Molecular MRI of Cerebral Venous Sinus Thrombosis Using a New Fibrin-Specific MR Contrast Agent

Abstract

Background and Purpose-Imaging of cerebral vein thrombosis is still challenging. Currently, diagnosis is based on CT venography and MRI including MRA and conventional digital subtraction angiography. However, especially in chronic cases, each method has shown its limitations. Newer strategies for MRI are found on molecular imaging using targeted contrast agents. The aim of this study was to prove the feasibility of a novel fibrin-targeted MR contrast agent (EP-2104R; EPIX Pharmaceuticals) for selective imaging of sinus venous thrombosis in an animal model. Methods-Thrombosis of the superior sagittal sinus with human blood was induced in 6 pigs using a combined microsurgical and interventional approach. MRI was then performed before and up to 120 minutes after injection of 4 mol/kg body weight EP-2104R. Molecular imaging was performed with a 3-dimensional high-resolution T1-weighted gradient echo sequence. Time courses of signal-to-noise ratio and contrast-to-noise ratio were analyzed. Thrombi were then surgically removed and the Gadolinium concentration was assessed. Results-In all cases the thrombosis could be successfully induced; the complete MR protocol could be performed in 5 animals. In these cases the thrombi showed selective enhancement after injection of the molecular contrast agent. However, a continuous contrast-to-noise ratio increase was seen up to 120 minutes after contrast administration, achieving a contrast-to-noise ratio of 14.2Ϯ0.7 between clot and the blood pool. Conclusion-The novel fibrin-targeted molecular MR contrast EP-2104R allows selective and high-contrast imaging of cerebral sinus vein thrombosis in an animal model.

MR imaging of thrombi using EP-2104R, a fibrin-specific contrast agent: initial results in patients

“…If a sufficiently high amount of (positive) contrast agent is accumulated in a target tissue of interest (e.g., a target that correlates with plaque rupture), a single heavily T1-weighted sequence may allow for detection of such vulnerable plaque. Recently, a novel fibrin-specific contrast agent (EP-2104R, EPIX Pharmaceuticals, Lexington, MA, USA) has been introduced in animal models, allowing for white-spot imaging of thrombi in different vascular beds [24][25][26][27][28]. Using such agents, the intraluminal thrombus layer, which potentially may represent vulnerable plaque, can be selectively enhanced while other plaque lesions do not enhance [29].…”

Molecular Imaging of Thrombosis

“…4) [19], pulmonary embolism (Fig. 5) [22], thrombi of the atria [43], sinus thrombosis [44], as well as chronic carotid [45], coronary [46], and pulmonary [47] thrombosis in experimental animal models. The administered dose was 4-7.5 μmol/kg, much lower than that for conventional nontargeted Gd-based contrast agents (typically ∼0.1 mmol/kg).…”

“…Recently, our group and others used a fibrin-targeted small peptide to detect thrombosis in a range of animal models [18,19,22,[43][44][45][46][47]. In the first experiments, imaging of acute thrombus in an animal model of plaque rupture was demonstrated with EP-1873 [18].…”

Peptide-based fibrin-targeting probes for thrombus imaging

“…Fibrin is present at high concentrations in both venous and arterial thrombosis providing high sensitivity, but fibrin is not present in circulating blood resulting in potentially high specificity. 55 In addition, the fibrin concentration in thrombus is in the hundreds of micromolar, 56 making this a target compatible with most imaging modalities. Lastly, fibrin is present in fresh thrombi but when the thrombus becomes aged and organized, the fibrin is replaced by collagen and other fibrotic proteins.…”