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

Rong Yan; Mengxing Chen; Na Ma; Lili Zhao; Cao Lijuan; Yiwen Zhang; Jie Zhang; Ziqiang Yu; Zhaoyue Wang; Lijun Xia; Changgeng Ruan; Kesheng Dai

doi:10.1160/TH14-03-0217

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2015; 113(01): 107-117
DOI: 10.1160/TH14-03-0217

Cellular Haemostasis and Platelets

Schattauer GmbH

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

Authors

Rong Yan^*

¹Jiangsu 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, China
Mengxing Chen^*

¹Jiangsu 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, China
Na Ma

¹Jiangsu 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, China
Lili Zhao

¹Jiangsu 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, China
Cao Lijuan

¹Jiangsu 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, China
Yiwen Zhang

¹Jiangsu 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, China
Jie Zhang

¹Jiangsu 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, China
Ziqiang Yu

¹Jiangsu 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, China
Zhaoyue Wang

¹Jiangsu 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, China
Lijun Xia

¹Jiangsu 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, China

²Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
Changgeng Ruan

¹Jiangsu 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, China
Kesheng Dai

¹Jiangsu 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, China

Abstract

Summary

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

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Referenzen

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