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DOI: 10.1148/radiol.2423052101
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(Radiology 2007;242:873-881.)
© RSNA, 2007

Technical Developments

Lower Extremity Deep Venous Thrombosis: Evaluation with Ferumoxytol-enhanced MR Imaging and Dual-Contrast Mechanism—Preliminary Experience1

Wei Li, MD, John Salanitri, MD, Sean Tutton, MD, Eugene E. Dunkle, RT, Joseph R. Schneider, MD, PhD, Joseph A. Caprini, MD, Linda N. Pierchala, BSN, Paula M. Jacobs, PhD and Robert R. Edelman, MD

1 From the Department of Radiology, Center for Advanced Imaging (W.L., J.S., S.T., E.E.D., L.N.P., R.R.E.), and Department of Surgery, Division of Vascular Surgery (J.R.S., J.A.C.), Evanston Northwestern Healthcare, Walgreen Building, Suite G507, 2650 Ridge Ave, Evanston, IL 60201; Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, Ill (W.L., J.S., S.T., J.R.S., J.A.C., R.R.E.); and Advanced Magnetics, Cambridge, Mass (P.M.J.). From the 2005 RSNA Annual Meeting. Received December 22, 2005; revision requested February 21, 2006; revision received April 10; accepted May 17; final version accepted, July 12. Address correspondence to W.L. (e-mail: lwei{at}enh.org).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Institutional review board approval and informed consent were obtained for this HIPAA-compliant study, whose purpose was to prospectively evaluate the use of a dual-contrast mechanism in conjunction with an iron oxide blood pool contrast agent, ferumoxytol, to depict deep venous thrombosis (DVT). Nine patients with lower extremity DVT detected with duplex ultrasonography (US) were imaged with magnetic resonance (MR) imaging and ferumoxytol. Three techniques, including precontrast two-dimensional time-of-flight (TOF) imaging, ferumoxytol-enhanced bright-blood imaging, and ferumoxytol-enhanced dark-blood imaging, were applied. Image quality for precontrast and ferumoxytol-enhanced images was analyzed by using a four-point scale. Thrombus was depicted as a filling defect within the blood pool on bright-blood images and as bright tissue that appeared highly contrasted against a dark background on dark-blood images. Image quality of ferumoxytol-enhanced images was uniformly superior to that of precontrast TOF images (P = .007). Compared with precontrast TOF images, ferumoxytol-enhanced bright-blood images had higher contrast-to-noise ratios (CNRs) between thrombus and blood (P = .051), whereas ferumoxytol-enhanced dark-blood images showed significantly higher CNRs between thrombus and surrounding muscle (P = .008). Ferumoxytol-enhanced MR imaging can depict DVT with a dual-contrast mechanism and show the extent of thrombus.

© RSNA, 2007


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Deep venous thrombosis (DVT) of the lower extremities is a frequent cause of pulmonary embolism, which can be a life-threatening condition (1,2). Because clinical signs and symptoms of DVT, such as pain, erythema, and swelling, are often nonspecific, further objective diagnostic testing is required. Although conventional venography has been the reference standard for evaluation of patients with suspected DVT, duplex ultrasonography (US) has become the initial diagnostic test of choice because of its accuracy, noninvasiveness, low cost, and ease of use (2–4). However, duplex US has limited accuracy for DVT involving the pelvis and calf (2,5,6).

Magnetic resonance (MR) imaging has been investigated for diagnosis of DVT. Several authors have reported that MR imaging has superior accuracy compared with other imaging modalities (3,5,7,8). Most studies were performed by using two-dimensional (2D) time-of-flight, phase-contrast, or gadolinium-enhanced MR angiography (5,9). However, time-of-flight and phase-contrast techniques are time consuming and are adversely affected by the slow, phasic flow that is typical for the peripheral venous system. Gadolinium-enhanced MR venography suffers from a relatively short time window for optimal venous enhancement, and soft-tissue enhancement occurs with delayed imaging (7,10). Compared with extracellular agents, blood pool contrast agents are advantageous for venous imaging in that they have a substantially longer intravascular half-life and produce much less soft-tissue enhancement (11–14).

