Antiangiogenic Therapy Inhibits Venous Thrombus Resolution

Abstract

Objective-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. Approach and Results-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. Conclusions-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. (Arterioscler Thromb Vasc Biol. 2014;34:565-570.)

Local accumulation of hypoxia-inducible factor 2 alpha during venous thrombus resolution

“…We showed that regions of the resolving thrombus that stained positively for HIF2α (when its level peaked at day 10) also stained positively for a macrophage-specific marker, Mac2. These observations are comparable with a previous study demonstrating that macrophages localise at the thrombus periphery at day 10 postinduction [11]. Macrophages are therefore likely to be the predominant cell type that expresses HIF2α in the resolving thrombus (e.g.…”

“…At days 7, 10, and 14 post-thrombus induction, discrete staining for HIF2α was observed in association with nucleated cells particularly at the periphery of the thrombus (i.e. in regions where vein recanalisation including neovascularisation commonly occurs in this model) [1,[11][12][13]. Target genes of HIF2α include the angiogenic factor, vascular endothelial growth factor, and upregulation of HIF2α in the naturally resolving thrombus could facilitate the formation of new vascular channels via transcriptional upregulation of multiple angiogenic HIF2 targets.…”

Involvement of inflammatory markers in pathogenesis of venous thromboembolism

“…The specific contribution of neutrophil influx in angiogenesis is still not defined, but the depletion of granulocytes is associated with larger thrombi with a higher concentration of collagen, while the supplementation with IL-8 is associated with smaller thrombi, concomitant with an increase in neo-vascularization [32]. Published data suggest the possibility of using angiogenic chemokines, such as IL-8, for the treatment of venous thrombosis because of its favorable effect on thrombus stabilization and neo-vascularization, thus promoting the early recanalization and restoring the perfusion, especially when injected directly into the thrombus [32,33].…”

High rates of venous thromboembolic events in patients undergoing systemic therapy for urothelial carcinoma: A systematic review and meta-analysis

“…[20] Anti-angiogenics have been shown to inhibit resolution of venous thrombi, which may further increase the risk for thrombosis already imposed by malignancy and surgery and can present a challenge in the management of thrombotic complications in patients being treated with these agents. [22] While the mechanisms behind the thrombogenic potential of angiogenesis inhibitiors remain ill-defined, one of the main hypotheses is that the drugs cause disruption of the tumor-associated endothelial lining, leading to a prothrombotic surface that can mediate activation of the coagulation cascade. [23] Though our publication only examined venous thromboembolism, bevacizumab has also been associated with a high rate of arterial thromboembolism.…”