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Magnetic Resonance Direct Thrombus Imaging

2003; Elsevier BV; Volume: 1; Issue: 7 Linguagem: Inglês

10.1046/j.1538-7836.2003.00333.x

1538-7933

Alan R. Moody,

Cardiac Imaging and Diagnostics

SummaryAs blood clots it goes through predictable stages that reflect the oxygenation state of hemoglobin within the red cells. One of these stages results in the formation of methemoglobin. This substance acts an endogenous contrast agent when imaged using a T1-weighted magnetic resonance sequence (Magnetic Resonance Direct Thrombus Imaging, MRDTI) – appearing as high signal. MRDTI can therefore be used to detect subacute thrombosis. This technique has been applied in a number of clinical settings arising as a result of thrombosis. Deep vein thrombosis and pulmonary embolism are both readily detected using MRDTI, providing a single imaging modality for the detection of venous thromboembolic disease. The technique is also effective in the peripheral arterial tree. Furthermore, thrombosis within vessel wall atherosclerosis is a marker of vulnerable plaque likely to produce symptoms. The MRDTI technique has thus proved useful in identifying complicated plaque in the carotid arteries in the setting of transient and permanent cerebral ischemia. MRDTI therefore holds promise as a technique that is capable of detecting high risk vessel wall disease prior to significant or permanent end organ damage. Because of the non-invasive nature of magnetic resonance imaging (MRI), application of MRDTI in the research setting for the monitoring of therapeutic interventions in a wide number of settings within vascular disease is very appealing. As blood clots it goes through predictable stages that reflect the oxygenation state of hemoglobin within the red cells. One of these stages results in the formation of methemoglobin. This substance acts an endogenous contrast agent when imaged using a T1-weighted magnetic resonance sequence (Magnetic Resonance Direct Thrombus Imaging, MRDTI) – appearing as high signal. MRDTI can therefore be used to detect subacute thrombosis. This technique has been applied in a number of clinical settings arising as a result of thrombosis. Deep vein thrombosis and pulmonary embolism are both readily detected using MRDTI, providing a single imaging modality for the detection of venous thromboembolic disease. The technique is also effective in the peripheral arterial tree. Furthermore, thrombosis within vessel wall atherosclerosis is a marker of vulnerable plaque likely to produce symptoms. The MRDTI technique has thus proved useful in identifying complicated plaque in the carotid arteries in the setting of transient and permanent cerebral ischemia. MRDTI therefore holds promise as a technique that is capable of detecting high risk vessel wall disease prior to significant or permanent end organ damage. Because of the non-invasive nature of magnetic resonance imaging (MRI), application of MRDTI in the research setting for the monitoring of therapeutic interventions in a wide number of settings within vascular disease is very appealing. Thrombosis, in its various forms, accounts for more deaths in the western world than any other disease. Major conditions in which thrombosis plays a principal role include myocardial infarction, stroke, peripheral vascular disease, deep vein thrombosis (DVT) and pulmonary embolism (PE). Medical management of these conditions relies on accurate diagnosis not only of the resultant tissue or organ damage but also of the causative vascular lesion. The development of cross-sectional imaging techniques (ultrasound, computed tomography, magnetic resonance imaging [MRI]) in recent years has resulted in huge advances in end organ imaging (brain and heart). Imaging of vascular disease, despite similar advances in sectional imaging techniques in the form of magnetic resonance and computed tomography angiography, have tended to mimic conventional angiographic techniques by visualizing flowing blood within the vessel lumen, rather than the causative obstructing lesion. Working on the premise that the acute primary event resulting in vascular obstruction is thrombosis, the ability to directly visualize vascular thromboses should provide a means of accurately assessing the culprit lesions, resulting in more accurate diagnosis and improved patient management, along with a better understanding of the disease process and providing an effective research tool. MRI is rapidly establishing itself as a first-line investigation in many clinical settings. Most recently MR angiography has made significant advances allowing accurate angiographic images comparable to conventional studies [1Prince M.R. Peripheral Vascular M.R. Angiography: the time has come.Radiol. 