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首页> 外文期刊>Toxicological Sciences >Doxorubicin-Induced Platelet Procoagulant Activities: An Important Clue for Chemotherapy-Associated Thrombosis
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Doxorubicin-Induced Platelet Procoagulant Activities: An Important Clue for Chemotherapy-Associated Thrombosis

机译：阿霉素诱导的血小板促凝活性：化疗相关血栓形成的重要线索

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摘要

Thrombotic risk associated with chemotherapy including doxorubicin (DOX) has been frequently reported; yet, the exact mechanism is not fully understood. Here, we report that DOX can induce procoagulant activity in platelets, an important contributor to thrombus formation. In human platelets, DOX increased phosphatidylserine (PS) exposure and PS-bearing microparticle (MP) generation. Consistently, DOX-treated platelets and generated MPs induced thrombin generation, a representative marker for procoagulant activity. DOX-induced PS exposure appeared to be from intracellular Ca2+ increase and ATP depletion, which resulted in the activation of scramblase and inhibition of flippase. Along with this, apoptosis was induced by DOX as determined by the dissipation of mitochondrial membrane potential (Δψ), cytochrome c release, Bax translocation, and caspase-3 activation. A Ca2+ chelator ethylene glycol tetraacetic acid, caspase inhibitor Q-VD-OPh, and antioxidants (vitamin C and trolox) can attenuate DOX-induced PS exposure and procoagulant activity significantly, suggesting that Ca2+, apoptosis, and reactive oxygen species (ROS) were involved in DOX-enhanced procoagulant activity. Importantly, rat in vivo thrombosis model demonstrated that DOX could manifest prothrombotic effects through the mediation of platelet procoagulant activity, which was accompanied by increased PS exposure and Δψ dissipation in platelets.
机译：经常报道与化疗有关的血栓风险，包括阿霉素（DOX）；然而，确切的机制还没有被完全理解。在这里，我们报道DOX可以诱导血小板中的促凝血活性，这是血栓形成的重要因素。在人的血小板中，DOX增加了磷脂酰丝氨酸（PS）的暴露和带有PS的微粒（MP）的产生。一致地，DOX处理的血小板和生成的MP诱导了凝血酶的生成，凝血酶是促凝活性的代表标记。 DOX诱导的PS暴露似乎是由于细胞内Ca 2 + 的增加和ATP的消耗，从而导致了scramblase的激活和对flippase的抑制。同时，通过线粒体膜电位（Δψ）的耗散，细胞色素c释放，Bax易位和caspase-3激活来确定DOX诱导的细胞凋亡。 Ca 2 + 螯合剂乙二醇四乙酸，半胱天冬酶抑制剂Q-VD-OPh和抗氧化剂（维生素C和trolox）可以显着减弱DOX诱导的PS暴露和促凝血活性，表明Ca > 2 + ，细胞凋亡和活性氧（ROS）参与DOX增强的促凝活性。重要的是，大鼠体内血栓形成模型表明DOX可以通过介导血小板促凝活性来表现血栓形成作用，并伴随着PS暴露增加和血小板中的Δψ消散。

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