One class of blood agents consists of iron oxide particles, which shorten T1, T2, and T2* (9,15). Previous studies using iron oxide blood pool agents for DVT detection have generally focused on the T1 effect (11–13). Ferumoxytol (Advanced Magnetics, Cambridge, Mass) is a semisynthetic carbohydrate-coated ultrasmall superparamagnetic iron oxide that is currently in phase II clinical trials (16–22). The mean crystal diameter of the iron oxide core of these particles is 6.76 nm ± 0.41 (standard deviation), and the particles have a mean size in solution of 30.0 nm ± 2. Ferumoxytol has a very long intravascular half-life (approximately 14 hours). At 20 MHz and 39°C, the T1 relaxivity (r1) and T2 relaxivity (r2) are 38 and 83 L · mmol–1 · sec–1, respectively. The highest dose for imaging is 4 mg (71.6 µmol) iron per kilogram of body weight, and the highest injection rate is 1 mL (537.2 µmol Fe) per second (18,21). To our knowledge, the use of a dual-contrast mechanism with iron oxide blood pool agents, in which both the T1 and T2 relaxation mechanisms are applied for DVT detection, has not been reported. Thus, the purpose of this study was to prospectively evaluate the use of a dual-contrast mechanism in conjunction with an iron oxide blood pool contrast agent, ferumoxytol, to depict DVT with MR imaging.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
The contrast agent used for this study, ferumoxytol, was provided by Advanced Magnetics. One author (P.M.J.) is an employee and one (R.R.E.) is a former consultant for Advanced Magnetics. The other authors had sole control over inclusion and evaluation of any study data or other information that might pose any conflict of interest. Institutional review board approval and informed consent were obtained for this Health Insurance Portability and Accountability Act–compliant study.

Patients
Nine patients (eight men and one women; age range, 42–86 years; mean age, 60.2 years) in whom DVT was detected with duplex US between September 2004 and August 2005 were evaluated with MR imaging with ferumoxytol. The MR imaging examinations were performed 1–19 days (average, 5.6 days) after the duplex US examinations. Three patients underwent bilateral duplex US, and six patients underwent unilateral (right, n = 2; left, n = 4) duplex US. A total of 10 thrombi were reported at 12 duplex US examinations in the nine patients.

Imaging
Duplex US evaluation of the lower extremities was performed in a dedicated vascular lab with a US imaging system (Sonoline Antares; Siemens Medical Solutions, Issaquah, Wash) and a VF7-3 transducer. The frequencies of the transducer ranged between 3 and 7 MHz. Examinations included gray-scale, color, and spectral Doppler evaluation of the common femoral, femoral, popliteal, saphenous, and calf veins in the longitudinal and transverse planes. Vessels were assessed for compressibility and intraluminal filling defects. Spectral evaluation of flow included augmentation with distal compression and observation for respiratory variation. A thrombus was considered acute when symptoms began fewer than 5 days prior to detection, subacute when symptoms began between 5 and 14 days prior to detection, and chronic when symptoms began greater than 14 days prior to detection. At duplex US, with time, a thrombus retracts and becomes more echogenic. Findings suggestive of acute thrombus included decreased echogenicity, near-complete luminal occlusion, and dilatation of the vein. Findings suggestive of chronic thrombus included a normal-sized or narrowed vein with thickened echogenic walls.

MR examinations were performed with a 1.5-T MR imaging unit (Signa 10.0 TwinSpeed, equipped with EXCITE technology; GE Healthcare, Waukesha, Wis) with a peak gradient strength of 40 mT/m, a maximum slew rate of 150 T/m/sec, and an eight-channel torso phased array coil. Depending on the location and extent of DVT detected with duplex US, one to three stations (Table 1) were imaged with MR for each patient. The following three imaging techniques (Table 2) were used: (a) precontrast transverse 2D time-of-flight venography (n = 9); (b) bright-blood imaging, including first-pass ferumoxytol-enhanced 3D TRICKS (n = 7) and equilibrium phase 3D spoiled gradient-echo angiography (n = 9); and (c) dark-blood imaging with a ferumoxytol-enhanced 2D T2-weighted fast spin-echo sequence performed with and without fat suppression (n = 9).


