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, Kwang Meyung Kim

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1376-1385
Number of pages10
JournalStroke
Volume48
Issue number5
DOIs
Publication statusPublished - 2017 May 1
Externally publishedYes

Fingerprint

Tissue Plasminogen Activator
Plasminogen Activators
Thrombosis
X-Ray Microtomography
Fibrin
Nanoparticles
Gold
Therapeutics
Internal Carotid Artery
Stroke
Research

Keywords

  • direct thrombus imaging
  • gold nanoparticles
  • microCT
  • thrombus evolution
  • tissue-type plasminogen activator

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialised Nursing

Cite this

Quantitative Imaging of Cerebral Thromboemboli in Vivo : The Effects of Tissue-Type Plasminogen Activator. / 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, Kwang Meyung.

In: Stroke, Vol. 48, No. 5, 01.05.2017, p. 1376-1385.

Research output: Contribution to journalArticle

Kim, DE, Kim, JY, Schellingerhout, D, Ryu, JH, Lee, SK, Jeon, S, Lee, JS, Kim, J, Jang, HJ, Park, JE, Kim, EJ, Kwon, IC, Ahn, CH, Nahrendorf, M & Kim, KM 2017, 'Quantitative Imaging of Cerebral Thromboemboli in Vivo: The Effects of Tissue-Type Plasminogen Activator', Stroke, vol. 48, no. 5, pp. 1376-1385. https://doi.org/10.1161/STROKEAHA.117.016511
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, Kwang Meyung. / Quantitative Imaging of Cerebral Thromboemboli in Vivo : The Effects of Tissue-Type Plasminogen Activator. In: Stroke. 2017 ; Vol. 48, No. 5. pp. 1376-1385.
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T1 - Quantitative Imaging of Cerebral Thromboemboli in Vivo

T2 - The Effects of Tissue-Type Plasminogen Activator

AU - Kim, Dong Eog

AU - Kim, Jeong Yeon

AU - Schellingerhout, Dawid

AU - Ryu, Ju Hee

AU - Lee, Su Kyoung

AU - Jeon, Sangmin

AU - Lee, Ji Sung

AU - Kim, Jiwon

AU - Jang, Hee Jeong

AU - Park, Jung E.

AU - Kim, Eo Jin

AU - Kwon, Ick Chan

AU - Ahn, Cheol Hee

AU - Nahrendorf, Matthias

AU - Kim, Kwang Meyung

PY - 2017/5/1

Y1 - 2017/5/1

N2 - 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.

AB - 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.

KW - direct thrombus imaging

KW - gold nanoparticles

KW - microCT

KW - thrombus evolution

KW - tissue-type plasminogen activator

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