From the Academic Department of Vascular Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, United Kingdom.
Arterioscler Thromb Vasc Biol. 2014 Mar;34(3):565-70. doi: 10.1161/ATVBAHA.113.302998. Epub 2014 Jan 16.
Venous thromboembolism is a common complication in patients with cancer, resulting in significant morbidity and mortality. Clinical studies suggest that the incidence of venous thromboembolic events increased after treatment of these patients with antiangiogenic agents. Thrombi resolve through a process of remodeling, involving the formation of microvascular channels within the thrombus. Our aim was to determine whether inhibiting angiogenesis affects venous thrombus resolution.
Thrombus was induced in the inferior vena cava of mice. These mice were treated with axitinib (50 mg/kg per day), 2-methoxyestradiol (2ME, 150 mg/kg per day), or vehicle control. Thrombus size, recanalization, neovascularization, inflammatory cell content, and collagen content were assessed after axitinib (days 3, 10, 17) and 2ME (day 10 only) treatment (n=6/group). Axitinib treatment resulted in reduced thrombus resolution (P<0.002) and vein recanalization (P<0.001) compared with vehicle-treated controls. This was associated with inhibition of organization as seen through reduced thrombus neovascularization (P<0.0001) and collagen (P<0.0001) content, as well as reduced macrophage accumulation in the thrombus (P<0.001). Treatment with a second antiangiogenic agent, 2ME, mirrored these findings, with a similar order of magnitude of effect of treatment over vehicle control in all of the parameters measured, with the exception of neutrophil content, which was significantly reduced after 2ME treatment but not affected by axitinib.
Antiangiogenic therapy (using axitinib and 2ME) inhibits the resolution of venous thrombi, which could lead to persistent venous obstruction and the possibility of thrombus extension. This potential prolongation of venous occlusion by antiangiogenic agents should therefore be taken into consideration in trials of these agents and when managing the complications of venous thromboembolic events in patients with cancer.
静脉血栓栓塞是癌症患者的常见并发症，可导致严重的发病率和死亡率。临床研究表明，这些患者在接受抗血管生成药物治疗后，静脉血栓栓塞事件的发生率增加。血栓通过重塑过程溶解，涉及血栓内微血管通道的形成。我们的目的是确定抑制血管生成是否会影响静脉血栓的溶解。
在小鼠下腔静脉中诱导血栓形成。这些小鼠用阿昔替尼（每天 50mg/kg）、2-甲氧基雌二醇（2ME，每天 150mg/kg）或载体对照物治疗。在阿昔替尼（第 3、10、17 天）和 2ME（仅第 10 天）治疗后评估血栓大小、再通、新生血管形成、炎症细胞含量和胶原含量（每组 n=6）。与载体治疗对照组相比，阿昔替尼治疗导致血栓溶解减少（P<0.002）和静脉再通减少（P<0.001）。这与血栓新生血管形成减少（P<0.0001）和胶原（P<0.0001）含量减少有关，以及血栓内巨噬细胞积累减少（P<0.001），这表明组织抑制。用第二种抗血管生成药物 2ME 进行治疗，与对照物相比，所有测量参数的治疗效果相似，除了中性粒细胞含量外，2ME 治疗后明显降低，但阿昔替尼治疗没有影响。
抗血管生成治疗（使用阿昔替尼和 2ME）抑制静脉血栓的溶解，这可能导致持续的静脉阻塞和血栓延伸的可能性。因此，在这些药物的试验中以及在管理癌症患者静脉血栓栓塞事件的并发症时，应考虑抗血管生成药物对静脉闭塞的潜在延长作用。