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  		Table 1. MR Imaging Locations and Techniques Used for Each Patient

 

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  		Table 2. Typical Parameters of Pulse Sequences Used for DVT Detection

 
The first-pass ferumoxytol TRICKS acquisition was performed to obtain selective venograms by using a subtraction technique in which an arterial phase was subtracted from the equilibrium phase. Bright-blood equilibrium phase and dark-blood images were acquired with spatial resolution of up to 512 x 512 of matrix over extended periods (eg, several minutes), which is feasible because of the long intravascular half-life of the contrast agent. For bright-blood equilibrium phase imaging, three coronal acquisitions were performed with different acquisition matrices (256 x 256, 384 x 512, and 512 x 512), a transverse acquisition was performed with a matrix of 256 x 256, and one or two signals were acquired. For dark-blood imaging, coronal and transverse images with and without fat suppression were acquired. In one patient, precontrast T2 fast spin-echo coronal images with and without fat suppression were also obtained. All patients completed their MR imaging examinations without complications.

Contrast Agent Administration
The contrast agent was diluted fourfold (ie, from 537.2 µmol Fe/mL to 134.3 µmol Fe/mL) to minimize T2* effects during the first pass. The diluted full dose of ferumoxytol (4 mg, 71.6 µmol Fe/kg) was administered with a power injector (Medrad Spectris; Medrad, Indianola, Pa) at a rate of 2 mL/sec, followed by 15 mL saline at the same injection rate (22).

Image Analysis
The 2D time-of-flight and bright-blood images were postprocessed with a maximum intensity projection (MIP) technique. Twelve or 18 MIP images were generated with 15° or 10° rotational angles between each projection, respectively. Multiplanar reformatting was performed as needed. An MIP technique was also applied for some dark-blood (T2-weighted fast spin-echo) images to better show the extent of DVT. Selective venography images were created by subtraction of arterial phase TRICKS images (in which only the arteries appeared bright) from equilibrium phase images (in which both arteries and veins appeared bright) and subsequent processing with MIP (22).

Each MR imaging study was interpreted by one of two radiologists (S.T. and J.S., both with 5 years of experience in vascular MR image interpretation). Qualitative analysis of image quality for precontrast and ferumoxytol-enhanced images was performed by using a four-point scale in which a score of 1 indicated that the study was nondiagnostic (the study would not be clinically useful; no diagnosis could be made with the images); a score of 2, that the study was fair (some useful information was provided; the study could be sufficient in some ways for making a diagnosis); a score of 3, that the study was good (clinically useful information was provided; the study was sufficient to make a diagnosis); and a score of 4, excellent (the study was definitely clinically useful; more than enough information was provided to enable a diagnosis).

For quantitative evaluation of the conspicuity of thrombi detected with the three techniques (precontrast time-of-flight imaging, ferumoxytol-enhanced bright-blood imaging, and ferumoxytol-enhanced dark-blood imaging), contrast-to-noise ratios (CNRs) of thrombus versus blood and thrombus versus nearby muscle were measured. For this purpose only, seven thrombi (four acute, one subacute, one chronic, and one not determined) that could be visualized with all three techniques in comparable locations were included for measurement. Regions of interest were placed in thrombi, nearby blood (either venous blood surrounding thrombi or the blood in nearby arteries if no nearby veins were seen), nearby muscle (vastus medialis in one, gastrocnemius in two, psoas major in one, and adductor magnus in three of the seven patients), and background (the area without anatomic structures). The average sizes of the regions of interest in thrombi, blood, muscle, and background were 30.2 mm2 (range, 5–168 mm2), 23.6 mm2 (range, 3–104 mm2), 151.6 mm2 (range, 37–397 mm2), and 332.5 mm2 (range, 81–489 mm2), respectively. The CNRs were calculated as signal intensity differences between the thrombus and blood (or between the thrombus and muscle), divided by the standard deviation of the background signal intensity. Absolute values were used for CNR expression.

The lengths of thrombi were measured on the basis of their appearance on ferumoxytol-enhanced images (source and MIP images). If a thrombus was not fully encompassed in the field of view, then only the visualized length was measured.

Statistical Analysis
Image quality scores of precontrast and ferumoxytol-enhanced images were compared by using the Wilcoxon signed rank test. CNRs for thrombus versus muscle and thrombus versus blood obtained with precontrast time-of-flight, ferumoxytol-enhanced bright-blood imaging, and ferumoxytol-enhanced dark-blood imaging techniques were compared with the paired t test. All statistical tests were two-tailed, with a .05 significance level.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Image Quality
Image quality scores for ferumoxytol-enhanced MR images were uniformly superior to those for precontrast 2D time-of-flight images (Table 3). The average image quality score for the former kind of images was 3.6, versus 1.4 for the latter kind of images (P = .007).


