Document Detail

Molecular MRI of early thrombus formation using a bimodal alpha2-antiplasmin-based contrast agent.
MedLine Citation:
PMID:  19679287     Owner:  NLM     Status:  MEDLINE    
OBJECTIVES: We aimed to investigate whether early thrombus formation can be visualized with in vivo magnetic resonance imaging (MRI) by the use of a novel bimodal alpha(2)-antiplasmin-based contrast agent (CA). BACKGROUND: Thrombus formation plays a central role in several vascular diseases. During the early phases of thrombus formation, activated factor XIII (FXIIIa) covalently cross-links alpha(2)-antiplasmin to fibrin, indicating the potential of alpha(2)-antiplasmin-based CAs in the detection of early thrombus formation. METHODS: A bimodal CA was synthesized by coupling gadolinium-diethylene triamine pentaacetic acid and rhodamine to an alpha(2)-antiplasmin-based peptide. For the control CA, a glutamine residue essential for cross-linking was replaced by alanine. In vitro-generated thrombi were exposed to both CAs and imaged by MRI and 2-photon laser-scanning microscopy. Immunohistochemistry was performed on human pulmonary thromboemboli sections to determine the presence of alpha(2)-antiplasmin and FXIII in different thrombus remodeling phases. In vivo feasibility of the CA in detecting early thrombus formation specifically was investigated with MRI. RESULTS: In vitro-generated thrombi exposed to the alpha(2)-antiplasmin-based CA showed hyperintense magnetic resonance signal intensities at the thrombus edge. No hyperintense signal was observed when we used the alpha(2)-antiplasmin-based CA in the presence of FXIII inhibitor dansylcadaverine nor when we used the control CA. Two-photon laser-scanning microscopy demonstrated that the alpha(2)-antiplasmin-based CA bound to fibrin. Immunohistochemistry demonstrated substantial alpha(2)-antiplasmin staining in fresh compared with lytic and organized thrombi. The administration of CA in vivo within seconds after inducing thrombus formation increased contrast-to-noise ratios (CNRs 2.28 +/- 0.39, n=6) at the site of thrombus formation compared with the control CA (CNRs -0.14 +/- 0.55, p = 0.003, n = 6) and alpha(2)-antiplasmin-based CA administration 24 to 48 h after thrombus formation (CNRs 0.11 +/- 0.23, p = 0.006, n = 6). CONCLUSIONS: A bimodal CA was developed, characterized, and validated. Our results showed that this bimodal CA enabled noninvasive in vivo magnetic resonance visualization of early thrombus formation.
Robbert-Jan J H M Miserus; M Veronica Herías; Lenneke Prinzen; Marc B I Lobbes; Robert-Jan Van Suylen; Anouk Dirksen; Tilman M Hackeng; Johan W M Heemskerk; Jos M A van Engelshoven; Mat J A P Daemen; Marc A M J van Zandvoort; Sylvia Heeneman; Marianne Eline Kooi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Validation Studies    
Journal Detail:
Title:  JACC. Cardiovascular imaging     Volume:  2     ISSN:  1876-7591     ISO Abbreviation:  JACC Cardiovasc Imaging     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-08-14     Completed Date:  2009-10-28     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  101467978     Medline TA:  JACC Cardiovasc Imaging     Country:  United States    
Other Details:
Languages:  eng     Pagination:  987-96     Citation Subset:  IM    
Department of Radiology, Maastricht University Medical Centre, Maastricht, the Netherlands.
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MeSH Terms
Cadaverine / analogs & derivatives,  pharmacology
Contrast Media / diagnostic use*
Disease Models, Animal
Factor XIII / metabolism
Factor XIIIa / metabolism
Feasibility Studies
Fibrin / metabolism
Gadolinium DTPA / analogs & derivatives,  diagnostic use*,  pharmacokinetics
Magnetic Resonance Imaging*
Microscopy, Fluorescence, Multiphoton
Predictive Value of Tests
Pulmonary Embolism / blood,  diagnosis*,  pathology
Reproducibility of Results
Rhodamines / diagnostic use*,  pharmacokinetics
Thrombosis / blood,  diagnosis*,  pathology
alpha-2-Antiplasmin / analogs & derivatives,  diagnostic use*,  pharmacology
Reg. No./Substance:
0/Contrast Media; 0/Rhodamines; 0/alpha-2-Antiplasmin; 10121-91-2/monodansylcadaverine; 462-94-2/Cadaverine; 80529-93-7/Gadolinium DTPA; 9001-31-4/Fibrin; 9013-56-3/Factor XIII; EC XIIIa

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