Duplex US is widely used for the diagnosis of acute DVT. Although noninvasive and readily available, methods to reliably distinguish acute from chronic thrombosis by duplex US have not been well validated. Newer techniques, including US elastography and photoacoustic imaging, may eventually prove to be useful but remains investigational.15,16
F-FDG PET/CT is a very sensitive imaging modality used commonly in oncology, which also has increasing utility in vasculature imaging (reviewed in Joshi et al3
). Acute thrombosis, often reflecting underlying systemic inflammation, is associated with endothelial cell activation and increased expression of cell adhesion molecules. These events subsequently promote leukocyte adhesion with accumulation of neutrophils and macrophages, which are metabolically active and avidly take up 18
F-FDG, within the developing thrombus (reviewed in Saha et al5
To our knowledge, this is the first prospective, comparative study to examine the role of 18
F-FDG PET/CT in patients with symptomatic, proximal DVT and supports and extends smaller reports of increased 18
F-FDG uptake in DVT.8,11,17
In the current study, we found that thrombosed vein segments universally appeared visually asymmetric. Furthermore, 18
F-FDG uptake in thrombosed vein segments was significantly increased in thrombosed vein segments. The presence of visual asymmetry and a SUVmax threshold of 1.645 or higher were very sensitive for the diagnosis of acute, proximal DVT with 100% specificity. The uptake of 18
F-FDG did not differ with regard to extremity or vein segments, and despite the small sample size, the absolute magnitude of difference in the SUVmax between thrombosed and nonthrombosed vein segments () was sufficient to provide 99.9% power to avoid a type 2 error (using a 2-sided, α = 0.05).
In our patients with DVT, metabolic activity was not increased in the nonthrombosed contralateral vein segments. Thus, if bilateral DVT is absent, comparing metabolic activity between the 2 extremities may assist clinicians in the diagnosis of DVT as seen on 18F-FDG PET/CT. Furthermore, the SUVmax of nonthrombosed vein segments (whether in our n = 12 DVT patients or n = 24 control subjects) was remarkably consistent between subjects with little variation.
Finally, these data also suggest that 18F-FDG PET may allow an assessment of the age of DVT. In both regression analyses and 2 patients who underwent serial PET imaging, the metabolic uptake and visually asymmetric of thrombosed vein segments declined with increasing time from DVT symptom onset. On the basis of these preliminary data, the SUVmax in thrombosed vein segments may take up to 3 months to normalize after an episode of acute, proximal DVT.
F-FDG PET/CT would not replace duplex US for the routine diagnosis of DVT, 18
F-FDG PET/CT have utility in a multitude of clinical settings for the evaluation of DVT. For example, acute thrombus may be suspected within the body cavity where duplex US cannot easily image (eg, iliofemoral DVT), particular when inability to compress veins limits the diagnostic utility (eg, obesity, plaster casts). Moreover, 18
F-FDG PET/CT is used commonly in oncology,18
a population at high risk for VTE,19
and may identify incidental thrombosis prompting additional investigations. Finally, 18
F-FDG PET/CT may be an important diagnostic tool for the assessment of the age of the thrombus—a distinction that is important given the marked differences in therapeutic approach. Acute DVT is treated with systemic anticoagulation and not uncommonly pharmacomechanical thrombolysis. Chronic DVT, however, may be treated with serial imaging only and thus distinguishing acute from chronic DVT is of key clinical importance. As duplex US-based techniques to difference acute from chronic DVT, including elastography and photoacoustic imaging,15,16
remain largely investigational and/or not widely available, the data of the current study provide novel evidence for the potential role of 18
F-FDG PET/CT in making this distinction.
Clinically, the distinction between “acute” and “chronic” DVT has been somewhat arbitrarily established. The success of venous recanalization, preservation of valve function, and symptom relief may depend on the timing of therapy after thrombosis. These factors influence the effectiveness of the intervention and the subsequent incidence of postthrombotic syndrome (PTS). Fresh thrombi respond better to catheter-directed thrombolysis than do organized clots. It has been suggested that 10 days may be the optimal interval from onset of symptoms during which to instigate treatment. However, the ATTRACT trial in the United States has used 14 days and the CaVenT trial has used 21 days as the cutoff for recruitment of patients for catheter-directed therapy.20–22
In the literature, it is recognized that the age at which a clot is not longer amenable to thrombolysis requires further study to determine the optimal time frame for intervention that will prevent valvular destruction and venous hypertension, which may result in an increase of the likelihood of longer-term sequelae.23–26
After the development of proximal DVT, it is suggested that anticoagulation be maintained for 3 to 6 months, and the use of graduated compression stockings for 2 years significantly reduces the incidence of PTS.27
The results of the current study suggest that thrombus may remain metabolically active up to 10 weeks. It is tempting to postulate that demonstration of increased metabolic activity in clot may signify that the clot is still capable of active propagation during this time, but this remains to be studied. 18
F-FDG PET may represent a novel mechanism by which a better refinement can be made between thrombus that is acute and metabolically active and that which is chronic, organized, and metabolically inert. These distinctions may translate to better refinement and more physiological assessment of the definition of “acute” versus “chronic” clot, which may have therapeutically significant implications.
The strengths of the study include the prospective study design, the objective adjudication of all DVT by duplex US, and the inclusion of carefully matched control subjects. We also carefully recorded the onset of DVT symptoms and excluded patients with isolated distal DVT, asymptomatic DVT, and provoked DVT due to surgery and hospitalization (which could introduce bias into the measured metabolic activity of vein segments due to generalized, systemic inflammation, or surgical manipulation). However, the disadvantage of such a study design is a lack of systematic information regarding the appearance of DVT on 18F-FDG PET in the face of intercurrent illnesses and inflammatory conditions. For example, patients with PTS have chronic extremity swelling, pain, skin ulcers, and inflammatory changes. These inflammatory changes could mimic the appearance of acute DVT. Conversely, the effect of antiinflammatory drugs on uptake of 18F-FDG by acute clot has not been assessed and was not a controlled factor in this specific study.
The primary limitation of this study was the small sample size, and this work should be considered preliminary. Nevertheless, this study still represents, to our knowledge, the only prospective evaluation of the role of 18F-FDG PET/CT in patients with DVT. Despite the small sample size, the magnitude of differences and correlation with time from DVT symptom onset remained robust. Furthermore, the inclusion of a matched control cohort, as well as using the contralateral vein segments from patients with DVT, allowed us to rigorously characterize and compare metabolic activity in nonthrombosed veins.
An additional limitation of this study was that serial or repeat 18
F-FDG PET/CT imaging was not performed on any DVT patients more than 70 days after DVT symptom onset. Thus, the prediction that the metabolic activity of thrombosed vein segments would return to normal at 84 to 91 days after acute DVT would require prospective confirmation. “Optimized” SUVmax cutoff values in the identification of acute thrombosis would also require independent confirmation. Bilateral duplex US was not performed on every subject. Nevertheless, none of our patients who only had unilateral ultrasound had symptoms of DVT in the contralateral leg and none of these patients had evidence of DVT on 18
F-FDG PET/CT. Because prospective studies have suggested that routine bilateral duplex US is not necessary in the absence of symptoms, active malignancy, or recent surgery or trauma,28
this is unlikely to represent a major limitation. Finally, it is recognized that other processes besides DVT could increase metabolic activity in the venous vasculature. Although 18
F-FDG PET/CT may be very sensitive for the diagnosis of DVT, the specificity was less than 90% (and inferior to reported values obtained by duplex US), and confirmatory testing with duplex US would be necessary.