Signal pathways involved in glycoprotein-specific antibody-induced platelet apoptosis

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Introduction: In immune thrombocytopenia (ITP), antibodies targeting platelet surface glycoproteins, particularly anti-GPIIb/IIIa and anti-GPIb/IX, are major contributors to platelet destruction. While it is well-established that these antibodies induce platelet clearance, the precise signaling pathways leading to platelet apoptosis remain poorly understood. This study investigates the signaling pathways involved in antibody-induced platelet apoptosis. Method: Washed human platelets were pretreated for 30 minutes with inhibitors, including IV.3 (an FcgammaRIIA-blocking antibody) and Syk inhibitors (Lanraplenib and R406). Platelets were then stimulated in vitro with monoclonal antibodies targeting GPIIb/IIIa (anti-CD41) or GPIb/IX (anti-CD42b) for 1 hour and 6 hours. Isotype antibodies and dimethyl sulfoxide (DMSO) were used as controls. Apoptosis was assessed using flow cytometry with CD62P, Annexin V, and mitochondrial membrane potential. Results: Anti-CD41 and anti-CD42b monoclonal antibodies targeting the epitopes on GPIIb and GPIbα, respectively, induced platelet apoptosis (isotype control 1.61%±2.18% vs anti-CD41 17.74%±8.85%, P <0.01; isotype control 10.93%±0.89% vs Anti-CD42b 39.73%±10.07%, P <0.01). Anti-CD41 triggered significant apoptosis after 1 hour of incubation, while anti-CD42b-induced apoptosis was more pronounced after 6 hours. Pretreatment with IV.3, a monoclonal antibody that inhibits the FcgammaRIIA signaling in platelets, reduced anti-CD41-induced apoptosis (isotype control 6.45%±3.79% vs IV.3 1.79%±0.20%, P <0.05) but did not affect apoptosis induced by anti-CD42b monoclonal antibody (isotype control 37.65%±4.52% vs IV.3 43.35%±4.57%, P >0.05). Similarly, Syk inhibitors significantly reduced anti-CD41-mediated apoptosis (vehicle 17.74%±8.85% vs Lanraplenib 1.81%±0.93%, P <0.05; vehicle 23.44%±7.95% vs R406 7.64%±3.90%, P <0.05 ) but had no effect on anti-CD42b-induced apoptosis (vehicle 29.08%±21.02% vs Lanraplenib 39.96%±18.88%, P >0.05; vehicle 29.08%±21.02% vs R406 29.92%±10.48%, P> 0.05 ) [ 1 ] [ 2 ] [ 3 ]. Conclusion: Platelet apoptosis triggered by anti-CD41 and anti-CD42b monoclonal antibodies involves distinct signaling pathways. Understanding these distinct mechanisms could inform therapeutic strategies in ITP. Publication History Article published online: 13 February 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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