Quantitative Imaging of Cerebral Thromboemboli In Vivo: The Effects of Tissue-Type Plasminogen Activator

• Published in: Stroke (1970) 2017-05, Vol.48 (5), p.1376-1385
• Main Authors: Kim, Dong-Eog, Kim, Jeong-Yeon, Schellingerhout, Dawid, Ryu, Ju Hee, Lee, Su-Kyoung, Jeon, Sangmin, Lee, Ji Sung, Kim, Jiwon, Jang, Hee Jeong, Park, Jung E, Kim, Eo Jin, Kwon, Ick Chan, Ahn, Cheol-Hee, Nahrendorf, Matthias, Kim, Kwangmeyung
• Format: Article
• Language: English
• Subjects: Animals; Disease Models, Animal; Fibrinolytic Agents - administration & dosage; Fibrinolytic Agents - pharmacology; Gold; Intracranial Embolism - diagnostic imaging; Intracranial Embolism - drug therapy; Intracranial Thrombosis - diagnostic imaging; Intracranial Thrombosis - drug therapy; Metal Nanoparticles; Mice; Tissue Plasminogen Activator - administration & dosage; Tissue Plasminogen Activator - pharmacology; X-Ray Microtomography - methods
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/STROKEAHA.117.016511

Quantitative imaging for the noninvasive assessment of thrombolysis is needed to advance basic and clinical thrombosis-related research and tailor tissue-type plasminogen activator (tPA) treatment for stroke patients. We quantified the evolution of cerebral thromboemboli using fibrin-targeted glycol chitosan-coated gold nanoparticles and microcomputed tomography, with/without tPA therapy. We injected thrombi into the distal internal carotid artery in mice (n=50). Fifty-five minutes later, we injected fibrin-targeted glycol chitosan-coated gold nanoparticles, and 5 minutes after that, we treated animals with tPA or not (25 mg/kg). We acquired serial microcomputed tomography images for 24 hours posttreatment. Thrombus burden at baseline was 784×10 ±59×10 μm for the tPA group (n=42) and 655×10 ±103×10 μm for the saline group (n=8; =0.37). Thrombus shrinkage began at 0.5 to 1 hour after tPA therapy, with a maximum initial rate of change at 4603±957 μm /min. The rate of change lowered to ≈61% level of the initial in hours 1 to 2, followed by ≈29% and ≈1% in hours 2 to 3 and 3 to 24, respectively. Thus, 85% of total thrombolysis over 24 hours (≈500 μm , equivalent to 64% of the baseline thrombus burden) occurred within the first 3 hours of treatment. Thrombus burden at 24 hours could be predicted at around 1.5 to 2 hours. Saline treatment was not associated with significant changes in the thrombus burden. Infarct size was smaller in the tPA group versus saline group (18.1±2.3 versus 45.8±3.3 mm ;