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(Circulation. 2008;118:258-267.)
© 2008 American Heart Association, Inc.

Imaging

Magnetic Resonance Imaging Contrast Agent Targeted Toward Activated Platelets Allows In Vivo Detection of Thrombosis and Monitoring of Thrombolysis

C. von zur Muhlen, MD^*; D. von Elverfeldt, PhD^*; J.A. Moeller, MS; R.P. Choudhury, DM; D. Paul, PhD; C.E. Hagemeyer, PhD; M. Olschewski, PhD; A. Becker, MA; I. Neudorfer, MA; N. Bassler, MA; M. Schwarz, MD; C. Bode, MD; K. Peter, MD

From the Departments of Cardiology and Angiology (C.v.z.M., J.A.M., I.N., M.S., C.B.), Radiology/Medical Physics (D.v.E., D.P., A.B.), and Medical Biometry and Statistics (M.O.), University of Freiburg, Freiburg, Germany; Department of Cardiovascular Medicine, University of Oxford, Oxford, UK (R.P.C.); and Baker Heart Research Institute, Melbourne, Australia (C.E.H., N.B., K.P.).

Correspondence to Constantin von zur Muhlen, MD, Department of Cardiology and Angiology, Albert Ludwigs University, Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany. E-mail constantin.vonzurmuehlen{at}uniklinik-freiburg.de

Received November 23, 2007; accepted May 7, 2008.

Background— Platelets are the key to thrombus formation and play a role in the development of atherosclerosis. Noninvasive imaging of activated platelets would be of great clinical interest. Here, we evaluate the ability of a magnetic resonance imaging (MRI) contrast agent consisting of microparticles of iron oxide (MPIOs) and a single-chain antibody targeting ligand-induced binding sites (LIBS) on activated glycoprotein IIb/IIIa to image carotid artery thrombi and atherosclerotic plaques.

Methods and Results— Anti-LIBS antibody or control antibody was conjugated to 1-µm MPIOs (LIBS MPIO/control MPIO). Nonocclusive mural thrombi were induced in mice with 6% ferric chloride. MRI (at 9.4 T) was performed once before and repeatedly in 12-minute-long sequences after LIBS MPIO/control MPIO injection. After 36 minutes, a significant signal void, corresponding to MPIO accumulation, was observed with LIBS MPIOs but not control MPIOs (P<0.05). After thrombolysis, in LIBS MPIO-injected mice, the signal void subsided, indicating successful thrombolysis. On histology, the MPIO content of the thrombus, as well as thrombus size, correlated significantly with LIBS MPIO-induced signal void (both P<0.01). After ex vivo incubation of symptomatic human carotid plaques, MRI and histology confirmed binding to areas of platelet adhesion/aggregation for LIBS MPIOs but not for control MPIOs.

Conclusions— LIBS MPIOs allow in vivo MRI of activated platelets with excellent contrast properties and monitoring of thrombolytic therapy. Furthermore, activated platelets were detected on the surface of symptomatic human carotid plaques by ex vivo MRI. This approach represents a novel noninvasive technique allowing the detection and quantification of platelet-containing thrombi.

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Clinical Summaries
Circulation 2008 118: 211-212. [Extract] [Full Text]