1998; 206: 592-3Crossref PubMed Scopus (34) Google Scholar]. The lack of ionizing radiation makes MRI an attractive technique in both the clinical and research setting. Multiplanar, 3-dimensional image acquisitions provide comprehensive imaging strategies. Above all the ability of MRI to exploit the differences in tissue make-up and display these as alterations in image contrast provides a unique opportunity to selectively discriminate between different tissues, both normal and pathological. It is this unique capability that is exploited in magnetic resonance direct thrombus imaging (MRDTI). It has long been known that as blood undergoes clotting it passes through a number of well defined stages reflecting the state of oxygenation of red blood cells trapped within the clot and these are reflected in alterations in their MRI contrast characteristics [2Bradley W.G. MR Appearance of Hemorrhage in the Brain.Radiology. 1993; 189: 15-26Crossref PubMed Scopus (636) Google Scholar]. When hemoglobin is removed from the normally high oxygen environment of the circulating blood it undergoes oxidative denaturation to the ferric (Fe3 +) form. In this form methemoglobin will cause shortening of T1, akin to MRI contrast agents, and will therefore result in high signal on a T1-weighted acquisition. This is due to the fact that methemoglobin is paramagnetic, containing 5 unpaired electrons. Potentially therefore this high signal generating derivative could be used as an endogenous contrast agent within clotting blood and therefore act a marker for thrombosis. For this to occur a number of important provisos must be met: •adequate methemoglobin must be generated to produce sufficient signal;•methemoglobin must be formed reliably within a thrombus;•methemoglobin must be formed sufficiently quickly to allow identification of acute thrombosis (hours);•methemoglobin must persist long enough to provide a suitable imaging window of opportunity (days). Potential pitfalls in the use of methemoglobin as a marker of thrombosis will occur if any of these are not fulfilled. For instance the difference in constituents between arterial (platelet rich) and venous (red blood cell rich) thrombi could produce different imaging characteristics. In order to detect methemoglobin the MRI sequence parameters used must not only be adjusted to provide a T1-weighted sequence but also remove or depress high signal arising from any other tissue that may obscure the thrombus signal. On a T1-weighted scan this high signal most commonly arises from tissue containing fat. To overcome this potentially obscuring and confusing effect the sequence must employ some form of fat suppression or saturation. While blood on a T1-weighted sequence is of low signal this can be artefactually increased as it flows into the imaging field. Dark blood can be generated by the application of inversion recovery prepulses to cause blood to generate zero signal. The remainder of the pulse sequence design can be selected on the basis of how quickly the data is to be acquired. Regions of the body that are stationary and undisturbed by physiological motion (i.e. breathing) can be acquired by longer sequences allowing high resolution 3-dimensional sequences. More rapid acquisition may require far shorter sequences acquired slice by slice in a 2-dimensional acquisition thus allowing acquisition in a breath-hold. Generation of methemoglobin in vitro has demonstrated that there is a linear relationship between the concentration of methemoglobin and T1 shortening [3Moody A, Morgan P, Fraser D, Hunt B. Methaemoglobin T1 High Signal. Its Generation and Application to MR Thrombus Imaging. In: International Angiology, Ghent; 2000: p. 7.Google Scholar]. Using a 3-dimensional fat suppressed, nulled blood sequence the first application of MRDTI for the detection of in vivo human deep vein thrombosis (DVT) [4Moody A.R. Direct imaging of deep-vein thrombosis with magnetic resonance imaging [letter].Lancet. 1997; 350: 1073Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar] confirmed that this technique had the potential to detect recent thrombosis in patients with known DVT. Various environments exist in which thrombus maturation may occur that potentially can give different imaging appearances. The formation of methemoglobin will obviously require sufficient hemoglobin, and therefore red blood cells, to allow detection. The theoretical difference in make-up between arterial and venous thrombus, one being platelet-rich, the other red blood cell-rich, could have significant effects. The ease with which hemoglobin can change from one state to another should also be considered. Formation of methemoglobin is an oxidative process. The availability of local oxygen in all parts of the thrombus could therefore lead to differential contrast generation. The relationship of the thrombus to the vessel wall is also important. Hemorrhage