FcγRII mediates platelet aggregation caused by disintegrins and GPIIb/IIIa monoclonal antibody, AP2

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• 作者：Tur-Fu Huang ; Chien-Hsin Chang ; Pei-Ling Ho ; Ching-Hu Chung
• 刊名：Experimental Hematology
• 出版年：2008
• 出版时间：December 2008
• 年：2008
• 卷：36
• 期：12
• 页码：1704-1713
• 全文大小：666 K

文摘

Objective

Disintegrins, snake venom−derived Arg-Gly-Asp (RGD)-containing polypeptides, and GPIIb/IIIa antagonist (AP2) block fibrinogen binding to GPIIb/IIIa of activated platelets, however, the combination of these two agents caused platelet aggregation. We hypothesize that disintegrin initially binds to specific epitope of GPIIb/IIIa, causing conformational change, and the recruitment of FcγRII, which can be bound by AP2, and finally triggering platelet aggregation.

Materials and Methods

We prepared human platelet suspensions and measured platelet aggregation, Ca²⁺ mobilization, thromboxane B2 formation, and signal transduction.

Results

Disintegrin (e.g., accutin) and AP2 (a monoclonal antibody [mAb]−raised against GPIIb/IIIa) individually inhibited human platelet aggregation caused by collagen. However, as both accutin and AP2 were sequentially added into platelet suspension, platelet aggregation occurred. Accutin/AP2 caused shape change, cytosolic Ca²⁺ mobilization, P-selectin expression, and thromboxane A₂ formation. Tirofiban, FcγRII mAb, or indomethacin completely inhibited platelet aggregation caused by accutin/AP2. Accutin/AP2 also caused tyrosine phosphorylation of signal molecules. Disintegrins enhanced AP2 binding to platelets, and AP2 also promoted disintegrin binding to platelets. FcγRII mAb inhibited the enhanced fluorescein isothiocyanate−disintegrin binding to platelet caused by AP2. Immunoprecipitation of the lysates of disintegrin/AP2-treated platelets using FcγRII Ab showed complex formation of GPIIb/IIIa and FcγRII.

Conclusion

FcγRII mediates platelet aggregation caused by disintegrin and AP2, triggering a phospholipase C, phospholipase A2, Src-, Syk kinases, and Ca²⁺-dependent activation process. AP2 triggers platelet aggregation via binding to accessible FcγRII and the conformation-altered GPIIb/IIIa caused by disintegrin.