Comparison of an animal model of arteriovenous malformation with human arteriovenous malformation.

This study assessed the blood flow and histological changes of an animal model of arteriovenous malformation (AVM) over 84 days in 71 rats, and compared the histological findings to 17 specimens of human AVM. Carotid-jugular fistula blood flow positively correlated with time. The maximum flow rate occurred at 42 days, at which time the nidus was considered mature and was histologically similar to human AVMs. Morphological similarities between the model and human AVM vessels included heterogeneously thickened walls, splitting of the elastic lamina, thickened endothelial layers, endothelial cushions, lack of tight junctions, loss of endothelial continuity, endothelial-subendothelial adherent junctions, and luminally directed filopodia. These findings support the theory that vascular changes in human AVMs are secondary to increased flow and provide a basis for using this model in studies of AVMs.

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. CONCLUSION: 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.

Thrombotic molecule expression in cerebral vascular malformations.

Thrombosis is an important end-point in the obliteration of vascular malformations after radiosurgery. The aim of this study was to investigate the expression of thrombotic molecules in arteriovenous malformations (AVMs) and cavernous malformations (CMs), and in AVMs after radiosurgery. Fresh-frozen surgical specimens from 18 AVMs (including three that had previously been treated with radiosurgery), seven CMs, and three control specimens were studied. The expression of tissue factor, thrombomodulin and von Willebrand factor (vWF) were examined using immunofluorescence. Thrombomodulin and vWF were expressed in the endothelium of all specimens, while tissue factor was predominately found in the perivascular region and vascular adventitia. Previous treatment of AVMs with either radiation or embolisation did not significantly alter the intensity of expression. In some irradiated lesions, vessels were found with absent endothelial vWF staining and exposed tissue factor. This study has demonstrated that loss of the endothelium and exposure of underlying tissue factor occurs in irradiated AVMs. There were no significant differences in the expression of these thrombotic molecules in vascular malformations when compared to control vessels. While no long-term alterations in antigen expression were observed after radiosurgery, further work may elucidate the nature of the immediate response to irradiation.