and thrombus formation within the vessel wall, either due to vessel dissection or complication of atheromatous plaque, will expose the thrombus to a completely different environment than if in the vessel lumen itself. One species that has particular affinity for hemoglobin, with the rapid formation of methemoglobin, and potentially found within the vessel wall, is nitric oxide. During the process of thrombus organization invasion of the thrombus by cellular constituents of blood (macrophages and white cells) may also alter image appearances. The exact effect of all of these components in vivo on MRI signal generated from thrombus has yet to be elucidated. Following the promising pilot study in patients with known DVT the utility of this technique in the setting of DVT was more rigorously tested against the gold standard of ascending contrast venography (ACV) [5Fraser D. Moody A. Martel A. Morgan P. Davidson I. Diagnosis of lower-limb deep venous thrombosis: a prospective blinded study of magnetic resonance direct thrombus imaging.Ann Intern Med. 2002; 136: 89-98Crossref PubMed Scopus (258) Google Scholar]. In 103 patients suspected of suffering DVT the overall sensitivity and specificity for MRDTI was 96% and 90%. Unlike other imaging techniques that struggle to maintain diagnostic accuracy throughout the lower limb venous system, MRDTI had no apparent blind spots, being just as sensitive and specific below the knee, above the knee or in the pelvis. The agreement between two readers for these areas was very good with kappa values varying between 0.89 and 0.98. Knowing that ACV is in fact a 'fuzzy' gold standard, incorporation of results from ultrasound in discordant cases was found to increase the sensitivity and specificity further (98% and 96%). Two of the major perceived drawbacks of using MRDTI as a first-line investigation of DVT are cost and availability. There is no doubt that with the current provision of MRI scanners in many countries this is problematic. However, as this situation improves a case can be made to include DVT diagnosis as part of the service provided by MRI. The technique appears to be accurate and is an 'end test' with few unresolved diagnoses. It can be combined with chest imaging for a comprehensive investigation of thromboembolic disease (TED) (see below). As there is no clinician input during acquisition making, availability of the test is only dependent upon scanner time. The images are easily interpreted and could be electronically transported and read from a central facility. The time required for scanning is short (15–20 min) allowing ease of inclusion during busy scanning schedules and maximizing scanner utilization. We are at present trialing (Trial of OutPatient MRDTI of DVT – TOP MD) an outpatient service using clinical scoring and d-dimer testing as screening tests prior to MRI which acts as the definitive end test. For those centers unable to provide this level of service a number of specific applications warrant consideration. Investigation of TED during or just after pregnancy can be difficult with standard techniques. The pelvis is often difficult to examine, but it is in this group that isolated pelvic thrombosis is likely to occur. Radiation and intravenous contrast agents are to be avoided wherever possible. In a small trial using MRDTI in pregnancy, all thromboses were detected that had been diagnosed by alternative diagnostic methods, but in addition the extent of thrombosis was found to be more extensive in five cases, and progression of disease was confidently diagnosed in three patients leading to alteration in management (Fig. 1). Despite repeated studies in a number of these patients the technique was well tolerated [6Fraser D, Moody A, Smith S. Magnetic Resonance Direct Thrombus Imaging of Venous Thrombosis Associated with Pregnancy. In: International Angiology, Ghent; 2000: p. 32.Google Scholar]. Because the contrast generation using MRDTI relies on the formation of methemoglobin, the time course of signal appearance/disappearance is similarly dependent. The accuracy of this technique for detecting DVT suggests that in the venous environment methemoglobin is formed sufficiently rapidly to be detected in the acute setting. The earliest reliable timing of formation in our experience is within 8 h [7Moody A.R. Pollock J.G. O'Connor A.R. Bagnall M. Lower-limb deep venous thrombosis: direct MR imaging of the thrombus.Radiology. 