Tetsuya Hara1, Jessica Truelove1, Ahmed Tawakol1, Gregory R Wojtkiewicz1, William J Hucker1, Megan H MacNabb1, Anna-Liisa Brownell1, Kimmo Jokivarsi1, Chase W Kessinger1, Michael R Jaff1, Peter K Henke1, Ralph Weissleder1, Farouc A Jaffer2. 1. From the Cardiovascular Research Center (T.H., C.W.K., F.A.J.), Center for Systems Biology (J.T., G.R.W., R.W.), Cardiology Division (A.T., W.J.H., M.H.M., M.R.J., F.A.J.), and Martinos Biomedical Imaging Center (A.-.L.B., K.J.), Massachusetts General Hospital, Harvard Medical School, Boston, MA; and Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI (P.K.H.). 2. From the Cardiovascular Research Center (T.H., C.W.K., F.A.J.), Center for Systems Biology (J.T., G.R.W., R.W.), Cardiology Division (A.T., W.J.H., M.H.M., M.R.J., F.A.J.), and Martinos Biomedical Imaging Center (A.-.L.B., K.J.), Massachusetts General Hospital, Harvard Medical School, Boston, MA; and Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI (P.K.H.). fjaffer@mgh.harvard.edu.
Abstract
BACKGROUND: Accurate detection of recurrent same-site deep vein thrombosis (DVT) is a challenging clinical problem. Because DVT formation and resolution are associated with a preponderance of inflammatory cells, we investigated whether noninvasive (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (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/computed tomography (CT) was performed at DVT time points 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 before 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 in comparison with 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.
BACKGROUND: Accurate detection of recurrent same-site deep vein thrombosis (DVT) is a challenging clinical problem. Because DVT formation and resolution are associated with a preponderance of inflammatory cells, we investigated whether noninvasive (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (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/computed tomography (CT) was performed at DVT time points 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 before 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 in comparison with 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.
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