Fibrin-targeted magnetic resonance imaging allows in vivo quantification of thrombus fibrin content and identifies thrombi amenable for thrombolysis.
OBJECTIVE
Deep venous thrombosis is a major health problem. Thrombolytic therapies are effective in recanalizing the veins and preventing post-thrombotic complications, but there is no consensus on selection criteria. The aim of this study was to investigate a fibrin-specific MRI contrast agent (EP-2104R) for the accurate quantification of thrombus' fibrin content in vivo and for the identification of thrombus suitable for thrombolysis.


RESULTS
Venous thrombosis was induced in the inferior vena cava of 8- to 10-week-old male BALB/C mice and MRI performed 2, 4, 7, 10, 14, and 21 days later. Eighteen mice were scanned at each time point pre and 2 hours post injection of EP-2104R (8.0 μmol/kg) with 12 mice at each time point used to correlate fibrin contrast uptake with thrombus' histological stage and fibrin content. Six mice at each time point were immediately subjected to intravascular thrombolytic therapy (10 mg/kg of tissue-type plasminogen activator). Mice were imaged to assess response to lytic therapy 24 hours after thrombolytic treatment. Two mice at each time point were scanned post injection of 0.2 mmol/kg of Gd-DTPA (gadolinium with diethylenetriaminepentacetate, Magnevist, Schering AG, Berlin, Germany) for control purpose. Contrast uptake was correlated positively with the fibrin content of the thrombus measured by Western blotting (R(2)=0.889; P<0.001). Thrombus relaxation rate (R1) post contrast and the change in visualized thrombus size on late gadolinium enhancement inversion recovery MRI pre-EP-2104R and post-EP-2104R injection were the best predictors for successful thrombolysis (area under the curve, 0.989 [95% confidence interval, 0.97-1.00] and 0.994 [95% confidence interval, 0.98-1.00] respectively).


CONCLUSIONS
MRI with a fibrin-specific contrast agent accurately estimates thrombus fibrin content in vivo and identifies thrombi that are amenable for thrombolysis.
Division of Imaging Sciences and Biomedical Engineering, School of Medicine, St Thomas' Hospital, King's College London, London, Received on: May 3, 2013; final version accepted on: April 1, 2014. United Kingdom (M.E.A., A.J.W., A.P., T.S., R.M.B.); Academic Department of Surgery, Cardiovascular Division (P.S., J.J., B.M., S.P.G., A.S.P., A.S.), Wellcome Trust and EPSRC Medical Engineering Centre (T.S., R.M.B.), BHF Centre of Excellence, Cardiovascular Division (T.S., A.S., R.M.B.), and NIHR Biomedical Research Centre, GSTT (T.S., A.S., R.M.B.), School of Medicine, King's College London, London, United Kingdom; and Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.).
Marcelo E
ME
Andia
Division of Imaging Sciences and Biomedical Engineering, School of Medicine, St Thomas' Hospital, King's College London, London, Received on: May 3, 2013; final version accepted on: April 1, 2014. United Kingdom (M.E.A., A.J.W., A.P., T.S., R.M.B.); Academic Department of Surgery, Cardiovascular Division (P.S., J.J., B.M., S.P.G., A.S.P., A.S.), Wellcome Trust and EPSRC Medical Engineering Centre (T.S., R.M.B.), BHF Centre of Excellence, Cardiovascular Division (T.S., A.S., R.M.B.), and NIHR Biomedical Research Centre, GSTT (T.S., A.S., R.M.B.), School of Medicine, King's College London, London, United Kingdom; and Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.).
Prakash
P
Saha
Division of Imaging Sciences and Biomedical Engineering, School of Medicine, St Thomas' Hospital, King's College London, London, Received on: May 3, 2013; final version accepted on: April 1, 2014. United Kingdom (M.E.A., A.J.W., A.P., T.S., R.M.B.); Academic Department of Surgery, Cardiovascular Division (P.S., J.J., B.M., S.P.G., A.S.P., A.S.), Wellcome Trust and EPSRC Medical Engineering Centre (T.S., R.M.B.), BHF Centre of Excellence, Cardiovascular Division (T.S., A.S., R.M.B.), and NIHR Biomedical Research Centre, GSTT (T.S., A.S., R.M.B.), School of Medicine, King's College London, London, United Kingdom; and Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.).
Julia
J
Jenkins
Division of Imaging Sciences and Biomedical Engineering, School of Medicine, St Thomas' Hospital, King's College London, London, Received on: May 3, 2013; final version accepted on: April 1, 2014. United Kingdom (M.E.A., A.J.W., A.P., T.S., R.M.B.); Academic Department of Surgery, Cardiovascular Division (P.S., J.J., B.M., S.P.G., A.S.P., A.S.), Wellcome Trust and EPSRC Medical Engineering Centre (T.S., R.M.B.), BHF Centre of Excellence, Cardiovascular Division (T.S., A.S., R.M.B.), and NIHR Biomedical Research Centre, GSTT (T.S., A.S., R.M.B.), School of Medicine, King's College London, London, United Kingdom; and Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.).