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  		Table 3. DVT Manifestations on MR Images before and after Ferumoxytol Administration

 
Thrombus Depiction
MR imaging showed agreement with duplex US in depicting nine of the 10 thrombi. A small muscular branch thrombus depicted by duplex US was not depicted with MR imaging because this vessel was accidentally excluded from the imaging volume (patient 2, left side). In two patients who underwent only unilateral duplex US, additional contralateral thrombi (in the right pelvis in patient 4 and in the left thigh in patient 9) were depicted with MR imaging. Thus, a total of 11 thrombi were depicted with MR imaging. The average thrombus length was 20.4 cm (range, 1.0–53.1 cm).

Thrombi on precontrast 2D time-of-flight images showed low signal intensity similar to that of muscle (Fig 1). The time-of-flight sequence depicted nine of 11 thrombi (vein occlusion, n = 6; filling defect, n = 3). However, substantial artifacts in seven of these patients undermined diagnostic confidence. Of the six subjects who had normal deep veins contralateral to the vein with the DVT, according to duplex US and ferumoxytol-enhanced MR imaging results, five had severe artifacts on time-of-flight images in the normal veins. Because of the artifacts, measurement of the extent of thrombi with time-of-flight images was problematic.


Figure 1A
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  		Figure 1a: MR venography in 58-year-old man with right-sided calf vein thrombosis. (a) Coronal MIP of ferumoxytol-enhanced coronal 3D MR venogram (equilibrium phase) with submillimeter in-plane spatial resolution (repetition time msec/echo time msec, 5.4/1.5; flip angle, 30°; matrix, 512 x 512) shows filling defect (arrow). (b) Transverse source image (3.8/1.1; flip angle, 30°) at level of thrombus shows filling defect (arrow) surrounded by blood with high signal intensity. (c) Transverse source image from precontrast 2D time-of-flight MR venography (25/5.6; flip angle, 60°). Note that the thrombus (arrow) is difficult to recognize. On (d), transverse ferumoxytol-enhanced T2-weighted fast spin-echo image (3000/48.8; flip angle, 90°) without fat suppression, the thrombus (arrow) is bright compared with dark blood. Thrombus (arrow) is more conspicuous on (e) transverse ferumoxytol-enhanced T2-weighted fast spin-echo image (3000/48.8; flip angle, 80°) with fat suppression than on d.

 

Figure 1B
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  		Figure 1b: MR venography in 58-year-old man with right-sided calf vein thrombosis. (a) Coronal MIP of ferumoxytol-enhanced coronal 3D MR venogram (equilibrium phase) with submillimeter in-plane spatial resolution (repetition time msec/echo time msec, 5.4/1.5; flip angle, 30°; matrix, 512 x 512) shows filling defect (arrow). (b) Transverse source image (3.8/1.1; flip angle, 30°) at level of thrombus shows filling defect (arrow) surrounded by blood with high signal intensity. (c) Transverse source image from precontrast 2D time-of-flight MR venography (25/5.6; flip angle, 60°). Note that the thrombus (arrow) is difficult to recognize. On (d), transverse ferumoxytol-enhanced T2-weighted fast spin-echo image (3000/48.8; flip angle, 90°) without fat suppression, the thrombus (arrow) is bright compared with dark blood. Thrombus (arrow) is more conspicuous on (e) transverse ferumoxytol-enhanced T2-weighted fast spin-echo image (3000/48.8; flip angle, 80°) with fat suppression than on d.

 

Figure 1C
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  		Figure 1c: MR venography in 58-year-old man with right-sided calf vein thrombosis. (a) Coronal MIP of ferumoxytol-enhanced coronal 3D MR venogram (equilibrium phase) with submillimeter in-plane spatial resolution (repetition time msec/echo time msec, 5.4/1.5; flip angle, 30°; matrix, 512 x 512) shows filling defect (arrow). (b) Transverse source image (3.8/1.1; flip angle, 30°) at level of thrombus shows filling defect (arrow) surrounded by blood with high signal intensity. (c) Transverse source image from precontrast 2D time-of-flight MR venography (25/5.6; flip angle, 60°). Note that the thrombus (arrow) is difficult to recognize. On (d), transverse ferumoxytol-enhanced T2-weighted fast spin-echo image (3000/48.8; flip angle, 90°) without fat suppression, the thrombus (arrow) is bright compared with dark blood. Thrombus (arrow) is more conspicuous on (e) transverse ferumoxytol-enhanced T2-weighted fast spin-echo image (3000/48.8; flip angle, 80°) with fat suppression than on d.

