D-dimer levels in VTE patients with distal and proximal clots.

OBJECTIVES: There is growing evidence that venous thromboembolism (VTE) patients with distal clots (distal calf deep vein thrombosis [DVT] and sub-segmental pulmonary embolism [PE]) may not routinely benefit from anticoagulation. We compared the D-dimer levels in VTE patients with distal and proximal clots. METHODS: We conducted a multinational, prospective observational study of low-to-intermediate risk adult patients presenting to the emergency department (ED) with suspected VTE. Patients were classified as distal (calf DVT or sub-segmental PE) or proximal (proximal DVT or non-sub-segmental PE) clot groups and compared with univariate and multivariate analyses. RESULTS: Of 1752 patients with suspected DVT, 1561 (89.1%) had no DVT, 78 (4.4%) had a distal calf DVT, and 113 (6.4%) had a proximal DVT. DVT patients with proximal clots had higher D-dimer levels (3760 vs. 1670 mg/dL) than with distal clots. Sensitivity and negative predictive value (NPV) for proximal DVT at an optimal D-dimer cutoff of 5770 mg/dL were 40.7% and 52.1% respectively. Of 1834 patients with suspected PE, 1726 (94.1%) had no PE, 7 (0.4%) had isolated sub-segmental PE, and 101 (5.5%) had non-sub-segmental PE. PE patients with proximal clots had higher D-dimer levels (4170 vs. 2520 mg/dL) than those with distal clots. Sensitivity and NPV for proximal PE at an optimal D-dimer cutoff of 3499 mg/dL were 57.4% and 10.4% respectively. CONCLUSIONS: VTE patients with proximal clots had higher D-dimer levels than patients with distal clots. However, D-dimer levels cannot be used alone to discriminate between VTE patients with distal or proximal clots.

Identification of High-Risk Plaques by MRI and Fluorescence Imaging in a Rabbit Model of Atherothrombosis.

INTRODUCTION: The detection of atherosclerotic plaques at risk for disruption will be greatly enhanced by molecular probes that target vessel wall biomarkers. Here, we test if fluorescently-labeled Activatable Cell Penetrating Peptides (ACPPs) could differentiate stable plaques from vulnerable plaques that disrupt, forming a luminal thrombus. Additionally, we test the efficacy of a combined ACPP and MRI technique for identifying plaques at high risk of rupture. METHODS AND RESULTS: In an atherothrombotic rabbit model, disrupted plaques were identified with in vivo MRI and co-registered in the same rabbit aorta with the in vivo uptake of ACPPs, cleaved by matrix metalloproteinases (MMPs) or thrombin. ACPP uptake, mapped ex vivo in whole aortas, was higher in disrupted compared to non-disrupted plaques. Specifically, disrupted plaques demonstrated a 4.5~5.0 fold increase in fluorescence enhancement, while non-disrupted plaques showed only a 2.2~2.5 fold signal increase. Receiver operating characteristic (ROC) analysis indicates that both ACPPs (MMP and thrombin) show high specificity (84.2% and 83.2%) and sensitivity (80.0% and 85.7%) in detecting disrupted plaques. The detection power of ACPPs was improved when combined with the MRI derived measure, outward remodeling ratio. CONCLUSIONS: Our targeted fluorescence ACPP probes distinguished disrupted plaques from stable plaques with high sensitivity and specificity. The combination of anatomic, MRI-derived predictors for disruption and ACPP uptake can further improve the power for identification of high-risk plaques and suggests future development of ACPPs with molecular MRI as a readout.

Detection of thrombus size and protein content by ex vivo magnetization transfer and diffusion weighted MRI.

BACKGROUND: To utilize a rabbit model of plaque disruption to assess the accuracy of different magnetic resonance sequences [T1-weighted (T1W), T2-weighted (T2W), magnetization transfer (MT) and diffusion weighting (DW)] at 11.7 T for the ex vivo detection of size and composition of thrombus associated with disrupted plaques. METHODS: Atherosclerosis was induced in the aorta of male New Zealand White rabbits (n = 17) by endothelial denudation and high-cholesterol diet. Subsequently, plaque disruption was induced by pharmacological triggering. Segments of infra-renal aorta were excised fixed in formalin and examined by ex vivo magnetic resonance imaging (MRI) at 11.7 T and histology. RESULTS: MRI at 11.7 T showed that: (i) magnetization transfer contrast (MTC) and diffusion weighted images (DWI) detected thrombus with higher sensitivity compared to T1W and T2W images [sensitivity: MTC = 88.2%, DWI = 76.5%, T1W = 66.6% and T2W = 43.7%, P < 0.001]. Similarly, the contrast-to-noise (CNR) between the thrombus and the underlying plaque was superior on the MTC and DWI images [CNR: MTC = 8.5 ± 1.1, DWI = 6.0 ± 0.8, T1W = 1.8 ± 0.5, T2W = 3.0 ± 1.0, P < 0.001]; (ii) MTC and DWI provided a more accurate detection of thrombus area with histology as the gold-standard [underestimation of 6% (MTC) and 17.6% (DWI) compared to an overestimation of thrombus area of 53.7% and 46.4% on T1W and T2W images, respectively]; (iii) the percent magnetization transfer rate (MTR) correlated with the fibrin (r = 0.73, P = 0.003) and collagen (r = 0.9, P = 0.004) content of the thrombus. CONCLUSIONS: The conspicuity of the thrombus was increased on MTC and DW compared to T1W and T2W images. Changes in the %MTR and apparent diffusion coefficient can be used to identify the organization stage of the thrombus.