Prakash Saha1, Marcelo E Andia1, Bijan Modarai1, Ulrike Blume1, Julia Humphries1, Ashish S Patel1, Alkystis Phinikaridou1, Colin E Evans1, Katherine Mattock1, Steven P Grover1, Anwar Ahmad1, Oliver T Lyons1, Rizwan Q Attia1, Thomas Renné1, Sobath Premaratne1, Andrea J Wiethoff1, René M Botnar1, Tobias Schaeffter1, Matthew Waltham1, Alberto Smith1. 1. Academic Department of Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, UK (P.S., B.M., J.H., A.S.P., C.E.E., K.M., S.P.G., A.A., O.T.L., R.Q.A., S.P., M.W., A.S.); Division of Imaging Sciences and Biomedical Engineering, Kings College London, BHF Centre of Research Excellence & Wellcome Trust - EPSRC Medical Engineering Centre & NIHR Biomedical Research Centre at Kings Health Partners, St. Thomas' Hospital, London, UK (M.E.A., U.B., A.P., A.J.W., T.S.); Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.); Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden (T.R.); and Philips Healthcare, Guildford, UK (A.J.W.).
Abstract
BACKGROUND: The magnetic resonance longitudinal relaxation time (T1) changes with thrombus age in humans. In this study, we investigate the possible mechanisms that give rise to the T1 signal in venous thrombi and whether changes in T1 relaxation time are informative of the susceptibility to lysis. METHODS AND RESULTS: Venous thrombosis was induced in the vena cava of BALB/C mice, and temporal changes in T1 relaxation time correlated with thrombus composition. The mean T1 relaxation time of thrombus was shortest at 7 days following thrombus induction and returned to that of blood as the thrombus resolved. T1 relaxation time was related to thrombus methemoglobin formation and further processing. Studies in inducible nitric oxide synthase (iNOS(-/-))-deficient mice revealed that inducible nitric oxide synthase mediates oxidation of erythrocyte lysis-derived iron to paramagnetic Fe3+, which causes thrombus T1 relaxation time shortening. Studies using chemokine receptor-2-deficient mice (Ccr2(-/-)) revealed that the return of the T1 signal to that of blood is regulated by removal of Fe3+ by macrophages that accumulate in the thrombus during its resolution. Quantification of T1 relaxation time was a good predictor of successful thrombolysis with a cutoff point of <747 ms having a sensitivity and specificity to predict successful lysis of 83% and 94%, respectively. CONCLUSIONS: The source of the T1 signal in the thrombus results from the oxidation of iron (released from the lysis of trapped erythrocytes in the thrombus) to its paramagnetic Fe3+ form. Quantification of T1 relaxation time appears to be a good predictor of the success of thrombolysis.
BACKGROUND: The magnetic resonance longitudinal relaxation time (T1) changes with thrombus age in humans. In this study, we investigate the possible mechanisms that give rise to the T1 signal in venous thrombi and whether changes in T1 relaxation time are informative of the susceptibility to lysis. METHODS AND RESULTS: Venous thrombosis was induced in the vena cava of BALB/C mice, and temporal changes in T1 relaxation time correlated with thrombus composition. The mean T1 relaxation time of thrombus was shortest at 7 days following thrombus induction and returned to that of blood as the thrombus resolved. T1 relaxation time was related to thrombus methemoglobin formation and further processing. Studies in inducible nitric oxide synthase (iNOS(-/-))-deficient mice revealed that inducible nitric oxide synthase mediates oxidation of erythrocyte lysis-derived iron to paramagnetic Fe3+, which causes thrombus T1 relaxation time shortening. Studies using chemokine receptor-2-deficient mice (Ccr2(-/-)) revealed that the return of the T1 signal to that of blood is regulated by removal of Fe3+ by macrophages that accumulate in the thrombus during its resolution. Quantification of T1 relaxation time was a good predictor of successful thrombolysis with a cutoff point of <747 ms having a sensitivity and specificity to predict successful lysis of 83% and 94%, respectively. CONCLUSIONS: The source of the T1 signal in the thrombus results from the oxidation of iron (released from the lysis of trapped erythrocytes in the thrombus) to its paramagnetic Fe3+ form. Quantification of T1 relaxation time appears to be a good predictor of the success of thrombolysis.
Entities:
Keywords:
macrophages; magnetic resonance imaging; therapeutic thrombolysis; venous thrombosis
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