1998; 209: 349-55Crossref PubMed Scopus (116) Google Scholar]. Just as important as the rapidity of formation is the duration of contrast. Follow-up of patients with proven DVT has shown that maximum signal is achieved at approximately 3 weeks, after which time the signal intensity plateaus. In the lead up to this point the development of signal within the thrombus is also indicative of its maturity. The high signal is initially seen in the periphery of the thrombus giving a characteristic target sign [8Fraser D. Moody A. Morgan P. Martel A. Predictors of thrombus age using magnetic resonance direct thrombus imaging of DVT within the external iliac vein.Haematol J. 2000; 1: 133Google Scholar]. This may reflect the interaction of the thrombus with components derived from the vessel wall, as outlined above. As more methemoglobin is generated the high signal is seen to migrate centripetally until the whole thrombus is of high signal. In a vessel the size of the femoral or iliac vein this process takes up to 3 weeks to complete. After 3 weeks the signal will persist up to, but not beyond, 6 months. During this phase the appearances of the thrombus are also characteristic. As the thrombus becomes organized and there is further oxidative denaturation of methemoglobin to hemosiderin, signal is lost. This does not tend to be a uniform process throughout the length of the thrombus but rather occurs at intervals, with the resultant appearance of islands of high signal, which disappear over the ensuing weeks. Caution however, should be taken in equating disappearance of high signal with recanalization as many of the vessels were found to recanalize incompletely, if at all. The major advantage of being able to image the maturation of thrombus in this manner is that aging of thrombus is possible. Even if this is a crude estimation the ability to discriminate between thrombus which is recent (within the last few weeks) and old (over 6 months) allows the ruling in or ruling out of recurrent DVT, within this time frame, with its resultant management implications. Inability to investigate the veins with other imaging techniques can occur for various reasons. Ultrasound requires direct access to the limb so plaster casts or bandaging may obstruct scanning. Venography may fail due to lack of venous access or inability to visualize the deep veins. Blind spots exist for both techniques and include the gastrocnemius and profunda femoris veins for venography, and the internal iliac veins for venography and ultrasound. Neither technique routinely images the superficial venous system which can be the site of thrombosis accounting for the patient's symptoms. Imaging of both legs with either method doubles imaging time. Because the MRDTI technique visualizes thrombus directly, has a field of view sufficient to visualize the whole of the lower leg venous system from ankles to IVC (Fig. 2), includes the superficial and deep veins, and requires no direct access to the leg or leg veins, many of the problems seen with conventional techniques are overcome. High-risk groups that require screening for DVT or patient populations in clinical trials need diagnostic tests that are repeatable and can detect asymptomatic disease. Ultrasound has been shown to be unsuitable, leaving venography as the conventional test of choice [9Kearon C. Ginsberg J.S. Hirsh J. The role of venous ultrasonography in the diagnosis of suspected deep venous thrombosis and pulmonary embolism.Ann Intern Med. 1998; 129: 1044-9Crossref PubMed Scopus (412) Google Scholar]. The inherent drawbacks (radiation exposure, venous cannulation, contrast media administration) of this technique lead to poor patient acceptance resulting in suboptimal management in both the clinical and research setting. MRDTI is however, ideally suited to the role of detecting asymptomatic disease. A recently completed study using this technique has confirmed the high rate of asymptomatic DVT in acute stroke patients; the incidence being directly related to the severity of stroke and therefore highlighting the potential for targeted prophylactic anticoagulation in this high-risk group (Fig. 3). A similar trial in oncology patients, known to be at risk of thromboembolism is planned. Provided methemoglobin is formed in sufficient quantity, MRDTI will detect high signal. The technique is therefore not limited to the deep veins of the legs but can be applied anywhere throughout the venous system. Axillary, subclavian, jugular and superior and inferior vena cavae venous thromboses have all been detected using this technique. Within the solid organs portal and renal vein thrombus acts in a similarly predictable fashion. The venous sinuses and cortical veins of the brain are also highly suitable targets. Within the spectrum of venous TED the other, and most clinically important, condition that potentially lends itself to the application of MRDTI is the diagnosis of pulmonary embolism (PE). It is now generally accepted that DVT and PE should be considered as manifestations of the same disease process, with PE being the potentially fatal result of what is otherwise a non-fatal condition (DVT). As the treatment for the two conditions is the same, imaging strategies in the