportion of sera from refractory patients with HLA antibodies induced FcγRIIa-dependent platelet activation. Our data show that a subset of HLA antibodies is capable of crosslinking HLA and FcγRIIa thereby promoting platelet activation and enhancing these cells’ phagocytosis by macrophages. Based on these findings we suggest that FcγRIIa-dependent platelet activation may contribute to the decreased platelet survival in platelet-transfusion-dependent patients with HLA antibodies.
Introduction
Antibodies against human leukocyte antigen (HLA) can be induced by pregnancy, blood transfusion or transplantation.1–3 During or after a pregnancy, 15-50% (depending on the number of pregnancies) of women develop HLA antibodies.4–6 Platelet reactive alloantibodies commonly directed toward HLA of the donor platelets develop in 20-30% of chronic platelet transfusion recipients.2,3,7 Although platelet refractoriness is more commonly caused by non-immune factors2,7,8, 30-50% of platelet-transfusion-dependent recipients with HLA antibodies become refracto- ry to platelet transfusions due to alloimmunization.2,7 HLA antibodies in this setting are primarily composed of immunoglobulin G (IgG) and are directed toward HLA-
Correspondence:
m.rijkers@sanquin.nl
Received: February 9, 2018. Accepted: May 30, 2018. Pre-published: June 1, 2018.
doi:10.3324/haematol.2018.189365
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/10/1741
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