Doxorubicin contributes to thrombus formation and vascular injury by interfering with platelet function

Abstract

Doxorubicin contributes to thrombus formation and vascular injury by interfering with platelet function. Am J Physiol Heart Circ Physiol 319: H133-H143, 2020. First published May 29, 2020; doi:10.1152/ajpheart.00456.2019.-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-1•day-1, followed by 5 mg•kg-1•day-1) 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 doxorubicininduced changes in the functionality of platelets can be effectively inhibited by antiplatelet drugs. NEW & NOTEWORTHY Doxorubicin therapy in mice (antitumor dosage) markedly enhanced platelet functions measured as agonistinduced platelet aggregation, degranulation, and adhesion to endothelial cells, actions leading to thrombus formation and thrombosisindependent vascular injury. Clopidogrel treatment ameliorated thrombus formation and vascular toxicity induced by doxorubicin via inhibiting platelet activity.