Thromb Res . 2024 Dec:244:109210. doi: 10.1016/j.thromres.2024.109210. Epub 2024 Nov 7.

题目：

The role of protein kinase C and the glycoprotein Ibα cytoplasmic tail in anti-glycoprotein Ibα antibody-induced platelet apoptosisand thrombocytopenia

作者：

Sai Zhang#, Chenglin Sun#, Qiuxia Huang, Jiahao Du, Yue Xia, Kangxi Zhou, Biao Yang, Kesheng Dai*, Rong Yan*

#?These authors contributed equally

*Corresponding author

摘要：

Introduction: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts. ITP patients with anti-platelet glycoprotein (GP) Ibα (a subunit of GPIb-IX-V complex) autoantibodies, which induce Fc-dependent signaling and platelet clearance, are refractory to conventional treatment. Protein kinase C (PKC) is activated and involved in GPIbα signaling upon binding of the ligand von Willebrand factor to GPIbα. However, the role of PKC in anti-GPIbα antibody-induced thrombocytopenia remains unknown.

Materials and Methods: The anti-GPIbα antibody-induced PKC activation and its underlying mechanisms were first detected by Western blot, and then the effects of PKC inhibitors, PKC knockout, or GPIbα C-terminal removal on anti-GPIbα antibody-induced platelet apoptosis, activation, aggregation, and clearance were investigated by flow cytometry, platelet aggregometry, and platelet posttransfusion, respectively. Meanwhile, platelet retention and co-localization with macrophages in the liver were detected by spinning disc intravital confocal microscopy.

Results: Anti-GPIbα antibody-induced PKC activation depends on GPIbα clustering and phosphoinositide 3-kinase (PI3K) activation and results in Akt phosphorylation. Pharmacologic inhibition or genetic ablation of PKC suppresses anti-GPIbα antibody-induced platelet apoptosis and activation. Moreover, the GPIbα cytoplasmic tail is required for antibody-induced PKC activation, platelet apoptosis, and activation. Inhibition or ablation of PKC and deletion of the GPIbα cytoplasmic tail protect platelets from clearance in vivo.

Conclusions: Our study indicates the important role of PKC and the GPIbα cytoplasmic tail in anti-GPIbα antibody-mediated platelet signaling and clearance and suggests a novel therapeutic target for ITP and other thrombocytopenic diseases.