The authors have no acknowledgements.

This study was approved by the local institutional review boards at all participating centers. All subjects in the multicenter trial provided written informed consent to participate in eTRIS at their respective institutions.
1. Image Acquisition
<ol>
	<li>Perform the MR imaging on a 1.5 T or 3 T whole body scanner using specialized phased-array coils for MRV such as a peripheral vascular coil, body matrix coils or run-off coils. Use these coils in conjunction with other body matrix coils or ...

<ol>
	<li>Goldhaber, S. Z. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Venous+thromboembolism:+epidemiology+and+magnitude+of+the+problem.">Venous thromboembolism: epidemiology and magnitude of the problem.</a> Best Pract Res Clin Haematol. 25, 235-242 (2012).</li><li>Huisman, M. V., Klok, F. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Diagnostic+management+of+acute+deep+vein+thrombosis+and+pulmonary+embolism.">Diagnostic management of acute deep vein thrombosis and pulmonary embolism.</a> J Thromb Haemost. 11, 412-422 (2013).</li><li>Ramzi, D. W., Leeper, K. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=DVT+and+pulmonary+embolism.">DVT and pulmonary embolism.</a> Part I. Diagnosis. Am Fam Physician. 69, 2829-2836 (2004).</li><li>Wilbur, J., Shian, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Diagnosis+of+deep+venous+thrombosis+and+pulmonary+embolism.">Diagnosis of deep venous thrombosis and pulmonary embolism.</a> Am Fam Physician. 86, 913-919 (2012).</li><li>Goodacre, S., Sampson, F., Thomas, S., van Beek, E., Sutton, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Systematic+review+and+meta-analysis+of+the+diagnostic+accuracy+of+ultrasonography+for+deep+vein+thrombosis.">Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis.</a> BMC Med Imaging. 5, 6 (2005).</li><li>Elias, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+single+complete+ultrasound+investigation+of+the+venous+network+for+the+diagnostic+management+of+patients+with+a+clinically+suspected+first+episode+of+deep+venous+thrombosis+of+the+lower+limbs.">A single complete ultrasound investigation of the venous network for the diagnostic management of patients with a clinically suspected first episode of deep venous thrombosis of the lower limbs.</a> Thromb Haemost. 89, 221-227 (2003).</li><li>Farahmand, S., Farnia, M., Shahriaran, S., Khashayar, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+accuracy+of+limited+B-mode+compression+technique+in+diagnosing+deep+venous+thrombosis+in+lower+extremities.">The accuracy of limited B-mode compression technique in diagnosing deep venous thrombosis in lower extremities.</a> Am J Emerg Med. 29, 687-690 (2011).</li><li>Sampson, F. C., Goodacre, S. W., Thomas, S. M., van Beek, E. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+accuracy+of+MRI+in+diagnosis+of+suspected+deep+vein+thrombosis:+systematic+review+and+meta-analysis.">The accuracy of MRI in diagnosis of suspected deep vein thrombosis: systematic review and meta-analysis.</a> Eur Radiol. 17, 175-181 (2007).</li><li>Moody, A. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Direct+imaging+of+deep-vein+thrombosis+with+magnetic+resonance+imaging.">Direct imaging of deep-vein thrombosis with magnetic resonance imaging.</a> Lancet. 350, 1073 (1997).</li><li>Phinikaridou, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=In+vivo+magnetization+transfer+and+diffusion-weighted+magnetic+resonance+imaging+detects+thrombus+composition+in+a+mouse+model+of+deep+vein+thrombosis.">In vivo magnetization transfer and diffusion-weighted magnetic resonance imaging detects thrombus composition in a mouse model of deep vein thrombosis.</a> Circ Cardiovasc Imaging. 6, 433-440 (2013).</li><li>Phinikaridou, A., Qiao, Y., Giordano, N., Hamilton, J. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Detection+of+thrombus+size+and+protein+content+by+ex+vivo+magnetization+transfer+and+diffusion+weighted+MRI.">Detection of thrombus size and protein content by ex vivo magnetization transfer and diffusion weighted MRI.</a> J Cardiovasc Magn Reson. 14, 45 (2012).</li><li>Carpenter, J. P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Magnetic+resonance+venography+for+the+detection+of+deep+venous+thrombosis:+comparison+with+contrast+venography+and+duplex+Doppler+ultrasonography.">Magnetic resonance venography for the detection of deep venous thrombosis: comparison with contrast venography and duplex Doppler ultrasonography.</a> J Vasc Surg. 18, 734-741 (1993).</li><li>Westerbeek, R. E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Magnetic+resonance+direct+thrombus+imaging+of+the+evolution+of+acute+deep+vein+thrombosis+of+the+leg.">Magnetic resonance direct thrombus imaging of the evolution of acute deep vein thrombosis of the leg.</a> J Thromb Haemost. 6, 1087-1092 (2008).