Bevacizumab immune complexes activate platelets and induce thrombosis in FCGR2A transgenic mice
Bevacizumab immune complexes activate platelets and induce thrombosis in FCGR2A transgenic mice
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DOI：
10.1111/j.1538-7836.2008.03212.x
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发表时间：
2009-01-01
影响因子：
10.4
通讯作者：
Amirkhosravi, A.
中科院分区：
文献类型：
--
作者：
Meyer, T.;Robles-Carrillo, L.;Amirkhosravi, A.
背景：贝伐单抗治疗与结直肠癌患者的动脉血栓栓塞症有关。然而，其机制尚不清楚，在小鼠身上的临床前试验也未能预测血栓形成。目的：我们研究血栓形成是否可能是通过Fc-Gamma RIIA(Ig G)受体介导的血小板激活的结果，该受体在小鼠血小板上不存在，目的是确定肝素和血小板表面定位在Bev诱导的Fc-Gamma RIIA激活中的功能作用。方法和结果：我们发现BEV免疫复合体(IC)通过Fc-Gamma RIIA激活血小板，因此尝试使用Fc-Gamma RIIA(HFcR)转基因小鼠在体内复制这一发现。在肝素存在的情况下，hFcR小鼠BEV IC呈血栓形成。这种活性需要BEV的靶标--血管内皮生长因子(VEGF)的肝素结合域。肝素促进BEV IC在血小板上沉积的机制与肝素引起的血小板减少患者的抗体相似。当使用亚活性剂量的ADP或凝血酶来激活血小板(模拟患者的高凝状态)时，BEV IC诱导的致密颗粒释放显著增强，而低得多的(亚治疗)肝素浓度足以满足BEV IC诱导的血小板聚集。结论：BEV治疗中血栓形成的主要原因是阻断血管内皮生长因子会导致血管炎症和凝血。然而，我们得出结论，BEV可通过与血管内皮生长因子形成复合体和激活血小板FcγRIIA受体而诱导血小板聚集、脱颗粒和血栓形成，这为体内观察到的血栓事件提供了更好的解释。
Background: Treatment with Bevacizumab has been associated with arterial thromboembolism in colorectal cancer patients. However, the mechanism of this remains poorly understood, and preclinical testing in mice failed to predict thrombosis. Objective: We investigated whether thrombosis might be the result of platelet activation mediated via the Fc gamma RIIa (IgG) receptor - which is not present on mouse platelets - and aimed to identify the functional roles of heparin and platelet surface localization in Bev-induced Fc gamma RIIa activation. Methods and results: We found that Bev immune complexes (IC) activate platelets via Fc gamma RIIa, and therefore attempted to reproduce this finding in vivo using Fc gamma RIIa (hFcR) transgenic mice. Bev IC were shown to be thrombotic in hFcR mice in the presence of heparin. This activity required the heparin-binding domain of Bev's target, vascular endothelial growth factor (VEGF). Heparin promoted Bev IC deposition on to platelets in a mechanism similar to that observed with antibodies from patients with heparin-induced thrombocytopenia. When sub-active amounts of ADP or thrombin were used to prime platelets (simulating hypercoagulability in patients), Bev IC-induced dense granule release was significantly potentiated, and much lower (sub-therapeutic) heparin concentrations were sufficient for Bev IC-induced platelet aggregation. Conclusions: The prevailing rationale for thrombosis in Bev therapy is that VEGF blockade leads to vascular inflammation and clotting. However, we conclude that Bev can induce platelet aggregation, degranulation and thrombosis through complex formation with VEGF and activation of the platelet Fc gamma RIIa receptor, and that this provides a better explanation for the thrombotic events observed in vivo.