title: 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.
  
  
  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.
authors.affiliation: 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.
authors.forename: Colin E
authors.initials: CE
authors.lastname: Evans
authors.forename: Steven P
authors.initials: SP
authors.lastname: Grover
authors.forename: Julia
authors.initials: J
authors.lastname: Humphries
authors.forename: Prakash
authors.initials: P
authors.lastname: Saha
authors.forename: Anant P
authors.initials: AP
authors.lastname: Patel
authors.forename: Ashish S
authors.initials: AS
authors.lastname: Patel
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Lyons
authors.forename: Matt
authors.initials: M
authors.lastname: Waltham
authors.forename: Bijan
authors.initials: B
authors.lastname: Modarai
authors.forename: Alberto
authors.initials: A
authors.lastname: Smith
mesh_terms: D000077584:2-Methoxyestradiol; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D000077784:Axitinib; D001777:Blood Coagulation / Q000187:drug effects* / Q000502:physiology; D002199:Capillary Permeability / Q000187:drug effects; D003094:Collagen / Q000032:analysis; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D007093:Imidazoles / Q000494:pharmacology / Q000633:toxicity*; D007191:Indazoles / Q000494:pharmacology / Q000633:toxicity*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000503:physiopathology; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D019851:Thrombophilia / Q000139:chemically induced; D014682:Vena Cava, Inferior; D020246:Venous Thrombosis / Q000473:pathology / Q000503:physiopathology*
chemical_list: D020533:Angiogenesis Inhibitors; D007093:Imidazoles; D007191:Indazoles; D004958:Estradiol; D000077584:2-Methoxyestradiol; D003094:Collagen; D000077784:Axitinib
keywords: 2-methoxyestradiol; angiogenesis inhibitors; axitinib; thrombosis