</li><li>Koizumi, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Magnetic+resonance+venography+of+the+lower+limb.">Magnetic resonance venography of the lower limb.</a> Int Angiol. 26, 171-182 (2007).</li><li>Goyen, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Gadofosveset:+the+first+intravascular+contrast+agent+EU-approved+for+use+with+magnetic+resonance+angiography.">Gadofosveset: the first intravascular contrast agent EU-approved for use with magnetic resonance angiography.</a> Future Cardiol. 3, 19-26 (2007).</li><li>Aime, S., Caravan, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Biodistribution+of+gadolinium-based+contrast+agents,+including+gadolinium+deposition.">Biodistribution of gadolinium-based contrast agents, including gadolinium deposition.</a> J Magn Reson Imaging. 30, 1259-1267 (2009).</li><li>Shamsi, K., Yucel, E. K., Chamberlin, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+summary+of+safety+of+gadofosveset+(MS-325)+at+0.03+mmol/kg+body+weight+dose:+Phase+II+and+Phase+III+clinical+trials+data.">A summary of safety of gadofosveset (MS-325) at 0.03 mmol/kg body weight dose: Phase II and Phase III clinical trials data.</a> Invest Radiol. 41, 822-830 (2006).</li><li>Zhang, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Trisodium-[(2-(R)-[(4,4-diphenylcyclohexyl)phosphono-oxymethyl]-diethylenetriamin+epentaacetato)(aquo)gadolinium(III).">Trisodium-[(2-(R)-[(4,4-diphenylcyclohexyl)phosphono-oxymethyl]-diethylenetriamin epentaacetato)(aquo)gadolinium(III).</a> Gadofosveset. , (2004).</li><li>Pfeil, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Magnetic+resonance+VIBE+venography+using+the+blood+pool+contrast+agent+gadofosveset+trisodium--an+interrater+reliability+study.">Magnetic resonance VIBE venography using the blood pool contrast agent gadofosveset trisodium--an interrater reliability study.</a> Eur J Radiol. 81, 547-552 (2012).</li><li>Rosset, A., Spadola, L., Ratib, O. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=OsiriX:+an+open-source+software+for+navigating+in+multidimensional+DICOM+images.">OsiriX: an open-source software for navigating in multidimensional DICOM images.</a> J Digit Imaging. 17, 205-216 (2004).</li><li>Ouriel, K., Greenberg, R. K., Green, R. M., Massullo, J. M., Goines, D. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+volumetric+index+for+the+quantification+of+deep+venous+thrombosis.">A volumetric index for the quantification of deep venous thrombosis.</a> J Vasc Surg. 30, 1060-1066 (1999).</li><li>Elias, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+single+complete+ultrasound+investigation+of+the+venous+network+for+the+diagnostic+management+of+patients+with+a+clinically+suspected+first+episode+of+deep+venous+thrombosis+of+the+lower+limbs.">A single complete ultrasound investigation of the venous network for the diagnostic management of patients with a clinically suspected first episode of deep venous thrombosis of the lower limbs.</a> Thromb Haemost. 89, 221-227 (2003).</li><li>Farahmand, S., Farnia, M., Shahriaran, S., Khashayar, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+accuracy+of+limited+B-mode+compression+technique+in+diagnosing+deep+venous+thrombosis+in+lower+extremities.">The accuracy of limited B-mode compression technique in diagnosing deep venous thrombosis in lower extremities.</a> Am J Emerg Med. 29, 687-690 (2011).</li><li>Thomas, S. M., Goodacre, S. W., Sampson, F. C., van Beek, E. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Diagnostic+value+of+CT+for+deep+vein+thrombosis:+results+of+a+systematic+review+and+meta-analysis.">Diagnostic value of CT for deep vein thrombosis: results of a systematic review and meta-analysis.</a> Clin Radiol. 63, 299-304 (2008).</li><li>Heverhagen, J. T., Krombach, G. A., Gizewski, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Application+of+Extracellular+Gadolinium-based+MRI+Contrast+Agents+and+the+Risk+of+Nephrogenic+Systemic+Fibrosis.">Application of Extracellular Gadolinium-based MRI Contrast Agents and the Risk of Nephrogenic Systemic Fibrosis.</a> Rofo. , (2014).</li><li>Alhadad, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Safety+aspects+of+gadofosveset+in+clinical+practice+-+analysis+of+acute+and+long-term+complications.">Safety aspects of gadofosveset in clinical practice - analysis of acute and long-term complications.</a> Magn Reson Imaging. , (2014).</li></ol>

This study demonstrated the feasibility of quantification of deep vein thrombosis on MR venography using gadofosveset trisodium as a contrast agent, with excellent reproducibility of analysis for quantifying thrombus volume in a multicenter setting. To compute total thrombus volume, the primary method utilized the post-contrast MRV scan to measure thrombus volume. The secondary method used was the direct thrombus imaging approach (DTHI), which leverages the presence of met-hemoglobin within a fresh thrombus to produce a ...