 

Figure 1D
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  		Figure 1d: MR venography in 58-year-old man with right-sided calf vein thrombosis. (a) Coronal MIP of ferumoxytol-enhanced coronal 3D MR venogram (equilibrium phase) with submillimeter in-plane spatial resolution (repetition time msec/echo time msec, 5.4/1.5; flip angle, 30°; matrix, 512 x 512) shows filling defect (arrow). (b) Transverse source image (3.8/1.1; flip angle, 30°) at level of thrombus shows filling defect (arrow) surrounded by blood with high signal intensity. (c) Transverse source image from precontrast 2D time-of-flight MR venography (25/5.6; flip angle, 60°). Note that the thrombus (arrow) is difficult to recognize. On (d), transverse ferumoxytol-enhanced T2-weighted fast spin-echo image (3000/48.8; flip angle, 90°) without fat suppression, the thrombus (arrow) is bright compared with dark blood. Thrombus (arrow) is more conspicuous on (e) transverse ferumoxytol-enhanced T2-weighted fast spin-echo image (3000/48.8; flip angle, 80°) with fat suppression than on d.

 

Figure 1E
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  		Figure 1e: MR venography in 58-year-old man with right-sided calf vein thrombosis. (a) Coronal MIP of ferumoxytol-enhanced coronal 3D MR venogram (equilibrium phase) with submillimeter in-plane spatial resolution (repetition time msec/echo time msec, 5.4/1.5; flip angle, 30°; matrix, 512 x 512) shows filling defect (arrow). (b) Transverse source image (3.8/1.1; flip angle, 30°) at level of thrombus shows filling defect (arrow) surrounded by blood with high signal intensity. (c) Transverse source image from precontrast 2D time-of-flight MR venography (25/5.6; flip angle, 60°). Note that the thrombus (arrow) is difficult to recognize. On (d), transverse ferumoxytol-enhanced T2-weighted fast spin-echo image (3000/48.8; flip angle, 90°) without fat suppression, the thrombus (arrow) is bright compared with dark blood. Thrombus (arrow) is more conspicuous on (e) transverse ferumoxytol-enhanced T2-weighted fast spin-echo image (3000/48.8; flip angle, 80°) with fat suppression than on d.

 
Equilibrium phase bright-blood imaging after ferumoxytol administration enabled detailed evaluation of the peripheral venous system without artifacts. Thrombi had low signal intensity similar to that of muscle but were highly contrasted with the bright blood pool. Thrombi manifested as abrupt vessel cutoffs (n = 6) or as filling defects partly surrounded by bright blood (n = 3) (Fig 1a, 1b). The source images, as well as the reformatted images, were helpful in showing thrombus extent. In seven patients who underwent ferumoxytol-enhanced first-pass TRICKS MR angiography, the arterial phase images showed the anatomy of the arterial system. Separation of arteries and veins was feasible with subtraction of TRICKS arterial phase images from equilibrium phase images; this process revealed thrombi in the veins without overlap from arteries (Fig 2).


Figure 2A
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  		Figure 2a: Coronal ferumoxytol-enhanced TRICKS MR venograms (3.5/1.0; flip angle, 30°) in 60-year-old man with DVT in right leg. (a) First-pass arterial phase collapsed image. (b) Equilibrium phase collapsed image. Note that arterial and venous structures are overlapped. (c) Selective venogram obtained by subtracting a from b. Arteries (arrows) appear dark, whereas veins appear bright. (d) MIP of subtracted images. Note apparent absence of right femoral and popliteal veins owing to thrombosis.

 

Figure 2B
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  		Figure 2b: Coronal ferumoxytol-enhanced TRICKS MR venograms (3.5/1.0; flip angle, 30°) in 60-year-old man with DVT in right leg. (a) First-pass arterial phase collapsed image. (b) Equilibrium phase collapsed image. Note that arterial and venous structures are overlapped. (c) Selective venogram obtained by subtracting a from b. Arteries (arrows) appear dark, whereas veins appear bright. (d) MIP of subtracted images. Note apparent absence of right femoral and popliteal veins owing to thrombosis.

