Visualization of clot lysis in a rat embolic stroke model: application to comparative lytic efficacy
Department of Neurology; Department of Radiology
Animals; Annexin A2; Disease Models, Animal; Drug Therapy, Combination; Fibrin; Fibrinogen; Fibrinolysis; Fibrinolytic Agents; Intracranial Embolism; Intracranial Thrombosis; Magnetic Resonance Imaging; Male; Rats; Rats, Wistar; Recombinant Proteins; Thrombolytic Therapy
Neurology | Neuroscience and Neurobiology
BACKGROUND AND PURPOSE: The purpose of this study was to develop a novel MRI method for imaging clot lysis in a rat embolic stroke model and to compare tissue plasminogen activator (tPA)-based clot lysis with and without recombinant Annexin-2 (rA2).
METHODS: In experiment 1 we used in vitro optimization of clot visualization using multiple MRI contrast agents in concentrations ranging from 5 to 50 muL in 250 muL blood. In experiment 2, we used in vivo characterization of the time course of clot lysis using the clot developed in the previous experiment. Diffusion, perfusion, angiography, and T1-weighted MRI for clot imaging were conducted before and during treatment with vehicle (n=6), tPA (n=8), or rA2 plus tPA (n=8) at multiple time points. Brains were removed for ex vivo clot localization.
RESULTS: Clots created with 25 muL Magnevist were the most stable and provided the highest contrast-to-noise ratio. In the vehicle group, clot length as assessed by T1-weighted imaging correlated with histology (r=0.93). Clot length and cerebral blood flow-derived ischemic lesion volume were significantly smaller than vehicle at 15 minutes after treatment initiation in the rA2 plus tPA group, whereas in the tPA group no significant reduction from vehicle was observed until 30 minutes after treatment initiation. The rA2 plus tPA group had a significantly shorter clot length than the tPA group at 60 and 90 minutes after treatment initiation and significantly smaller cerebral blood flow deficit than the tPA group at 90 minutes after treatment initiation.
CONCLUSIONS: We introduce a novel MRI-based clot imaging method for in vivo monitoring of clot lysis. Lytic efficacy of tPA was enhanced by rA2.
DOI of Published Version
Stroke. 2011 Apr;42(4):1110-5. Epub 2011 Mar 3. Link to article on publisher's site
Stroke; a journal of cerebral circulation
Walvick, Ronn P.; Bratane, Bernt T.; Henninger, Nils; Sicard, Kenneth M.; Bouley, James P.; Yu, Zhanyang; Lo, Eng H.; Wang, Xiaoying; and Fisher, Marc, "Visualization of clot lysis in a rat embolic stroke model: application to comparative lytic efficacy" (2011). Neurology Publications and Presentations. 408.