## 3 Cardiovascular Disease
### Venous Thromboembolism
#### 3.4.3 Imaging Venous Thromboembolisms
Mean ADC of this acute thrombus was above the cut-off of \(0.32\times 10^{-3}\) mm\({}^{2}\)/s, while that of non-acute thrombus was below the cut-off. Reproduced with permission from [PERSON] et al., 2019 [136]. In a different study, [PERSON] et al. demonstrated the potential of black blood non-contrast direct thrombus imaging in a cohort of 15 healthy volunteers and 30 patients with acute DVT. Thrombus appeared either iso- or hyperintense in the acute phase with comparable diagnostic confidence to contrast enhanced CMR venography: sensitivity (95%), specificity (99%), positive predictive value (96%), negative predictive value (98%), and accuracy (98%) (Figure 21) [137]. Fibrin is heavily involved in thrombus formation [71; 72] and is therefore an important molecular target for imaging of DVT. In a pre-clinical murine model of DVT, [PERSON] et al. investigated the fibrin-specific MRI contrast agent (EP-2104R) for the in vivo quantification of thrombus fibrin content the identification of thrombus suitable for thrombolysis [138] (Figure 22). Contrast uptake positively correlated with the fibrin content of the thrombus measured by Western blotting (\(R^{2}\) = 0.889; \(p\) < 0.001). Furthermore, thrombus relaxation rate post contrast and the change in visualised thrombus size pre and post EP-2104R injection were the best predictors for successful thrombolysis. Figure 21: Representative images obtained by CE-CMRV and BBTI from a patient with DVT symptom onset at 10 days. The small thrombus can also be detected by BBTI and matched well with that seen with CE-CMRV (yellow arrows). BBTI—black-blood thrombus imaging; CE-CMRV—contrast-enhanced CMR venography. Reproduced with permission from [PERSON] et al., 2018 [137]. In another study, [PERSON] et al. demonstrated the successful imaging of thrombus (both freshly engineered thrombi and human thrombus removed from patients) by using EP-2104R in a swine model of pulmonary embolism [139]. In a clinical translational study, [PERSON] et al. assessed the use of EP-2104R in patients with confirmed PE or DVT [79]. Use of the agent enhanced the signal of the thrombus and enabled visualisation of additional thrombus features, not visible on the pre-contrast images (Figure 23). In a different approach, [PERSON] et al. combined a novel fibrin-targeted probe (FTP 11-Cy7) with near-infrared fluorescence (NIRF) in a mouse model of DVT [140]. In vitro human clot-binding analyses showed a 6-fold higher NIRF signal for the clot target-to-background ratio (TBR) using the FTP11-Cy7 probes compared to the free Cy7. Moreover, the thrombus TBR of acute and sub-acute femoral DVT with FTP11-Cy7 obtained by intravital fluorescence microscopy was 4-fold higher than control free Cy7. Indeed, in vivo imaging of fibrin in jugular DVT via fluorescence molecular computed tomography demonstrated strong NIRF signal in thrombi compared to sham-operated jugular veins using FTP11-Cy7. Recently, [PERSON] et al. combined whole-body PET/MRI with the fibrin-binding probe \({}^{64}\)Cu-FBP8 in a rodent model of carotid artery and femoral vein thrombosis [141]. Figure 22: **(A)**, Changes in thrombus relaxation rate \(\Delta\)R1 (s-1) pre–EP-2104R and post–EP-2104R administration at different time point during thrombus organization. Greatest differences in \(\Delta\)R1 pre and post contrast are observed at days 7 and 10. **(B)**, Thrombus gadolinium concentration (\(\mu\)mol/L) mirrored the changes in R1 over time. **(C)**, R1 mapping images pre EP-2104R and post EP-2104R injection and Martius Scarlet Blue (MSB) histology sections at the corresponding levels and fibrin selective segmentation. Gd-DTPA indicates gadolinium with diethylenetriaminepentacetate ([PERSON], Schering AG, Berlin, Germany). Reproduced with permission from [PERSON] et al., 2014 [138]. A single whole-body PET/MRI scan revealed the location of both arterial and venous thrombi after the administration of \({}^{64}\)Cu-FBP8.