diagnosis of PE can exploit this link, as the demonstration of DVT in someone suspected of suffering a PE provides an adequate diagnostic surrogate. That notwithstanding, diagnosis of PE directly is often required. In the knowledge that MRDTI can accurately diagnose DVT, and that PE arises from DVT, it would seem a fairly safe assumption that the theory behind diagnosing DVT should hold for diagnosing PE. A possible pitfall is that the embolus arises from the proximal leading edge of the DVT and is therefore the youngest part of thrombus, with decreased methemoglobin formation and lowest signal. Application of MRDTI in the chest in patients suspected of suffering from a PE have been shown to detect emboli [10Moody A.R. Liddicoat A. Krarup K. Magnetic resonance pulmonary angiography and direct imaging of embolus for the detection of pulmonary emboli.Invest Radiol. 1997; 32: 431-40Crossref PubMed Scopus (63) Google Scholar]. These techniques may be 2-dimensional single slices acquisitions or 3-dimensional volume acquisitions. Both of these ideally require breath-holding, in the order of 15–16 s, but the 2-dimensional technique is sufficiently robust to tolerate shallow respiration in patients unable to breath-hold. Comparison with V/Q scanning has shown that MRDTI provides a definitive diagnosis in 95% of patients, compared with 66% in the V/Q group [11Moody A.R. Wastie M. Gregson R. Whitaker S.C. Comparison of Direct Embolus Imaging and V/Q Scanning in the Detection of Acute Pulmonary Embolism.Proceedings of RSNA. 1998; : 299Google Scholar]. Comparison with conventional pulmonary angiography in a small group of patients has shown high sensitivity and specificity for the diagnosis of PE [12Moody A. Wastie M. Gregson R. Whitaker S. Diagnostic accuracy of direct MR imaging of pulmonary emboli compared to conventional pulmonary angiography.Radiol. 1997; 268: 205Google Scholar]. Some of the obvious advantages of this technique are the lack of radiation and intravenous contrast, but also its ability to be combined with leg imaging to improve diagnostic accuracy of venous thromboembolism (VTE) (see below). This combination could herald a new era of VTE management with a more targeted approach to duration and intensity of therapy. The ability to detect future embolic load (residual DVT within the legs) and susceptibility to the effects of PE (right heart strain), which can also be detected using MRI, will allow a more logical approach to treatment. MRDTI-assisted management in patients being considered for IVC interruption may be feasible. Resolution of thrombus in patients with a known reversible cause of DVT may allow more rapid cessation of anticoagulation. Detection of asymptomatic PE may be useful in the research setting in the assessment of new anticoagulant therapy. The detection of occult PE however, may also be important in patients with DVT as it has the potential to lead on to pulmonary vascular occlusive disease in the future. MRDTI investigation of patients with proven DVT has shown that there is a direct relationship between the volume of thrombus and/or proximity of the thrombus to the IVC and the development of asymptomatic PE. Furthermore the size of vessels occluded by these asyptomatic PEs are also proportional to site and size of DVT. These two factors may therefore be used in the future for predicting the occurrence of PE. The combination of leg and chest imaging with these techniques should therefore provide a powerful one-stop diagnostic tool for the diagnosis of VTE (Fig. 4). This has recently been tested in the Pulmonary embolus Diagnosis at Queen's trial in which patients suspected of PE were randomized to one of four diagnostic pathways [13Crossley I. Moorby S. Macdonald I. Delay S. Moody A. A randomised trial comparing four methods of investigating patients with suspected pulmonary embolism: the Pulmonary Embolism Diagnosis at Queens (PDQ) Trial.Radiol. 2001; 479: 221Google Scholar]– one of which was MRDTI of the legs and chest [14Crossley I, Moorby S, Macdonald I, Delay S, Moody A. Magnetic Resonance Direct Clot Imaging as a First Line Test in the Evaluation of Patients with Suspected Pulmonary Embolism. In: Radiology 2001: p. 221.Google Scholar]. Of 153 patients were randomized to this pathway 21% did not undergo scanning for various reasons: 18% were due to factors such as claustrophobia and patient refusal to be scanned. Of those scanned, 31 (25%) were positive, and this was diagnosed by identification of DVT in isolation in 11 (34%). On follow-up eight patients died, four in the positive and four in the negative PE groups. In the negative group none of these deaths was attributable to recurrent TED. No one in this group suffered a significant bleed related to anticoagulation. These preliminary data would therefore seem to suggest that for those patients