Coadministration of low-dose lipopolysaccharide and soluble tissue factor induces thrombosis after radiosurgery in an animal arteriovenous malformation model.
OBJECTIVE
Radiosurgery for arteriovenous malformations is limited to small lesions and may take 3 years to produce total occlusion. It has recently been shown that coadministration of low-dose lipopolysaccharide (LPS) and soluble tissue factor (sTF) selectively induces thrombosis in murine tumor models, attributable perhaps to the prothrombotic phenotype of tumor vasculature. Radiosurgery may induce changes in endothelial prothrombotic molecules similar to those found in tumors. This study aimed to determine if a similar strategy could be used to stimulate thrombus formation in an animal arteriovenous malformation model.


METHODS
Seventeen rats underwent creation of a carotid-to-jugular anastomosis. Animals were intravenously injected with sTF, low-dose LPS, a combination of both, or placebo 24 hours after stereotactic irradiation of the anastomosis. Control animals received both agents after sham irradiation.


RESULTS
Coadministration of sTF and LPS led to the formation of thrombi in up to 69% of small vessels and 39% of medium-sized vessels within the target region. The irradiated vasculature demonstrated intermediate rates of thrombosis after treatment with either sTF or LPS alone as did vessels within the fistula in the control group. Logistic regression analysis demonstrated significant associations between development of thrombi and treatment with radiation, sTF, or LPS (P < 0.005). There was no evidence of systemic thrombus formation or toxicity in any group.


CONCLUSIONS
Treatment with sTF and LPS selectively induces thrombosis of irradiated vessels in a rat model of arteriovenous malformation. Stimulation of thrombosis may improve the efficacy of radiosurgery, increasing the treatable lesion size and reducing latency.
Storer
Kingsley
K
Prince of Wales Medical Research Institute, University of New South Wales, Sydney, Australia.
Tu
Jian
J
Karunanayaka
Athula
A
Smee
Robert
R
Short
Richard
R
Thorpe
Philip
P
Stoodley
Marcus
M
D000818:Animals; D001165:Arteriovenous Malformations / Q000473:pathology / Q000601:surgery*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000633:toxicity; D008297:Male; D016634:Radiosurgery / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013925:Thromboplastin / Q000008:administration & dosage* / Q000633:toxicity; D013927:Thrombosis / Q000139:chemically induced* / Q000209:etiology / Q000473:pathology
D008070:Lipopolysaccharides; D013925:Thromboplastin