 

Figure 2C
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  		Figure 2c: Coronal ferumoxytol-enhanced TRICKS MR venograms (3.5/1.0; flip angle, 30°) in 60-year-old man with DVT in right leg. (a) First-pass arterial phase collapsed image. (b) Equilibrium phase collapsed image. Note that arterial and venous structures are overlapped. (c) Selective venogram obtained by subtracting a from b. Arteries (arrows) appear dark, whereas veins appear bright. (d) MIP of subtracted images. Note apparent absence of right femoral and popliteal veins owing to thrombosis.

 

Figure 2D
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  		Figure 2d: Coronal ferumoxytol-enhanced TRICKS MR venograms (3.5/1.0; flip angle, 30°) in 60-year-old man with DVT in right leg. (a) First-pass arterial phase collapsed image. (b) Equilibrium phase collapsed image. Note that arterial and venous structures are overlapped. (c) Selective venogram obtained by subtracting a from b. Arteries (arrows) appear dark, whereas veins appear bright. (d) MIP of subtracted images. Note apparent absence of right femoral and popliteal veins owing to thrombosis.

 
Dark-blood fast spin-echo imaging after ferumoxytol administration showed uniform suppression of blood pool signal intensity without artifacts. Thrombi appeared bright and were highly contrasted with the low signal intensity of the blood pool and background tissue, particularly on images acquired with fat suppression (Fig 1d, 1e). In one patient, the thrombus was not encompassed within the imaging volume, as already noted above. The other 10 thrombi, including small calf vein thrombi with diameters of a few millimeters, were visualized. The full extent of a thrombus could be shown on MIP views of the fast spin-echo image stack (Fig 3). Vein expansion caused by thrombi was observed in two cases (patients 3 and 9). Two thrombi not detected with bright-blood imaging were seen on dark-blood images (Fig 4). In addition, as expected, fat-suppressed fast spin-echo images were sensitive for inflammatory changes in the soft tissues.


Figure 3A
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  		Figure 3a: Fast spin-echo T2-weighted coronal MR images in same patient as in Figure 2 show thrombi as bright. (a) Precontrast image (3000/50.2; flip angle, 90°) shows thrombus on right side (arrows), but contrast with blood in nearby artery and fat is poor. Small thrombus on left side (arrow) is overlapped with fat. (b) Ferumoxytol-enhanced equilibrium image (3000/48.8; flip angle, 90°) shows greatly decreased blood signal in the artery (dark blood). Thrombus-to-blood contrast is much higher (arrows) on this image than on a. Note thrombus (arrow) on left side. (c) Ferumoxytol-enhanced image with fat suppression (3000/47.2; flip angle, 90°). Note that the thrombus on right side (arrows) is highly contrasted with arterial blood, as well as background tissue. Thrombus on left side (arrow) can be better seen than in b owing to the decreased signal from fat. (d) MIP of c. Note that the entire extent of thrombi (arrows) is seen bilaterally; associated soft-tissue inflammation is also seen.

 

Figure 3B
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  		Figure 3b: Fast spin-echo T2-weighted coronal MR images in same patient as in Figure 2 show thrombi as bright. (a) Precontrast image (3000/50.2; flip angle, 90°) shows thrombus on right side (arrows), but contrast with blood in nearby artery and fat is poor. Small thrombus on left side (arrow) is overlapped with fat. (b) Ferumoxytol-enhanced equilibrium image (3000/48.8; flip angle, 90°) shows greatly decreased blood signal in the artery (dark blood). Thrombus-to-blood contrast is much higher (arrows) on this image than on a. Note thrombus (arrow) on left side. (c) Ferumoxytol-enhanced image with fat suppression (3000/47.2; flip angle, 90°). Note that the thrombus on right side (arrows) is highly contrasted with arterial blood, as well as background tissue. Thrombus on left side (arrow) can be better seen than in b owing to the decreased signal from fat. (d) MIP of c. Note that the entire extent of thrombi (arrows) is seen bilaterally; associated soft-tissue inflammation is also seen.

