An absence of platelet activation following thalidomide treatment in vitro or in vivo.
An absence of platelet activation following thalidomide treatment in vitro or in vivo.
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体外或体内沙利度胺治疗后血小板不活化
DOI：
10.18632/oncotarget.16205
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发表时间：
2017-05-30
期刊：
影响因子：
--
通讯作者：
Xu K
中科院分区：
文献类型：
--
作者：
Qiao J;Wu Y;Wu X;Liu Y;Li X;Ju W;Qi K;Li D;Gardiner EE;Andrews RK;Zeng L;Xu K
在接受沙利度胺治疗的患者中报告了血栓栓塞和血小板高反应性的风险增加。沙利度胺是否直接或通过其他因素诱导血小板活化尚不清楚。本研究的目的是评价沙利度胺对血小板活化的影响在体外和体内静息条件下。分离的人或小鼠血小板用不同浓度的沙利度胺（10、50和100 μg/ml）在37 ℃处理60 min，然后通过流式细胞术和胶原或ADP诱导的血小板聚集分析血小板受体GPIbα、GPVI、αIIbβ3和P-选择素的血小板表面表达，以及PAC-1或纤维蛋白原结合。此外，将沙利度胺（200 mg/kg）腹腔注射到小鼠中以分析沙利度胺对体内血小板活化的影响。在37°C下，沙利度胺体外处理60分钟后，在人和小鼠血小板中均未观察到P-选择素、PAC-1或纤维蛋白原结合的表达增加。沙利度胺治疗也不影响GPIbα、GPVI或αIIbβ3的表达，也不影响胶原或ADP诱导的血小板聚集。然而，虽然注射沙利度胺的小鼠没有显示血小板P-选择素或αIIbβ3的表面表达增加，但尾部出血时间、凝血酶时间、凝血酶原时间显著缩短，因子IX和纤维蛋白原水平升高。总之，沙利度胺在治疗剂量不会直接诱导血小板活化在体外或体内静息条件下，但结果增加促凝血活性，这可以解释沙利度胺依赖性血栓形成倾向的患者。
Increased risk of thromboembolism and platelet hyperreactivity has been reported in patients receiving thalidomide therapy. Whether thalidomide induces platelet activation directly or through other factors remains unclear. The aim of this study was to evaluate the effect of thalidomide on platelet activation under resting conditions in vitro and in vivo. Isolated human or mouse platelets were treated with different concentrations of thalidomide (10, 50 and 100 μg/ml) for 60 min at 37°C followed by analysis of platelet surface expression of platelet receptors GPIbα, GPVI, αIIbβ3 and P-selectin, and PAC-1 or fibrinogen binding, by flow cytometry and collagen- or ADP-induced platelet aggregation. In addition, thalidomide (200 mg/kg) was intraperitoneally injected into mice for analysis of the effect of thalidomide on platelet activation in vivo. No increased expression of P-selectin, PAC-1 or fibrinogen binding was observed in either human and mouse platelets after thalidomide treatment in vitro for 60 min at 37°C. Thalidomide treatment also did not affect expression of GPIbα, GPVI or αIIbβ3, nor did it affect collagen- or ADP-induced platelet aggregation at threshold concentrations. However, while mice injected with thalidomide displayed no increased surface expression of platelet P-selectin or αIIbβ3, there was a significantly shortened tail bleeding time, thrombin time, prothrombin time together with higher levels of Factor IX and fibrinogen. In conclusion, thalidomide at therapeutic doses does not directly induce platelet activation under resting conditions in vitro or in vivo, but results in increased procoagulant activity, which could explain the thalidomide-dependent prothrombotic tendency in patients.