Changes in Hemostasis System in Outbred Female Mice with Cisplatin-Induced Procoagulant Status
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stasis System in Outbred Female Mice with Cisplatin-Induced Procoagulant Status
M. V. Filonova1,2, E. P. Fedorova1, A. A. Churin1,2, L. Yu. Kotlovskaya1,2, M. A. Solov’ev1, and V. V. Udut1,2 Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 170, No. 7, pp. 21-25, July, 2020 Original article submitted April 8, 2020 Procoagulant status was modeled in outbred female mice by single injection of cisplatin in a maximum tolerated dose and hemostasis parameters monitored over 30 days by methods of coagulogram and low-frequency piezothromboelastography (global test). Monitoring revealed waveform changes in the hemostatic potential: the structural and chronometric hypercoagulation recorded starting from the first day and attaining its maximum on days 5-7 was followed by hypocoagulation and returned to normocoagulation on day 30. This pattern reflects prolonged effect of cisplatin: formation of severe dysfunction of the endothelium providing the main anticoagulant pool of hemostasis (day 1) aggravated by disturbances of the plastic functions of the liver (days 15-20), and recovery (days 20-30). Key Words: hemostatic potential; endothelial dysfunction; cisplatin; low-frequency piezothromboelastography; outbred mice The association of chemotherapy with thrombohemorrhagic complications is demonstrated in numerous studies [1,6,7]. Cisplatin attracts much attention as one of the most commonly used chemotherapeutic agents particularly in the framework of the development of thrombohemorrhagic complications in tumor patients. The main mechanism of its cytotoxic effect is the formation of adducts with purine bases of DNA with simultaneous development of pronounced oxidative stress, which leads to activation of external and internal pathways of apoptosis [2] and necroptosis [9]. Cisplatin, like the vast majority of antitumor agents, has a damaging effect on all cells with high proliferative activity, including vascular endothelium. Structural and functional damage to the vascular endothelium observed during chemotherapy results in a decrease in the anticoagulant potential of the vascular wall, release of the content of Weibel—Palade bodies (von Willebrand factor, p-selectin, etc.), deE. D. Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia; 2National Research Tomsk State University, Tomsk, Russia. Address for correspondence: [email protected]. M. V. Filonova 1
endothelization, etc., leading to sharp intensification of procoagulant activity accompanied by dysfunction of anticoagulation mechanisms [4]. Chemotherapeutic agents produce significant negative effect on the liver, the main detoxifying organ, which can trigger hemorrhagic complications [1]. In this context, experimental modeling and monitoring of dysfunction of the system controlling aggregate state of the blood under the action of chemotherapeutic drugs is a pressing problem. Analysis of compensation mechanisms and terms of functional recovery of th
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