 

Figure 3C
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  		Figure 3c: Fast spin-echo T2-weighted coronal MR images in same patient as in Figure 2 show thrombi as bright. (a) Precontrast image (3000/50.2; flip angle, 90°) shows thrombus on right side (arrows), but contrast with blood in nearby artery and fat is poor. Small thrombus on left side (arrow) is overlapped with fat. (b) Ferumoxytol-enhanced equilibrium image (3000/48.8; flip angle, 90°) shows greatly decreased blood signal in the artery (dark blood). Thrombus-to-blood contrast is much higher (arrows) on this image than on a. Note thrombus (arrow) on left side. (c) Ferumoxytol-enhanced image with fat suppression (3000/47.2; flip angle, 90°). Note that the thrombus on right side (arrows) is highly contrasted with arterial blood, as well as background tissue. Thrombus on left side (arrow) can be better seen than in b owing to the decreased signal from fat. (d) MIP of c. Note that the entire extent of thrombi (arrows) is seen bilaterally; associated soft-tissue inflammation is also seen.

 

Figure 3D
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  		Figure 3d: Fast spin-echo T2-weighted coronal MR images in same patient as in Figure 2 show thrombi as bright. (a) Precontrast image (3000/50.2; flip angle, 90°) shows thrombus on right side (arrows), but contrast with blood in nearby artery and fat is poor. Small thrombus on left side (arrow) is overlapped with fat. (b) Ferumoxytol-enhanced equilibrium image (3000/48.8; flip angle, 90°) shows greatly decreased blood signal in the artery (dark blood). Thrombus-to-blood contrast is much higher (arrows) on this image than on a. Note thrombus (arrow) on left side. (c) Ferumoxytol-enhanced image with fat suppression (3000/47.2; flip angle, 90°). Note that the thrombus on right side (arrows) is highly contrasted with arterial blood, as well as background tissue. Thrombus on left side (arrow) can be better seen than in b owing to the decreased signal from fat. (d) MIP of c. Note that the entire extent of thrombi (arrows) is seen bilaterally; associated soft-tissue inflammation is also seen.

 

Figure 4A
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  		Figure 4a: Fast spin-echo T2 weighted images with fat suppression (3000/48.8; flip angle, 90°) in 63-year-old man with thrombosis of left popliteal vein. (a) Coronal image shows small bright area (length, 10 mm) representing a small thrombus (arrow) that is well contrasted with background tissue in the left popliteal fossa. (b) Reconstructed transverse image and (c) sagittal image confirm that the bright area (arrow) is within the popliteal vein.

 

Figure 4B
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  		Figure 4b: Fast spin-echo T2 weighted images with fat suppression (3000/48.8; flip angle, 90°) in 63-year-old man with thrombosis of left popliteal vein. (a) Coronal image shows small bright area (length, 10 mm) representing a small thrombus (arrow) that is well contrasted with background tissue in the left popliteal fossa. (b) Reconstructed transverse image and (c) sagittal image confirm that the bright area (arrow) is within the popliteal vein.

 

Figure 4C
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  		Figure 4c: Fast spin-echo T2 weighted images with fat suppression (3000/48.8; flip angle, 90°) in 63-year-old man with thrombosis of left popliteal vein. (a) Coronal image shows small bright area (length, 10 mm) representing a small thrombus (arrow) that is well contrasted with background tissue in the left popliteal fossa. (b) Reconstructed transverse image and (c) sagittal image confirm that the bright area (arrow) is within the popliteal vein.

 
CNRs
The CNRs of thrombus versus blood and thrombus versus muscle were measured (Table 4) for seven thrombi. Compared with time-of-flight images, ferumoxytol-enhanced bright-blood images showed higher CNRs for thrombus versus blood. This finding, however, was not significant (P = .051), whereas ferumoxytol-enhanced dark-blood images showed significantly higher CNRs for thrombus versus muscle (P = .008).


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  		Table 4. CNRs for Seven Thrombi with Different Imaging Techniques

