Eptifibatide-induced thrombocytopenia and thrombosis in humans require FcγRIIa and the integrin β3 cytoplasmic domain
Eptifibatide-induced thrombocytopenia and thrombosis in humans require FcγRIIa and the integrin β3 cytoplasmic domain
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DOI：
10.1172/jci36745
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发表时间：
2009-03-01
影响因子：
15.9
通讯作者：
Newman, Peter J.
中科院分区：
文献类型：
--
作者：
Gao, Cunji;Boylan, Brian;Newman, Peter J.
用整合素αIIBβ3拮抗剂Eptibibatide治疗后，血小板减少症和血栓形成是由对配体占用的ααβ3的患者抗体引起的罕见并发症。理解不佳。为了深入了解eptifibatide依赖性抗体启动血小板清除率的机制，我们将正常的人血小板与含有Alpha IIBβ的患者血小板孵育，该血小板含有3个特异性，Eptifibatide依赖性抗体。我们观察到，在存在Eptifibatide，患者IgG诱导的血小板分泌和聚集以及整合蛋白β3细胞质结构域的酪氨酸磷酸化的情况下，血小板FC Gamma RIIA FC受体，蛋白质酪蛋白 - 酪氨酸激酶SYK和磷酸酶C gamma c gamma c gamma c gamma clampase of。每个激活事件都被血小板与FAB预孵育所抑制FC伽马RIIA特异性mAb IV.3或SRC家族激酶抑制剂PP2的片段。然而，患者血清和eptibibatide并未激活具有变异形式的Glanzmann血栓性血栓形式的患者的血小板，该血小板表达了正常水平的Fc Gamma riiA和Alpha IIB IIB Beta 3复合物，但缺乏大多数Beta Beta 3细胞质域。综上所述，这些数据提出了一种新的机制，在这种机制中，Eptifibatide依赖性抗体与整合蛋白β3亚基相关，使FC Gamma riiA及其下游信号成分被激活，从而导致血小板减少症和倾向到血栓形成。
Thrombocytopenia and thrombosis following treatment with the integrin alpha IIb beta 3 antagonist eptifibatide are rare complications caused by patient antibodies specific for ligand-occupied alpha IIb beta 3. Whether such antibodies induce platelet clearance by simple opsonization, by inducing mild platelet activation, or both is poorly understood. To gain insight into the mechanism by which eptifibatide-dependent antibodies initiate platelet clearance, we incubated normal human platelets with patient serum containing an alpha IIb beta 3-specific, eptifibatide-dependent antibody. We observed that in the presence of eptifibatide, patient IgG induced platelet secretion and aggregation as well as tyrosine phosphorylation of the integrin beta 3 cytoplasmic domain, the platelet Fc gamma RIIa Fc receptor, the protein-tyrosine kinase Syk, and phospholipase C gamma 2. Each activation event was inhibited by preincubation of the platelets with Fab fragments of the Fc gamma RIIa-specific mAb IV.3 or with the Src family kinase inhibitor PP2. Patient serum plus eptifibatide did not, however, activate platelets from a patient with a variant form of Glanzmann thrombasthenia that expressed normal levels of Fc gamma RIIa and the alpha IIb beta 3 complex but lacked most of the beta 3 cytoplasmic domain. Taken together, these data suggest a novel mechanism whereby eptifibatide-dependent antibodies engage the integrin beta 3 subunit such that Fc gamma RIIa and its downstream signaling components become activated, resulting in thrombocytopenia and a predisposition to thrombosis.