A subset of anti-HLA antibodies induces FcγRIIa-dependent platelet activation.

Abstract

HLA antibodies are associated with refractoriness to platelet transfusion, 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 currently 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 activate 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-dependent signaling with Syk inhibitor IV. Furthermore, activation required the presence of the IgG-Fc part, as F(ab')2 fragments of HLA monoclonal antibodies were unable to induce platelet activation. Mixing experiments revealed that activation of platelets occurred in an intra-platelet dependent 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.

• 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 (Haematologica) Vol. 103 Issue 10 Pg. 1741-1752 (10 2018) ISSN: 1592-8721 [Electronic] Italy
• PMID: 29858387 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Ferrata Storti Foundation.

Chemical References

• Antibodies, Monoclonal
• FCGR2A protein, human
• HLA Antigens
• Immunoglobulin Fab Fragments
• Immunoglobulin Fc Fragments
• Immunoglobulin G
• Receptors, IgG

Topics

• Antibodies, Monoclonal (pharmacology)
• Blood Platelets (metabolism)
• HLA Antigens (metabolism)
• Humans
• Immunoglobulin Fab Fragments (pharmacology)
• Immunoglobulin Fc Fragments (pharmacology)
• Immunoglobulin G (pharmacology)
• Platelet Activation (drug effects)
• Receptors, IgG (metabolism)