PET Scan Using Tagged Fibrin Can Detect Hidden Blood Clots

Peter Caravan, PhD Co-Director, Institute for Innovation in Imaging (I3) Martinos Center for Biomedical Imaging Massachusetts General Hospital Associate Professor of Radiology Harvard Medical SchoolMedicalResearch.com Interview with:
Peter Caravan, PhD
Co-Director, Institute for Innovation in Imaging (I3)
Martinos Center for Biomedical Imaging
Massachusetts General Hospital
Associate Professor of Radiology
Harvard Medical School

Medical Research: What is the background for this study? What are the main findings?

Dr. Caravan: The motivation for this work was to develop a technique that would allow the detection of thrombus (clot) anywhere in the body after injection of a molecular probe called 64Cu-FBP8.  Current techniques for thrombus detection are limited to specific vascular territories.  In instances where the location of the thrombus is unknown or if there is suspicion of multiple thrombi, then multiple imaging tests must be performed.  We sought to develop a test that could be used to find clots anywhere:  brain, thorax, abdomen, legs and in arteries, veins, or the cardiac chambers.  In addition to whole body thrombus detection, we sought a technique that could address some of the limitations with current thrombus imaging techniques.  For example computed tomography (CT), which is used to detect pulmonary emboli, requires a contrast agent that cannot be used in patients with poor kidney function.  Transesophageal echocardiography used to identify thrombus in the chambers of the heart requires that the patient be sedated.

Our approach is to use a small peptide that recognizes the protein fibrin, which is a key component of blood clots.  We tagged the peptide with an isotope of copper, Cu-64, that allows the peptide to be detected by positron emission tomography (PET). 64Cu-FBP8 binds specifically to fibrin but not to other proteins in the blood and this means that the uptake in the clot is high while background signal is very low.  We combined PET imaging which finds the clot with CT imaging or magnetic resonance imaging (MRI).  By overlaying the PET image with the CT or MRI image, we could precisely localize the clot within the We were interested to see if the age of the clot impacted our ability to detect it.  We imaged animals with a total of 42 arterial or venous clots and then the images were analyzed by two reviewers who had no prior knowledge of the location of the clot.  Overall the accuracy was 98% for detection.

Another key finding was that the uptake of 64Cu-FBP8 strongly correlated with the amount of fibrin in the clot and that younger, fresher clots had more fibrin than older clots.  This could be very useful in distinguishing newer clots which may be the source of cardiovascular events from older, clots that may pose less risk.

We also showed using combined PET-MRI that we could detect multiple blood clots in the animal in a single whole body scan.  The procedure involves a single intravenous administration of 64Cu-FBP8 and clots in the deep veins of the legs or in the carotid arteries were readily detected.

Medical Research: What should clinicians and patients take away from your report?

Dr. Caravan: These results are very promising and have the potential to impact patient care.  For instance, translating this to patients would not require the need for patient sedation and it would not involve a potentially nephrotoxic contrast agent. The ability to detect clots in different anatomical regions could be very useful in contexts where the clinician is concerned about the presence of thrombus in different and/or unknown areas.  For instance pulmonary embolism arises from a clot breaking off from a larger clot in the deep veins of the legs and traveling to the lungs.  A study where both the lungs and the legs could be evaluated in a single session would speed patient throughput and minimize the number of procedures that the patients must undergo.

Another example is in searching for the cause of a stroke.  Most strokes are caused by a piece of clot breaking off from a larger clot in the carotid arteries, the aortic arch, the left atrium of the heart, or in some cases from the deep veins of the legs, and then traveling to the brain to stop blood flow.  Despite best clinical practice, about 30-40% of strokes are termed “cryptogenic” in that the clinician does not know the source of the stroke.  Where the stroke originated is very important because location dictates the type of treatment that will be given to prevent a second stroke. If source thrombus remains, there is a high risk of secondary stroke.  The ability to noninvasively search multiple anatomical regions for clot would be very valuable in this context.  A related example is transient ischemic attack (TIA) which is similar to a stroke but the effect is temporary and resolves without long term damage.  However having a TIA puts a patient at extremely high risk for a stroke, and so having the ability to scan TIA patients for the underlying source thrombus could also be extremely valuable.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Caravan: This study was performed in rats, but the results are so compelling that we are planning to perform human studies in the near future.  That involves demonstrating to the FDA that 64Cu-FBP8 is safe for taking forward and we are in the process of submitting that documentation.  Then will come studies in patients to first test how accurate 64Cu-FBP8 PET scanning is for detection of clot.  Should these studies prove effective, it may be possible to gain regulatory approval for widespread clinical use of this technique.

Citation: Francesco Blasi, Bruno L. Oliveira, Tyson A. Rietz, Nicholas J. Rotile, Pratap C. Naha, David P. Cormode, David Izquierdo-Garcia, Ciprian Catana, Peter Caravan. Multisite Thrombus Imaging and Fibrin Content Estimation With a Single Whole-Body PET Scan in Rats.Arteriosclerosis, Thrombosis, and Vascular Biology, 2015; ATVBAHA.115.306055 DOI: 10.1161/ATVBAHA.115.306055

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Peter Caravan, PhD (2015). PET Scan Using Tagged Fibrin Can Detect Hidden Blood Clots 

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