who can tolerate the test, which may improve as MRI scanning and its acceptance by the public increases, MRDTI of the legs and chest provides a single test, which, if negative, safely rules out PE. Imaging thrombus within the pulmonary arterial system is akin to imaging within the veins as the thrombus visualized is merely embolic venous material. In situ arterial thrombus does not necessarily behave in the same manner. The make-up of arterial thrombus is different, having a greater proportion of platelets and decreased number of trapped red blood cells; endogenous contrast generation, reliant on the presence of methemoglobin within red blood cells, may therefore be less and could reduce the utility of this technique in the arterial system. In vivo animal studies of arterial thrombus have shown that the imaging characteristics can be used to age thrombus [15Corti R. Osende J.I. Fayad Z.A. Fallon J.T. Fuster V. Mizsei G. Dickstein E. Drayer B. Badimon J.J. In vivo noninvasive detection and age definition of arterial thrombus by MRI.J Am Coll Cardiol. 2002; 39: 1366-73Crossref PubMed Scopus (108) Google Scholar] and thrombosis associated with induced plaque rupture in animals is also detectable using MRI [16Johnstone M.T. Botnar R.M. Perez A.S. Stewart R. Quist W.C. Hamilton J.A. Manning W.J. In vivo magnetic resonance imaging of experimental thrombosis in a rabbit model.Arterioscler Thromb Vasc Biol. 2001; 21: 1556-60Crossref PubMed Scopus (84) Google Scholar]. A preliminary in vivo human study of acute peripheral arterial occlusion has shown however, that sufficient high signal is generated to detect acute occlusion (Fig. 5). 14 patients with acute (<4 weeks of symptoms) limb ischemia underwent MRDTI and MR angiography. The MRDTI scan was positive in 11 of these patients. In six of these patients there was a discrepancy between the length of the thrombus and that of the occlusion demonstrated by angiography. In these patients undergoing thrombolysis recanalization was not achieved, suggesting that the discrepancy in the two measurements reflected a difference between more longstanding arterial disease, not amenable to thrombolytic treatment, and superimposed acute thrombosis. Atherosclerosis is the underlying chronic vascular disease that commonly results in the acute occurrence of arterial thrombosis. The development of vessel wall disease, due to a number of predisposing genetic and acquired triggers, follows a fairly predictable evolution. Much of the early disease is accompanied by compensatory vessel remodeling. This may result in significant disease being invisible to conventional luminal imaging techniques such as angiography. The accumulation of lipid within the vessel wall accompanied by secondary inflammation and repair leads to progressive wall thickening and eventual encroachment on the vessel lumen. Interspersed with this slowly progressive stenotic disease are episodes of more rapid progression which may present with acute clinical symptoms due to vessel narrowing/occlusion or thromboembolic events. These various stages have been categorized by the American Heart Association (AHA) [17Stary H.C. Chandler A.B. Dinsmore R.E. Fuster V. Glagov S. Insull Jr, W. Rosenfeld M.E. Schwartz C.J. Wagner W.D. Wissler R.W. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association.Circulation. 1995; 92: 1355-74Crossref PubMed Scopus (2354) Google Scholar] allowing better definition of these different disease states and their likelihood to cause symptoms. Once the atheromatous plaque has become complicated (AHA type VI disease) the occurrence of symptoms is much more likely. The plaques may become complicated in a number of ways, including rupture of the overlying fibrous cap resulting in exposure of highly thrombogenic plaque contents to the circulating system, and plaque thrombosis and propagation into the vessel lumen with resultant rapid stenosis or occlusion. In addition embolic material may detach and flow downstream to lodge in more distal vessels causing end organ ischemia. As part of the response to atherosclerotic progression the plaque tends to become highly vascular due to neovessel formation. An alternative mechanism of intraplaque hemorrhage and thrombus formation is via rupture of one of these vessels which may or may not cause disruption of the overlying plaque cap, but can be associated with rapid plaque enlargement. While the plaque may become acutely complicated the end result therefore is not always accompanied by clinical symptoms. Whatever the mechanism, one of the common features of plaque complications is the presence of intraplaque hemorrhage/thrombosis. As a result this provides a potential target for MRDTI (Fig. 6). A clinical model to investigate this is carotid artery atherothrombotic disease. A significant proportion of cerebral ischemic events are due to emboli arising from carotid vessel wall disease. Slowly progressive carotid atherosclerotic disease undergoes episodes of complication due to cap rupture and/or intraplaque hemorrhage. If sufficient luminal thrombus is formed the potential exists for distal embolization resulting in transient ischemic attacks or frank cerebral infarction. Study of patients suffering acute cerebral infarction has confirmed that a significant majority of them have complicated carotid plaque ipsilateral to the side of their cerebral event (69%) [18Moody A.R. Allder S. Lennox G. Gladman J. Fentem P. Direct magnetic resonance imaging of carotid artery thrombus in acute stroke [Letter].Lancet. 