Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
Am J Physiol Heart Circ Physiol. 2020 Jul 1;319(1):H133-H143. doi: 10.1152/ajpheart.00456.2019. Epub 2020 May 29.
In clinical studies, platelet aggregation and risk of thrombosis are increased in patients after doxorubicin treatment. However, the exact role of doxorubicin in platelet functions and thrombus formation in vivo remain unclear. The present study is to investigate the role of doxorubicin in platelet function in relation to thrombus formation and vascular toxicity, as well as the efficacy of antiplatelet therapy. Mice were treated with doxorubicin or vehicle (5 mg/kg iv, 4 wk), and the following parameters were determined: platelet count and size, platelet surface adhesive receptors by flow cytometry, density of granules by electron microscopy, platelet aggregation and degranulation at resting or agonist-stimulated state, platelet adhesion on fibrinogen or endothelial cells, and thrombus formation on collagen matrix. The efficacy of clopidogrel (15 mg·kg·day, followed by 5 mg·kg·day) on doxorubicin-induced changes in the aforementioned parameters as well as vascular injury were also determined. Whereas platelet count and size were similar between doxorubicin-treated and vehicle-treated mice, doxorubicin promoted thrombus formation evidenced by greater platelet aggregation, degranulation, and adhesion to endothelial cells evoked by agonists. Clopidogrel treatment attenuated the enhanced platelet activity and thrombus formation by doxorubicin, as well as vascular platelet infiltration and reactive oxygen species generation. Collectively, this study demonstrates that platelet functions are enhanced after long-term doxorubicin administration, which leads to thrombus formation and vascular toxicity, and that doxorubicin-induced changes in the functionality of platelets can be effectively inhibited by antiplatelet drugs. Doxorubicin therapy in mice (antitumor dosage) markedly enhanced platelet functions measured as agonist-induced platelet aggregation, degranulation, and adhesion to endothelial cells, actions leading to thrombus formation and thrombosis-independent vascular injury. Clopidogrel treatment ameliorated thrombus formation and vascular toxicity induced by doxorubicin via inhibiting platelet activity.
在临床研究中，多柔比星治疗后的患者血小板聚集和血栓形成风险增加。然而，多柔比星在体内血小板功能和血栓形成中的确切作用仍不清楚。本研究旨在探讨多柔比星在血小板功能与血栓形成和血管毒性中的作用，以及抗血小板治疗的疗效。小鼠用多柔比星或载体（5mg/kgiv，4 周）处理，并测定以下参数：血小板计数和大小、血小板表面黏附受体的流式细胞术、电子显微镜下颗粒密度、静息或激动剂刺激状态下的血小板聚集和脱颗粒、血小板在纤维蛋白原或内皮细胞上的黏附以及胶原基质上的血栓形成。还测定了氯吡格雷（15mg·kg·天，随后 5mg·kg·天）对多柔比星诱导的上述参数变化和血管损伤的疗效。虽然多柔比星处理和载体处理的小鼠的血小板计数和大小相似，但多柔比星促进了血栓形成，表现为激动剂引起的血小板聚集、脱颗粒和黏附在内皮细胞上的作用增强。氯吡格雷治疗减轻了多柔比星增强的血小板活性和血栓形成，以及血管内血小板浸润和活性氧生成。总之，这项研究表明，长期多柔比星给药后血小板功能增强，导致血栓形成和血管毒性，并且抗血小板药物可有效抑制多柔比星诱导的血小板功能变化。多柔比星治疗（抗肿瘤剂量）明显增强了血小板功能，表现为激动剂诱导的血小板聚集、脱颗粒和黏附在内皮细胞上的作用，这些作用导致血栓形成和非血栓形成相关的血管损伤。氯吡格雷通过抑制血小板活性改善了多柔比星引起的血栓形成和血管毒性。
