¹⁸ F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Enables the Detection of Recurrent Same-Site Deep Vein Thrombosis by Illuminating Recently Formed, Neutrophil-Rich Thrombus

Abstract

Background Accurate detection of recurrent same-site deep vein thrombosis (DVT) is a challenging clinical problem. As DVT formation and resolution are associated with a preponderance of inflammatory cells, we investigated whether noninvasive 18F-fluorodeoxyglucose (FDG)-PET imaging could identify inflamed, recently formed thrombi and thereby improve the diagnosis of recurrent DVT. Methods and Results We established a stasis-induced DVT model in murine jugular veins and also a novel model of recurrent stasis DVT in mice. C57BL/6 mice (n=35) underwent ligation of the jugular vein to induce stasis DVT. FDG-PET/CT was performed at DVT timepoints of day 2, 4, 7, 14, or 2+16 (same-site recurrent DVT at day 2 overlying a primary DVT at day 16). Antibody-based neutrophil depletion was performed in a subset of mice prior to DVT formation and FDG-PET/CT. In a clinical study, 38 patients with lower extremity DVT or controls undergoing FDG-PET were analyzed. Stasis DVT demonstrated that the highest FDG signal occurred at day 2, followed by a time-dependent decrease (p<0.05). Histological analyses demonstrated that thrombus neutrophils (p<0.01), but not macrophages, correlated with thrombus PET signal intensity. Neutrophil depletion decreased FDG signals in day 2 DVT compared to controls (p=0.03). Recurrent DVT demonstrated significantly higher FDG uptake than organized day 14 DVT (p=0.03). The FDG DVT signal in patients also exhibited a time-dependent decrease (p<0.01). Conclusions Noninvasive FDG-PET/CT identifies neutrophil-dependent thrombus inflammation in murine DVT, and demonstrates a time-dependent signal decrease in both murine and clinical DVT. FDG-PET/CT may offer a molecular imaging strategy to accurately diagnose recurrent DVT.

Multisite Thrombus Imaging and Fibrin Content Estimation With a Single Whole-Body PET Scan in Rats

“…Scintigraphy with the 99m Technetium-labeled activated platelets inhibitor DPM-444 10 and 99m Technetium-rtPA 36 have shown good feasibility identifying fresh clots over organized thrombi, but at the same time the low efficacy in detecting mature clots reduced their clinical applications. Fluorodeoxyglucose (FDG)-PET has been recently used to stage thrombosis by imaging neutrophilic infiltration in fresh venous thrombi 37 . However, FDG uptake is also increased in other pathologies associated with high cellularity and hypermetabolism (e.g., cancer, chronic inflammatory conditions), which may limit the specificity of this imaging approach.…”

Current and future perspectives in imaging of venous thromboembolism

“…As with MRDTI, the positive signal of FDG PET decreases over time after initiation of anticoagulant treatment. The proposed ability to differentiate acute from chronic clots in the leg veins may suggest a potential role of FDG‐PET in the diagnostic workup of patients with suspected recurrent ipsilateral DVT . Of note, its feasibility in clinical practice has to be evaluated, taking into account the necessary fasting period of 6 h and the > 1 h waiting time after isotope administration before scanning .…”

Resolution of Deep Venous Thrombosis: Proposed Immune Paradigms

“…By week 4, only 20% of the thrombus area is fibrin (mostly granular patches within the interior), with collagen comprising the rest [170]. Surprisingly, there remains disagreement regarding whether neutrophils and macrophages are more numerous within the murine thrombus over this late time period [65,170,171]. The liver-secreted zymogen plasminogen, following activation and conversion to plasmin, degrades fibrin [172] into an E-fragment and D-dimer [173].…”