1999; 353: 122-3Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. Interestingly, in a significant minority this occurred in vessels with stenoses less than 50%, which would be considered non-contributory by standard criteria. The detection of intraplaque hemorrhage/thrombosis by this technique has the potential therefore to better define carotid vessel wall disease than those merely measuring vessel stenosis. Further investigation of the high signal associated with carotid vessel wall disease has shown that this has a strong positive predictive value of complicated plaque (93%) when compared with excised carotid endarterectomy specimens [19Murphy R. Moody A. MacSweeney S. Tennant W. Lowe J. A new MRI technique to detect high-risk carotid plaque in patients with cerebral ischaemia.Br J Surg. 2001; 388 (62 (Abstract 013))Google Scholar]. The high prevalence of MRDTI detected complicated plaque in patients suffering anterior circulation infarction has also been demonstrated in those suffering transient ischemic attacks. Ipsilateral high signal was found in 60% of patients with TIA. Interestingly an even higher prevalence (67%) was found in patients with lesser (50–70%) degrees of stenosis than those with high-grade stenosis. The occurrence of high signal material is not however, confined to the symptomatic side: 30% of patients were also found to have contralateral disease, though this only occurred in 8% of patients in isolation [20Murphy R, Moody A, Morgan P. et al. The Prevalence and Relevance of MRI High Signal Within the Carotid Arteries of Patients with Cerebral Ischaemia In: ISMRM; Glasgow; 2001: p. 647.Google Scholar]. Furthermore, in a small population of age/sex matched controls no MRDTI-positive disease was detected. These observations would add weight to the theory that atherosclerotic disease is a systemic vascular condition which is not static. The disease is triggered and becomes complicated though not necessarily becoming clinically apparent – hence the presence of 'image positive' disease in the absence of symptoms. MRDTI therefore lends itself to the study of this systemic condition, and its ability to detect both symptomatic and asymptomatic disease is particularly valuable. In addition to endogenous contrast mechanisms recent efforts have been directed towards the manufacture of exogenous contrast agents that will allow detection of different aspects of the clotting process. Targeted contrast agents for fibrin [21Flacke S. Fischer S. Scott M.J. Fuhrhop R.J. Allen J.S. McLean M. Winter P. Sicard G.A. Gaffney P.J. Wickline S.A. Lanza G.M. Novel MRI contrast agent for molecular imaging of fibrin: implications for detecting vulnerable plaques.Circulation. 2001; 104: 1280-5Crossref PubMed Scopus (471) Google Scholar] could have an advantage over endogenous contrast, reliant on trapped red blood cells, of detecting occult microthrombi within the damaged intima of atherosclerotic vessels. These agents have shown early promise in in vitro and animal models. Contrast agents based on ultrasmall particles of iron oxide (USPIO) also appear to have the ability to detect intraluminal thrombus. Following administration 24 h prior to imaging, incorporation or migration of USPIO into recent thrombus demonstrated thrombus to a greater extent than the endogenous contrast technique [22Schmitz S.A. Winterhalter S. Schiffler S. Gust R. Wagner S. Kresse M. Coupland S.E. Semmler W. Wolf K.J. USPIO-enhanced direct MR imaging of thrombus: preclinical evaluation in rabbits.Radiology. 2001; 221: 237-43Crossref PubMed Scopus (51) Google Scholar]. Over the last few years there has been an increased interest in directly demonstrating the lesions that are causing vascular narrowing or occlusion, whether these arise in the lumen or the vessel wall itself. An obvious advantage to this approach is the application of therapeutic regimens that act directly on these culprit lesions, which can therefore be monitored with far greater accuracy. The development of techniques that enable the direct demonstration of vascular thrombosis should play a significant part in this process in a number of clinical settings.