Fibrin-Targeted PET/CMR Highly Accurate for Detecting Thrombosis

Most noninvasive methods for thrombus detection employ nephrotoxic contrast agents and have limited anatomical coverage, and transesophageal echocardiography (TEE) involves heavy sedation and presents a risk of esophageal trauma.

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In 2014, Massachusetts General Hospital researchers announced the development of a small peptide–based, fibrin-specific probe labeled with the copper-64 isotope to detect thrombus by positron emission tomography (PET). As they explained in Circulation: Cardiovascular Imaging and other papers, this probe, called [⁶⁴Cu]FBP8, facilitated rapid detection of venous, arterial and embolic thrombi in a number of animal models.

Now, Mass General's David Izquierdo-Garcia, PhD, assistant in biomedical engineering in the Department of Radiology, Peter Caravan, PhD, co-director of the Institute for Innovation in Imaging, and David Sosnovik, MD, director of the Program in Cardiovascular Imaging, all of the Martinos Center for Biomedical Imaging, have reported the first human experience with [⁶⁴Cu]FBP8. They found that using it to detect left atrial appendage (LAA) thrombi in patients with atrial fibrillation (AF) performed as well as more invasive approaches. The team's report appears in JACC: Cardiovascular Imaging.

Healthy Volunteers

The team first studied the [⁶⁴Cu]FBP8 in eight healthy volunteers. It was stable in metabolism and was rapidly eliminated, with little activity remaining four hours after injection.

[⁶⁴Cu]FBP8 vs. TEE

For detection of thrombi, the study subjects were 24 patients with AF presenting for TEE-guided cardioversion who had:

• No sign of LAA thrombus on TEE (n=12)
• Spontaneous thrombi in the LAA on TEE (n=4)
• Thrombus in the LAA purposefully induced through the placement of an LAA occlusion device (n=8)

All subjects underwent PET with [⁶⁴Cu]FBP8 within 14 days of their reference TEE. Most patients with occlusion devices were imaged within 12 days of device placement, but one was imaged 54 days later.

The maximum standardized uptake value (SUV_max) of [⁶⁴Cu]FBP8 in the LAA distinguished the 12 TEE-positive patients from the 12 TEE-negative patients:

• TEE-positive group—median SUV_max, 4.0
• TEE-negative group—2.3 (P<0.001)

An SUV_max threshold of 2.6 correctly classified all TEE-positive subjects (sensitivity of 100%) and 10 TEE-negative patients (specificity of 84%). The area under the receiver operating curve (AUC) was 0.97.

Integrated T₁ Mapping

Degradation of red blood cells in subacute thrombi results in the production of methemoglobin, which can be detected with longitudinal magnetic relaxation (T₁) maps of the heart, a routine component of CMR. Subjects underwent CMR simultaneously with PET.

Joint analysis of SUV and T₁ data was 100% accurate in distinguishing between TEE-positive and TEE-negative patients, and the AUC was 1.

The integrated approach also warned of TEE-negative patients who were actually at high risk. Of six TEE-negative patients who had data available on both fibrin and methemoglobin, two had high levels of both. One of them had a factor V Leiden mutation and the other had a history of transient ischemic attack.

Looking Ahead

[⁶⁴Cu]FBP8 allows imaging of the composite burden of arterial thrombosis and venous thrombi, particularly those in larger veins that might embolize. Detecting LAA thrombus with the probe could potentially be valuable for refining the risk of thromboembolism in patients being considered for anticoagulation and pinpointing the source of embolism after transient ischemic attack or stroke.

In addition, high fibrin in a thrombus (high uptake of [⁶⁴Cu]FBP8) might predict the likelihood of successful thrombolysis.

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