Ahmed Muhammad Usman, Receveur Nicolas, Janus-Bell Emily, Mouriaux Clarisse, Gachet Christian, Jandrot-Perrus Martine, Hechler Béatrice, Gardiner Elizabeth E, Mangin Pierre H
Université de Strasbourg INSERM EFS Grand-Est BPPS UMR-S1255 FMTS Strasbourg France.
Université de Paris INSERM Hôpital Bichat UMR-S1148 Paris France.
Res Pract Thromb Haemost. 2021 Jul 2;5(5):e12551. doi: 10.1002/rth2.12551. eCollection 2021 Jul.
The interplay between platelets and fibrinogen is the cornerstone of thrombus formation. Integrin αIIbβ3 is the main platelet adhesion receptor for fibrinogen and mediates an outside-in signal upon ligand binding that reinforces platelet activation. In addition, FcγRIIA and glycoprotein VI (GPVI) contribute to platelet activation on fibrinogen, thereby participating in thrombus growth and stability. To date, the relative importance of these two immunoreceptor tyrosine-based activation motif-bearing receptors in these processes remains unknown.
The aim of this study was to evaluate the relative contributions of FcγRIIA and GPVI to platelet activation on fibrinogen and subsequent thrombus growth and stability.
We evaluated human and mouse platelet adhesion to fibrinogen in static assays and a flow-based approach to evaluate the contribution of FcγRIIA and GPVI to thrombus growth and stability.
We first confirmed that integrin αIIbβ3 is the key receptor supporting platelet adhesion and spreading on fibrinogen. Using human platelets treated with pharmacological blocking agents and transgenic mouse platelets expressing human receptors, data indicate that GPVI, but not FcγRIIA, plays a prominent role in platelet activation on fibrinogen. Moreover, using a flow-based assay, we observed that blockade of GPVI with 1G5, but not FcγRIIA with IV.3, prevents thrombus growth. Finally, we observed that 1G5, but not IV.3, promotes the disaggregation of thrombi formed on collagen in vitro.
This study provides evidence that GPVI, but not FcγRIIA, induces platelet activation and spreading on fibrinogen, and promotes thrombus buildup and stability.
血小板与纤维蛋白原之间的相互作用是血栓形成的基石。整合素αIIbβ3是纤维蛋白原的主要血小板黏附受体，在配体结合时介导由外向内的信号，增强血小板活化。此外，FcγRIIA和糖蛋白VI（GPVI）有助于血小板在纤维蛋白原上的活化，从而参与血栓的生长和稳定。迄今为止，这两种带有免疫受体酪氨酸激活基序的受体在这些过程中的相对重要性尚不清楚。
本研究旨在评估FcγRIIA和GPVI对血小板在纤维蛋白原上的活化以及随后血栓生长和稳定的相对贡献。
我们在静态试验和基于流动的方法中评估了人和小鼠血小板对纤维蛋白原的黏附，以评估FcγRIIA和GPVI对血栓生长和稳定的贡献。
我们首先证实整合素αIIbβ3是支持血小板在纤维蛋白原上黏附与铺展的关键受体。使用经药理学阻断剂处理的人血小板和表达人受体的转基因小鼠血小板，数据表明GPVI而非FcγRIIA在血小板在纤维蛋白原上的活化中起重要作用。此外，使用基于流动的试验，我们观察到用1G5阻断GPVI可阻止血栓生长，而用IV.3阻断FcγRIIA则不能。最后，我们观察到1G5而非IV.3可促进体外在胶原上形成的血栓解体。
本研究提供的证据表明，GPVI而非FcγRIIA可诱导血小板在纤维蛋白原上的活化与铺展，并促进血栓形成和稳定。