Bijan
B
Modarai
Division of Imaging Sciences and Biomedical Engineering, School of Medicine, St Thomas' Hospital, King's College London, London, Received on: May 3, 2013; final version accepted on: April 1, 2014. United Kingdom (M.E.A., A.J.W., A.P., T.S., R.M.B.); Academic Department of Surgery, Cardiovascular Division (P.S., J.J., B.M., S.P.G., A.S.P., A.S.), Wellcome Trust and EPSRC Medical Engineering Centre (T.S., R.M.B.), BHF Centre of Excellence, Cardiovascular Division (T.S., A.S., R.M.B.), and NIHR Biomedical Research Centre, GSTT (T.S., A.S., R.M.B.), School of Medicine, King's College London, London, United Kingdom; and Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.).
Andrea J
AJ
Wiethoff
Division of Imaging Sciences and Biomedical Engineering, School of Medicine, St Thomas' Hospital, King's College London, London, Received on: May 3, 2013; final version accepted on: April 1, 2014. United Kingdom (M.E.A., A.J.W., A.P., T.S., R.M.B.); Academic Department of Surgery, Cardiovascular Division (P.S., J.J., B.M., S.P.G., A.S.P., A.S.), Wellcome Trust and EPSRC Medical Engineering Centre (T.S., R.M.B.), BHF Centre of Excellence, Cardiovascular Division (T.S., A.S., R.M.B.), and NIHR Biomedical Research Centre, GSTT (T.S., A.S., R.M.B.), School of Medicine, King's College London, London, United Kingdom; and Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.).
Alkystis
A
Phinikaridou
Division of Imaging Sciences and Biomedical Engineering, School of Medicine, St Thomas' Hospital, King's College London, London, Received on: May 3, 2013; final version accepted on: April 1, 2014. United Kingdom (M.E.A., A.J.W., A.P., T.S., R.M.B.); Academic Department of Surgery, Cardiovascular Division (P.S., J.J., B.M., S.P.G., A.S.P., A.S.), Wellcome Trust and EPSRC Medical Engineering Centre (T.S., R.M.B.), BHF Centre of Excellence, Cardiovascular Division (T.S., A.S., R.M.B.), and NIHR Biomedical Research Centre, GSTT (T.S., A.S., R.M.B.), School of Medicine, King's College London, London, United Kingdom; and Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.).
Steven P
SP
Grover
Division of Imaging Sciences and Biomedical Engineering, School of Medicine, St Thomas' Hospital, King's College London, London, Received on: May 3, 2013; final version accepted on: April 1, 2014. United Kingdom (M.E.A., A.J.W., A.P., T.S., R.M.B.); Academic Department of Surgery, Cardiovascular Division (P.S., J.J., B.M., S.P.G., A.S.P., A.S.), Wellcome Trust and EPSRC Medical Engineering Centre (T.S., R.M.B.), BHF Centre of Excellence, Cardiovascular Division (T.S., A.S., R.M.B.), and NIHR Biomedical Research Centre, GSTT (T.S., A.S., R.M.B.), School of Medicine, King's College London, London, United Kingdom; and Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.).
Ashish S
AS
Patel
Division of Imaging Sciences and Biomedical Engineering, School of Medicine, St Thomas' Hospital, King's College London, London, Received on: May 3, 2013; final version accepted on: April 1, 2014. United Kingdom (M.E.A., A.J.W., A.P., T.S., R.M.B.); Academic Department of Surgery, Cardiovascular Division (P.S., J.J., B.M., S.P.G., A.S.P., A.S.), Wellcome Trust and EPSRC Medical Engineering Centre (T.S., R.M.B.), BHF Centre of Excellence, Cardiovascular Division (T.S., A.S., R.M.B.), and NIHR Biomedical Research Centre, GSTT (T.S., A.S., R.M.B.), School of Medicine, King's College London, London, United Kingdom; and Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.).
Tobias
T
Schaeffter
Division of Imaging Sciences and Biomedical Engineering, School of Medicine, St Thomas' Hospital, King's College London, London, Received on: May 3, 2013; final version accepted on: April 1, 2014. United Kingdom (M.E.A., A.J.W., A.P., T.S., R.M.B.); Academic Department of Surgery, Cardiovascular Division (P.S., J.J., B.M., S.P.G., A.S.P., A.S.), Wellcome Trust and EPSRC Medical Engineering Centre (T.S., R.M.B.), BHF Centre of Excellence, Cardiovascular Division (T.S., A.S., R.M.B.), and NIHR Biomedical Research Centre, GSTT (T.S., A.S., R.M.B.), School of Medicine, King's College London, London, United Kingdom; and Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.).
Alberto
A
Smith
Division of Imaging Sciences and Biomedical Engineering, School of Medicine, St Thomas' Hospital, King's College London, London, Received on: May 3, 2013; final version accepted on: April 1, 2014. United Kingdom (M.E.A., A.J.W., A.P., T.S., R.M.B.); Academic Department of Surgery, Cardiovascular Division (P.S., J.J., B.M., S.P.G., A.S.P., A.S.), Wellcome Trust and EPSRC Medical Engineering Centre (T.S., R.M.B.), BHF Centre of Excellence, Cardiovascular Division (T.S., A.S., R.M.B.), and NIHR Biomedical Research Centre, GSTT (T.S., A.S., R.M.B.), School of Medicine, King's College London, London, United Kingdom; and Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.).
Rene M
RM
Botnar
D000818:Animals; D005337:Fibrin / Q000032:analysis*; D005682:Gadolinium; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides; D015912:Thrombolytic Therapy; D020246:Venous Thrombosis / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism
C503783:EP-2104R; D010455:Peptides; D005337:Fibrin; D005682:Gadolinium
fibrin; magnetic resonance imaging; molecular imaging; thrombolytic therapy; venous thrombosis