Venous thromboembolism (VTE) affects 300,000-600,000 individuals in the United States every year1. Deep vein thrombosis (DVT) is the most common presentation of VTE, and most commonly affects the calf, thigh or pelvic veins. The diagnosis, management, and follow-up of subjects with DVT cannot be based solely on clinical examinations, since the signs and symptoms of this disease are non-specific2,3. While blood tests (such as D-dimer) can help rule out the diagnosis of DVT, imaging is required to establish the presence of DVT4. Compression ultrasound (CUS) is currently the most commonly used imaging test in the diagnosis of suspected acute DVT. CUS is inexpensive and has high sensitivity and specificity to detect acute DVT5. However, CUS cannot reliably assess the deep veins in the pelvis6. Additionally, CUS cannot directly quantify thrombus volume and composition, which are important when distinguishing between acute DVT (a potential source of pulmonary embolism (PE)) and chronic DVT (less likely to embolize) and for evaluation of therapeutic efficacy7.
Unlike computed tomography (CT), magnetic resonance imaging (MRI) does not deliver ionizing radiation, and is therefore suitable for serial examinations to evaluate thrombus evolution or regression. Compared with CUS, MRI can detect pelvic DVT and can more precisely define proximal (popliteal vein and above) and distal leg (below popliteal vein) DVT8, to better assess the risk of PE. MRI can characterize thrombus age and organization, and may help differentiate acute from chronic DVT9-11 (refs updated). Quantification of thrombus volume, an important metric to assess the disease evolution and response to treatment, is feasible with MR imaging. Current magnetic resonance venography protocols are performed after injection of gadolinium (Gd) based contrast agents12. These are small molecular weight molecules that extravasate quickly after injection, and require careful timing to capture the venous enhancement phase needed to correctly visualize the thrombus13,14.
A proof-of-concept study, edoxaban Thrombus Reduction Imaging Study (eTRIS), utilizing an open label design, investigated the efficacy and safety of edoxaban 90 mg once a day for 10 days, followed by edoxaban 60 mg once a day in the treatment of acute, symptomatic DVT (ClinicalTrials.gov Identifier: NCT01662908). eTRIS addresses whether edoxaban monotherapy, without concomitant low molecular weight heparin (LMW heparin) at the time of treatment initiation, is more effective than standard treatment with LMW heparin/warfarin therapy in subjects with DVT, as assessed by the percent (%) change from baseline in thrombus volume/size (measured by MRI) at Day 14-21.
Another goal of eTRIS was to develop and validate a straightforward MR venography (MRV) image acquisition and analysis protocol for the quantification of thrombus volume in DVT. To overcome some challenges faced by current MRV protocols in multicenter settings, we utilized a recently FDA-approved, long-circulating, gadolinium-based blood pool contrast agent (gadofosveset trisodium). Compared to the use of extracellular Gd-based chelates (e.g., Gd-DTPA) for MRV, gadofosveset has a significantly longer circulation time, which allows use of a simpler MR acquisition scheme, without any timing of acquisitions. Gadofosveset trisodium is a blood pool MRI contrast agent that circulates for 2-3 hr after intravenous injection15,16. Its safety profile is similar to those of traditional extravascular extracellular MRI contrast agents17. It allows steady-state imaging of the vasculature over a period of 1 hr. Therefore, no operator dependent timing of image acquisition is required after contrast agent injection. The additional advantage of using this contrast agent is that it is a small molecule (molecular weight 857 Da)18 and can permeate the sides of even a fully occluded thrombus, thereby providing excellent contrast of the DVT from surrounding areas on the MRV and enabling quantitative computation of DVT volumes. Previous studies have established the inter-rater reliability of visualizing veins using the MR Volume Interpolated Breath-hold Examination (VIBE) venography using gadofosveset trisodium19. Here, we use a similar approach in a multicenter clinical trial setting to evaluate deep vein thrombosis and use the volume of DVT measured by MRI as an endpoint. eTRIS provides an ideal platform to evaluate the feasibility and reproducibility of analysis of the MRV imaging approach proposed here, using a long-circulating Gd-based blood pool contrast agent for evaluating DVT volumes. We also evaluate the use of a direct thrombus imaging (DTHI) approach to quantify the extent of fresh DVT prior to the injection of contrast agents.
Two MRI examinations were performed during the course of the study: the first within 36 hr after randomization into the edoxaban monotherapy group or heparin/warfarin group, and the second between 14 to 21 days after randomization. The analyses of all the images were performed by a centralized core laboratory. Volume of fresh thrombus is calculated from a Direct Thrombus Imaging (DTHI) in the legs and lower pelvis before the injection of any contrast agent. The total thrombus volume (fresh and old) is computed from a post contrast magnetic resonance venography (MRV) images of the veins in the legs and lower pelvis.

