Glycoprotein Ibα clustering induces macrophage-mediated platelet clearance in the liver

• DOI: 10.1160/th14-03-0217
• Publication Date: 2014-09-18T08:22:43Z
• Authors: Na Ma; Lili Zhao; Cao Lijuan; Yiwen Zhang; Jie Zhang; Ziqiang Yu; Zhaoyue Wang; Lijun Xia; Changgeng Ruan; Rong Yan; Mengxing Chen; Kesheng Dai
• Keywords: Adult; Blood Platelets; Male; Adolescent; Dose-Response Relationship, Drug; Platelet Aggregation; Macrophages; Guinea Pigs; Platelet Glycoprotein GPIIb-IIIa Complex; Middle Aged; Antibodies; 3. Good health; Macaca fascicularis; 03 medical and health sciences; 0302 clinical medicine; Liver; Injections, Intravenous; Animals; Humans; Female; Child; Aged; Autoantibodies

SummaryMany immune thrombocytopenia (ITP) patients, particularly patients with anti-glycoprotein (GP) Ib-IX autoantibodies, do not respond to the conventional treatments such as splenectomy. However, the underlying mechanism remains unclear. Here we found that anti-GPIbα N-terminus antibody AN51, but not other anti-GPIbα antibodies (AK2, HIP1, VM16d, or WM23), induced GPIbα clustering that led to integrin αIIbβ3-dependent platelet aggregation. After intravenous injection, AN51 dose-dependently induced thrombocytopenia in guinea pigs, and the platelets were mainly removed by macrophages in the liver. N-acetyl-D-glucosamine, previously shown to inhibit integrin αMβ2-mediated phagocytosis of refrigerated platelets, dose-dependently inhibited AN51-induced platelet clearance. Furthermore, AN51 but not VM16d, induced rapid platelet clearance in the liver of cynomolgus macaques. Five of 22 chronic ITP patients had anti-GPIbα autoantibodies, and the autoantibodies from four of the five patients competed with AN51 for binding to platelets. These data indicate that GPIbα clustering induced by anti-GPIbα N-terminus antibody causes integrin αIIbβ3-dependent platelet aggregation, phagocytosis, and rapid platelet clearance in the liver. Our findings reveal a novel Fc-independent mechanism underlying the pathogenesis of ITP, and suggest new therapeutic strategies for ITP patients with anti-GPIbα autoantibodies.