Antiangiogenic Therapy Inhibits Venous Thrombus Resolution

Colin E. Evans; Steven P. Grover; Julia Humphries; Prakash Saha; Anant P. Patel; Ashish S. Patel; Oliver T. Lyons; Matt Waltham; Bijan Modarai; Alberto Smith

doi:10.1161/ATVBAHA.113.302998

Antiangiogenic Therapy Inhibits Venous Thrombus Resolution

Colin E. Evans, Steven P. Grover, Julia Humphries, Prakash Saha, Anant P. Patel, Ashish S. Patel, Oliver T. Lyons, Matt Waltham, Bijan Modarai, Alberto Smith^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

49 Citations (Scopus)

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.

Original language	English
Pages (from-to)	565-570
Number of pages	6
Journal	Arteriosclerosis, Thrombosis, and Vascular Biology
Volume	34
Issue number	3
Early online date	16 Jan 2014
DOIs	https://doi.org/10.1161/ATVBAHA.113.302998
Publication status	Published - Mar 2014

Keywords

2-methoxyestradiol
angiogenesis inhibitors
axitinib
thrombosis
ENDOTHELIAL GROWTH-FACTOR
ENDOGENOUS ESTROGEN METABOLITE
DEEP-VEIN THROMBOSIS
SOLID TUMORS
PHASE-I
ANGIOGENESIS INHIBITORS
MONOCYTE ACTIVATION
AXITINIB AG-013736
CANCER-PATIENTS
RECANALIZATION

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1161/ATVBAHA.113.302998

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@article{c436df260d4c4d2aa649f7afd8c2f3a5,

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. 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.",

keywords = "2-methoxyestradiol, angiogenesis inhibitors, axitinib, thrombosis, ENDOTHELIAL GROWTH-FACTOR, ENDOGENOUS ESTROGEN METABOLITE, DEEP-VEIN THROMBOSIS, SOLID TUMORS, PHASE-I, ANGIOGENESIS INHIBITORS, MONOCYTE ACTIVATION, AXITINIB AG-013736, CANCER-PATIENTS, RECANALIZATION",

author = "Evans, {Colin E.} and Grover, {Steven P.} and Julia Humphries and Prakash Saha and Patel, {Anant P.} and Patel, {Ashish S.} and Lyons, {Oliver T.} and Matt Waltham and Bijan Modarai and Alberto Smith",

year = "2014",

month = mar,

doi = "10.1161/ATVBAHA.113.302998",

language = "English",

volume = "34",

pages = "565--570",

journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",

issn = "1079-5642",

publisher = "Lippincott Williams and Wilkins",

number = "3",

}

TY - JOUR

T1 - Antiangiogenic Therapy Inhibits Venous Thrombus Resolution

AU - Evans, Colin E.

AU - Grover, Steven P.

AU - Humphries, Julia

AU - Saha, Prakash

AU - Patel, Anant P.

AU - Patel, Ashish S.

AU - Lyons, Oliver T.

AU - Waltham, Matt

AU - Modarai, Bijan

AU - Smith, Alberto

PY - 2014/3

Y1 - 2014/3

N2 - 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.

AB - 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.

KW - 2-methoxyestradiol

KW - angiogenesis inhibitors

KW - axitinib

KW - thrombosis

KW - ENDOTHELIAL GROWTH-FACTOR

KW - ENDOGENOUS ESTROGEN METABOLITE

KW - DEEP-VEIN THROMBOSIS

KW - SOLID TUMORS

KW - PHASE-I

KW - ANGIOGENESIS INHIBITORS

KW - MONOCYTE ACTIVATION

KW - AXITINIB AG-013736

KW - CANCER-PATIENTS

KW - RECANALIZATION

U2 - 10.1161/ATVBAHA.113.302998

DO - 10.1161/ATVBAHA.113.302998

M3 - Article

SN - 1079-5642

VL - 34

SP - 565

EP - 570

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

IS - 3

ER -

Antiangiogenic Therapy Inhibits Venous Thrombus Resolution

Abstract

Keywords

UN SDGs

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