 
Thrombus Age
Among the seven thrombi in which CNRs for thrombus versus muscle and thrombus versus blood were measured, four acute thrombi showed higher CNRs for thrombus versus muscle (18.3, 26.5, 26.5, and 30.7) compared with the subacute thrombus and the chronic thrombus (7.4, 18.2, respectively). The age of another thrombus was not determined with duplex US.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
Our study results demonstrate the feasibility of using a dual-contrast mechanism in conjunction with ferumoxytol, an iron oxide blood pool contrast agent, for evaluation of DVT with MR imaging. Thrombus was shown by bright-blood imaging (which uses a 3D gradient-echo pulse sequence, as is standard for MR angiography) and dark-blood imaging (which uses a fast spin-echo pulse sequence). Each approach has benefits. Bright-blood imaging is best for showing the overall anatomy of the venous system and for demonstrating venous occlusion. Dark-blood imaging is best for showing the extent of a thrombus and for detecting thrombi that are incompletely or not surrounded by blood (eg, small calf thrombi). Although fast spin-echo imaging without contrast enhancement will tend to suppress the signal intensity from flowing blood, a considerable amount of intravascular signal intensity will tend to persist due to the very slow flow, or absence of flow, in the peripheral veins. On the other hand, the signal intensity from all vessels is eliminated on ferumoxytol-enhanced T2-weighted images, irrespective of flow patterns, owing to the T2-shortening effect of the iron oxide contrast agent.

Note that acute thrombus is not the only structure that will appear bright on a fat-suppressed fast spin-echo MR image. Soft-tissue inflammation, as well as lymph nodes, will also show increased signal intensity; however, it is unlikely that these tissues would be confused with thrombi, particularly when dark-blood images are interpreted in conjunction with the bright-blood images that show detailed venous anatomy.

Standard 2D time-of-flight imaging has the benefit of not requiring the administration of a contrast agent, and reasonable accuracy for DVT has been reported by previous investigators. However, the method is intrinsically sensitive to flow patterns. Flow in the lower extremity veins is slow or absent depending on muscular contraction and other factors. In our study, the time-of-flight image quality was generally poor, and prevalent artifacts undermined diagnostic confidence. Moreover, the method did not depict small calf thrombi.

By virtue of the approximately 14-hour plasma half-life of ferumoxytol, high-spatial-resolution images (such as those acquired with a 512 x 512 matrix) with stable contrast enhancement can be acquired, even after a time delay of hours. One can use this feature of stable blood pool enhancement to greatly improve the signal-to-noise ratio by signal averaging over many minutes. Unlike gadolinium-enhanced venography, where the useful imaging window is only a few minutes, with this method, one can perform multiple pulse sequences and image at multiple stations with no loss of image quality or diagnostic accuracy. Gadolinium-based blood pool agents such as MS-325 also offer great promise for evaluation of the veins. However, unlike iron oxide contrast agents, gadolinium-based agents do not manifest a disproportionate reduction in the T2 relaxation time of the blood pool. Therefore, dark-blood imaging for direct imaging of thrombus might not be feasible with such contrast agents.

Our study design was limited in that it did not permit an evaluation of diagnostic accuracy. A different study design involving the use of conventional venography as a reference standard and much larger numbers of patients would be required. However, even in this preliminary study, ferumoxytol-enhanced MR imaging appears to more readily depict the full extent of thrombus than duplex US and, in some patients, better shows small calf vein thrombi. Moreover, with a minor degree of technique optimization, it should be possible to improve the spatial resolution of ferumoxytol-enhanced MR imaging.

In conclusion, ferumoxytol-enhanced MR imaging with a dual-contrast mechanism is able to depict DVT of the lower extremities and shows the extent of thrombus. Dark-blood imaging appears especially promising for detection of small calf vein thrombi. The long intravascular half-life of the contrast agent enables signal-averaged images to be acquired with large matrix sizes over multiple stations. On the basis of these preliminary results, we believe further evaluation in a larger patient cohort seems warranted to determine the relative accuracies of ferumoxytol-enhanced MR imaging and duplex US and to assess the potential clinical utility of this imaging approach.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   ACKNOWLEDGMENTS
 
The authors thank Carolyn Donaldson, MD, for her helpful contribution to the manuscript.


   FOOTNOTES
 

Abbreviations: CNR = contrast-to-noise ratio • DVT = deep venous thrombosis • MIP = maximum intensity projection • TRICKS = time-resolved imaging of contrast kinetics • 3D = three-dimensional • 2D = two-dimensional

See Materials and Methods for pertinent disclosures.

Author contributions: Guarantors of integrity of entire study, W.L., S.T., R.R.E.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, W.L., J.S., J.A.C., R.R.E.; clinical studies, J.S., S.T., R.R.E.; experimental studies, W.L., S.T., E.E.D., L.N.P.; statistical analysis, W.L.; and manuscript editing, W.L., J.S., S.T., E.E.D., J.A.C., L.N.P., P.M.J., R.R.E.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

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