<table border="0" cellpadding="0" cellspacing="0">
	<tbody>
		<tr>
			<td>Ablavar (gadofosveset trisodium)</td>
			<td>Lantheus</td>
			<td></td>
			<td>Contrast Agent</td>
		</tr>
		<tr>
			<td>1.5T or 3T Scanners</td>
			<td>GE, Siemens, or Phillips</td>
			<td></td>
			<td>GE(Horizon, Signa, Hdx, 750), Siemens (Symphony, Avanto, Sonata, Trio, Aera) or Philips (Intera, Achieva)</td>
		</tr>
	</tbody>
</table>

a multicenter mri protocol for the evaluation and quantification of deep vein thrombosis

We evaluated a magnetic resonance venography (MRV) approach with gadofosveset to quantify total thrombus volume changes as the principal criterion for treatment efficacy&#160;in a multicenter randomized study comparing edoxaban monotherapy with a heparin/warfarin regimen for acute, symptomatic lower extremities deep vein thrombosis (DVT) treatment. We also used a direct thrombus imaging approach (DTHI, without the use of a contrast agent) to quantify fresh thrombus. We then sought to evaluate the reproducibility of the analysis methodology and applicability of using 3D magnetic resonance venography and direct thrombus imaging for the quantification of DVT in a multicenter trial setting. From 10 randomly selected subjects participating in the edoxaban Thrombus Reduction Imaging Study (eTRIS), total thrombus volume in the entire lower extremity deep venous system was quantified bilaterally. Subjects were imaged using 3D-T1W gradient echo sequences before (direct thrombus imaging, DTHI) and 5 min after injection of 0.03 mmol/kg of gadofosveset trisodium (magnetic resonance venography, MRV). The margins of the DVT on corresponding axial, curved multi-planar reformatted images were manually delineated by two observers to obtain volumetric measurements of the venous thrombi. MRV was used to compute total DVT volume, whereas DTHI was used to compute volume of fresh thrombus. Intra-class correlation (ICC) and Bland Altman analysis were performed to compare inter and intra-observer variability of the analysis. The ICC for inter and intra-observer variability was excellent (0.99 and 0.98, p &#60;0.001, respectively) with no bias on Bland-Altman analysis for MRV images. For DTHI images, the results were slightly lower (ICC = 0.88 and 0.95 respectively, p &#60;0.001), with bias for inter-observer results on Bland-Altman plots. This study showed feasibility of thrombus volume estimation in DVT using MRV with gadofosveset trisodium, with good intra- and inter-observer reproducibility in a multicenter setting.

For the purpose of the reproducibility assessments, the baseline and follow up scans were pooled and analyzed as separate cases. From the 10 randomly selected subjects (2 visits each), there were 59 vessels with DVT identified using the MRV approach and 29 vessels with fresh thrombus identified by the DTHI. In the subset of these 10 randomly selected subjects analyzed for the reproducibility metrics, no vessels with DVT were deemed to be of un-analyzable quality (defined as subjective scoring 0-2 for both MRV and DTHI im...

Watch this Scientific Journal Video about A Multicenter MRI Protocol for the Evaluation and Quantification of Deep Vein Thrombosis at JoVE.com

A Multicenter MRI Protocol for the Evaluation and Quantification of Deep Vein Thrombosis

The goal of this study is to use magnetic resonance venography with long-circulating gadolinium-based contrast agent and direct thrombus imaging for quantitative evaluation of DVT volume in a multicenter, clinical trial setting. Inter- and intra-observer variability assessments were conducted, and reproducibility of the protocol was determined.

We evaluated a magnetic resonance venography (MRV) approach with gadofosveset to quantify total thrombus volume changes as the principal criterion for ...

a-multicenter-mri-protocol-for-evaluation-quantification-deep-vein

Research

JoVE Journal

Medicine

16.9K 조회수.  Icahn School of Medicine at Mount Sinai. The goal of this study is to use magnetic resonance venography with long-circulating gadolinium-based contrast agent and direct thrombus imaging for quantitative evaluation of DVT volume in a multicenter, clinical trial setting. Inter- and intra-observer variability assessments were conducted, and reproducibility of the protocol was determined.