Glycoprotein-specific antibodies induce distinct platelet destruction pathways in ITP

Introduction Apoptosis and desialylation are well-established mechanisms contributing to platelet destruction in immune thrombocytopenia (ITP). However, the precise signaling pathways mediating platelet clearance remain incompletely characterized. This study aims to elucidate the signaling pathways involved in antibody-mediated platelet destruction by employing monoclonal antibodies (mAbs) and autoantibodies (AAbs) targeting GPIb/IX or GPIIb/IIIa complexes. Method Washed human platelets (wPLTs) were utilized to evaluate apoptosis and desialylation. Apoptosis was assessed via flow cytometry by identifying P-selectin negativity (CD62P−), phosphatidylserine exposure (Annexin V+), and alterations in mitochondrial membrane potential (TMRE−). Desialylation was quantified by measuring the increase in ricinus communis agglutinin (RCA) binding relative to baseline levels. Initially, ten distinct monoclonal antibodies (mAbs) targeting GPIb/IX or GPIIb/IIIa were screened to identify candidates capable of inducing platelet apoptosis and desialylation. Concurrently, sera from ITP patients harboring glycoprotein-specific autoantibodies (AAbs) were evaluated for their capacity to trigger these processes. To investigate the signaling pathways involved, platelets were pretreated with the FcγRIIA- inhibitors followed by assessment of apoptosis and desialylation inhibition. Results In the screening study, one mAb against GPIbα and one against GPIIb out of 20 tested ones were identified to induce wPLT apoptosis and desialylation. 3 out of 8 (37.5%) ITP sera with anti-GPIb/IX Ab and 18 out of 28 (64.28%) ITP sera with anti-GPIIb/IIIa Ab induced apoptosis in washed platelets. 5 of 13 (38.46%) ITP sera with anti-GPIb/IX Ab and 6 of 28 (25%) ITP sera with anti-GPIIb/IIIa Ab induced desialylation. While blockade of PLT FcγRIIA effectively inhibited apoptosis and desialylation induced by antibodies against GPIIb/IIIa, they had no inhibitory effect on apoptosis and desialylation induced by antibodies against GPIb/IX. Conclusion Platelet destruction triggered by anti-GPIb/IX and anti-GPIIb/IIIa antibodies involves distinct signaling pathways. While anti-GPIIb/IIIa mediates platelet destruction through the FcγRIIA, anti-GPIb/IX appears to engage alternative mechanisms. Elucidating these divergent pathways may facilitate the development of targeted therapeutic strategies for ITP. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany