Deletion of platelet CLEC-2 decreases GPIbα-mediated integrin αIIbβ3 activation and decreases thrombosis in TTP.
Deletion of platelet CLEC-2 decreases GPIbα-mediated integrin αIIbβ3 activation and decreases thrombosis in TTP.
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DOI：
10.1182/blood.2021012896
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发表时间：
2022-04-21
期刊：
影响因子：
20.3
通讯作者：
Xia, Lijun
中科院分区：
文献类型：
--
作者：
Shao, Bojing;Hoover, Christopher;Shi, Huiping;Kondo, Yuji;Lee, Robert H.;Chen, Junmei;Shan, Xindi;Song, Jianhua;McDaniel, J. Michael;Zhou, Meixiang;McGee, Samuel;Vanhoorelbeke, Karen;Bergmeier, Wolfgang;Lopez, Jose A.;George, James N.;Xia, Lijun
Shao及其同事使用血栓性血小板减少性紫癜（TTP）小鼠模型表明，血小板CLEC-2的缺失降低了肺动脉血栓形成和血小板减少症的严重程度。他们还表明，整合素αaIIbβ3拮抗剂、依替巴肽或阿司匹林可减少TTP小鼠的肺动脉血栓形成。这些数据表明，血小板CLEC-2调节TTP中GPIbα介导的整合素αIIbβ3的活化，并且可能被间接操纵以获得治疗益处。血小板CLEC-2调节VWF和GPIbα介导的整合素αIIbβ3活化，这有助于TTP小鼠模型中的血栓形成。依替巴肽和阿司匹林减少TTP小鼠的血栓形成，证明了整合素αIIbβ3活化的临床重要性。血栓性血小板减少性紫癜（TTP）患者的微血管血栓形成是由GPIbα介导的血小板与血管性血友病因子（VWF）结合引发的。VWF与GPIbα结合导致血小板表面整合素αIIbβ3活化。然而，GPIbα激活αIIbβ3的机制及其在微血管血栓形成中的临床意义仍不清楚。在小鼠中，血小板C型凝集素样受体2（CLEC-2）的缺失并不能阻止VWF与血小板的结合，但特异性地抑制VWF结合诱导的血小板聚集。血小板CLEC-2的缺失也抑制VWF与GPIbα结合诱导的αIIbβ3活化。使用TTP小鼠模型，这是通过输注抗小鼠ADAMTS 13单克隆抗体，然后输注VWF创建的，我们发现，删除血小板CLEC-2减少肺动脉血栓形成和血小板减少症的严重程度。重要的是，预防性口服阿司匹林（一种血小板活化抑制剂）和用依替巴肽（一种整联蛋白αIIbβ3拮抗剂）治疗性治疗TTP小鼠可减少TTP小鼠模型中的肺动脉血栓形成。我们的观察结果表明，GPIbα介导的整合素αIIbβ3的激活在TTP血栓形成中起重要作用。这些观察结果表明，阿司匹林预防血小板活化可降低TTP患者血栓形成的风险。
Using a mouse model of thrombotic thrombocytopenic purpura (TTP), Shao and colleagues show that the deletion of platelet CLEC-2 decreases pulmonary arterial thrombosis and the severity of thrombocytopenia. They also show that an integrin αaIIbβ3 antagonist, eptifibatide, or aspirin reduces pulmonary arterial thrombosis in the TTP mice. These data indicate that platelet CLEC-2 regulates GPIbα-mediated activation of integrin αIIbβ3 in TTP and may be pharmacologically manipulated for therapeutic benefit. Platelet CLEC-2 regulates VWF and GPIbα-mediated integrin αIIbβ3 activation that contributes to thrombosis in a mouse model of TTP. Eptifibatide and aspirin decrease thrombosis in mice with TTP, documenting the clinical importance of integrin αIIbβ3 activation. Microvascular thrombosis in patients with thrombotic thrombocytopenic purpura (TTP) is initiated by GPIbα-mediated platelet binding to von Willebrand factor (VWF). Binding of VWF to GPIbα causes activation of the platelet surface integrin αIIbβ3. However, the mechanism of GPIbα-initiated activation of αIIbβ3 and its clinical importance for microvascular thrombosis remain elusive. Deletion of platelet C-type lectin-like receptor 2 (CLEC-2) did not prevent VWF binding to platelets but specifically inhibited platelet aggregation induced by VWF binding in mice. Deletion of platelet CLEC-2 also inhibited αIIbβ3 activation induced by the binding of VWF to GPIbα. Using a mouse model of TTP, which was created by infusion of anti-mouse ADAMTS13 monoclonal antibodies followed by infusion of VWF, we found that deletion of platelet CLEC-2 decreased pulmonary arterial thrombosis and the severity of thrombocytopenia. Importantly, prophylactic oral administration of aspirin, an inhibitor of platelet activation, and therapeutic treatment of the TTP mice with eptifibatide, an integrin αIIbβ3 antagonist, reduced pulmonary arterial thrombosis in the TTP mouse model. Our observations demonstrate that GPIbα-mediated activation of integrin αIIbβ3 plays an important role in the formation of thrombosis in TTP. These observations suggest that prevention of platelet activation with aspirin may reduce the risk for thrombosis in patients with TTP.
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DOI：
10.1111/jth.12144
发表时间：
2013-04
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
--
作者：
Li R;Emsley J
通讯作者：
Emsley J
影响因子：
6.7
作者：
Jamasbi, Janina;Ayabe, Keng;Siess, Wolfgang
通讯作者：
Siess, Wolfgang
影响因子：
20.3
作者：
Li, ZY;Zhang, GY;Du, XP
通讯作者：
Du, XP
影响因子：
20.3
作者：
Kanaji, T;Russell, S;Ware, J
通讯作者：
Ware, J
影响因子：
20.3
作者：
Gitz, Eelo;Pollitt, Alice Y.;Watson, Steve P.
通讯作者：
Watson, Steve P.