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Thromb Haemost. 2015 Jan;113(1):107-17. doi: 10.1160/TH14-03-0217. Epub 2014 Sep 18.

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

Author information

1
Kesheng Dai, Jiangsu Institute of Haematology, The First Affiliated Hospital of Soochow University, Collaborative Innovation Center of Haematology, Key Laboratory of Thrombosis and Haemostasis, Ministry of Health, Suzhou, 215006 China, Tel./Fax: + 86 512 67781370, E-mail: kdai@suda.edu.cn.

Abstract

Many 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.

KEYWORDS:

Antibodies; glycoprotein Ib-IX; immune thrombocytopenia; macrophages; platelets

PMID:
25231551
DOI:
10.1160/TH14-03-0217
[Indexed for MEDLINE]

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