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

Dong-Eog Kim; Jeong-Yeon Kim; Dawid Schellingerhout; Ju Hee Ryu; Su-Kyoung Lee; Sangmin Jeon; Ji Sung Lee; Jiwon Kim; Hee Jeong Jang; Jung E Park; Eo Jin Kim; Ick Chan Kwon; Cheol-Hee Ahn; Matthias Nahrendorf; Kwangmeyung Kim

doi:10.1161/STROKEAHA.117.016511

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

Stroke. 2017 May;48(5):1376-1385. doi: 10.1161/STROKEAHA.117.016511.

Authors

Affiliations

¹ From Molecular Imaging and Neurovascular Research Laboratory, Departments of Neurology (D.-E.K., J.-Y.K., S.-K.L., J.K., H.J.J., J.E.P.) and Pathology (E.J.K.), Dongguk University College of Medicine, Goyang, South Korea; Biomedical Research Center, Korea Institute of Science and Technology, Seoul, South Korea (J.H.R., S.J., I.C.K., K.K.); Departments of Diagnostic Radiology and Cancer Systems Imaging, University of Texas M.D. Anderson Cancer Center, Houston (D.S.); Clinical Research Center, Asan Medical Center, Seoul, South Korea (J.S.L.); Research Institute of Advanced Materials, Department of Materials Science and Engineering, Seoul National University, South Korea (C.-H.A.); and Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (M.N.). kdongeog@duih.org.
² From Molecular Imaging and Neurovascular Research Laboratory, Departments of Neurology (D.-E.K., J.-Y.K., S.-K.L., J.K., H.J.J., J.E.P.) and Pathology (E.J.K.), Dongguk University College of Medicine, Goyang, South Korea; Biomedical Research Center, Korea Institute of Science and Technology, Seoul, South Korea (J.H.R., S.J., I.C.K., K.K.); Departments of Diagnostic Radiology and Cancer Systems Imaging, University of Texas M.D. Anderson Cancer Center, Houston (D.S.); Clinical Research Center, Asan Medical Center, Seoul, South Korea (J.S.L.); Research Institute of Advanced Materials, Department of Materials Science and Engineering, Seoul National University, South Korea (C.-H.A.); and Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (M.N.).

PMID: 28432262
DOI: 10.1161/STROKEAHA.117.016511

Abstract

Background and purpose: 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.

Methods: 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.

Results: Thrombus burden at baseline was 784×10³±59×10³ μm² for the tPA group (n=42) and 655×10³±103×10³ μm² for the saline group (n=8; P=0.37). Thrombus shrinkage began at 0.5 to 1 hour after tPA therapy, with a maximum initial rate of change at 4603±957 μm²/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 μm², 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 mm²; P<0.01). Infarct size correlated to final thrombus burden (r=0.71; P<0.01). Time to thrombolysis, completeness of thrombolysis, and tPA therapy were independent predictors of infarct size.

Conclusions: Thromboembolic burden and the efficacy of tPA therapy can be assessed serially, noninvasively, and quantitatively using high-resolution microcomputed tomography and a fibrin-binding nanoparticle imaging agent.

Keywords: direct thrombus imaging; gold nanoparticles; microCT; thrombus evolution; tissue-type plasminogen activator.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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*

Substances

Fibrinolytic Agents
Gold
Tissue Plasminogen Activator