MiRNA 126 as a New Predictor Biomarker in Venous Thromboembolism of Persistent Residual Vein Obstruction: A Review of the Literature Plus a Pilot Study

Venous thromboembolism (VTE) is the third most common cardiovascular disease. Interleukins (ILs) and micro-ribonucleic acids (miRNAs) have been proposed as molecules able to modulate endothelial inflammation and platelet hyperactivity. At present, no early biomarkers are available to predict the outcome of VTE. We investigated in a pilot study a selected number of miRNAs and ILs as prognostic VTE biomarkers and reviewed literature in this setting. Twenty-three patients (aged 18–65) with a new diagnosis of non-oncological VTE and free from chronic inflammatory diseases were enrolled. Twenty-three age- and sex-matched healthy blood donors were evaluated as control subjects. Serum miRNAs (MiRNA 126, 155, 17.92, 195), inflammatory cytokines (IL-6, tumor necrosis factor-α, IL-8), and lymphocyte subsets were evaluated in patients at enrolment (T0) and in controls. In VTE patients, clinical and instrumental follow-up were performed assessing residual vein obstruction, miRNA and ILs evaluation at 3 months' follow-up (T1). At T0, IL-8, activated T lymphocytes, Treg lymphocytes, and monocytes were higher in patients compared with healthy controls, as were miRNA 126 levels. Moreover, miRNA 126 and IL-6 were significantly increased at T0 compared with T1 evaluation in VTE patients. Higher levels of MiR126 at T0 correlated with a significant overall thrombotic residual at follow-up. In recent years an increasing number of studies (case–control studies, in vivo studies in animal models, in vitro studies) have suggested the potential role of miRNAs in modulating the cellular and biohumoral responses involved in VTE. In the frame of epidemiological evidence, this pilot study with a novel observational approach supports the notion that miRNA can be diagnostic biomarkers of VTE and first identifies miRNA 126 as a predictor of outcome, being associated with poor early recanalization.

A Systematic Review of the Utility of Residual Vein Obstruction Studies in Primary and Secondary Venous Thrombosis

Background. Residual vein obstruction (RVO), the persistence of venous thrombosis with time and often after anticoagulation, may indicate a systemic prothrombotic condition. Prior studies have shown varying efficacy in using RVO as a risk factor for future venous thromboembolic (VTE) recurrence. Methods. To assess whether positive RVO imaging predicts recurrent VTE events, we performed a meta-analysis on studies in which patients with documented VTEs, anticoagulated for a minimum of 4 weeks, had repeat sonography to assess RVO and were subsequently followed for recurrent events. Results. Thirteen studies met inclusion criteria: 3531 patient VTE events with 3474 evaluable results were analyzed. The presence of RVO was associated with recurrence in all VTE (OR 1.93; 95% CI: 1.29, 2.89) and secondary VTE (OR 2.78; 95% CI: 1.41, 5.5) but not for primary VTE (OR 1.35; 95% CI: 0.87, 2.08). When cancer patients were eliminated from the secondary VTE group, there was no longer a significant association of RVO with VTE recurrence (OR 1.73; 95% CI: 0.81, 3.67) while in the subset of cancer patients, presence of RVO was associated with an increase in VTE recurrence risk (OR 5.14; 95% CI: 1.59, 16.65, P<0.006). Conclusions. We conclude that the presence of RVO is associated with recurrence in secondary VTE but not in primary VTE and that association may be driven by the subset with cancer.

The influence of factor V Leiden and G20210A prothrombin mutation on the presence of residual vein obstruction after idiopathic deep-vein thrombosis of the lower limbs

SummaryIt was our aim to assess whether factor V Leiden (FVL) and G20210A prothrombin (FII) mutation are associated with the presence of residual vein obstruction (RVO) after a standard course of anticoagulation for a first episode of idiopathic proximal deep-vein thrombosis (DVT) of the lower limbs, with or without symptomatic pulmonary embolism (PE). Patients were enrolled in two prospective multicentre studies: PROLONG and PROLONG II. RVO was detected by compression ultra-sonography according to the method of Prandoni on the day of anticoagulation withdrawal. Patients were also screened for FVL and FII mutation. The presence of FVL and/or FII mutation was determined in 872/963 (90.5%) patients, in 753 of whom RVO was assessed. FVL was significantly less frequent among subjects with isolated PE (7/176:4%) than among patients with either DVT and PE (15/133:11.3%; p=0.0018) or isolated DVT (89/563:15.8%; p<0.0001), confirming the FVL paradox. The rate of FII mutation was similar among patients with isolated PE (11/176:6.2%) and patients with either DVT and PE (12/133:9%) or isolated DVT (52/563:9.2%). FVL and FII mutation were not significantly associated with RVO at the multivariate analysis in all patients, although data suggest that FVL and FII mutation may have a differential effect on RVO in the subgroups of patients with DVT and DVT plus PE patients. Male sex and isolated DVT were significantly associated with RVO in all patients. In conclusion, male sex and isolated DVT are associated with RVO, while FVL and FII mutations are not significantly associated with RVO in this study.

Residual Vein Obstruction (RVO) Predicts Recurrence for Cancer Patients with Secondary VTE: A Meta-Analysis.

Abstract 2259 Background: Venous thrombosis is a common disease and long term anticoagulation is effective in the prevention of venous thromboembolism (VTE). Studies to detect residual vein obstruction (RVO) performed at the end of the anticoagulation period has been investigated as a predictive marker for recurrent thrombotic risk. The value of this test has been questioned, and different methodologies, different patient populations, and varying lengths of prior anticoagulation may be responsible for the disparate results published. In order to assess the true predictive worth of RVO we performed a meta-analysis of published studies to determine whether RVO can predict the risk of recurrent VTE. Methods: A comprehensive literature search with the terms “deep vein thrombosis”, “residual vein thrombosis“, and “recurrent venous thromboembolism” was performed on PubMed, MEDLINE, EMBASE, Web of Science, the Cochrane dataset, Science Direct and CINAHL. Clinical trials published in English between January 1990 and December 2011 were eligible for this analysis. The selection of abstracts was based on the following criteria: studies had to be prospective, VTE patients had to have been anticoagulated with unfractionated heparin, low molecular weight heparin or warfarin for at least 6 weeks, and the presence of RVO and recurrent thromboembolic events had to have been recorded. The diagnosis of RVO was allowed if 1) a venous thrombosis of >2mm was present 2) the thrombus occupied >40% of vein diameter or 3) the presence of positive thrombosis on duplex was noted. Recurrent events were defined if a new contralateral deep vein thrombosis (DVT), a new ipsilateral DVT (if the prior DVT was documented to be recanalised) or a new PE (documented by perfusion scan, Computed Tomographic Angiography or pulmonary angiography) was noted. Data were analyzed with STATS Direct meta-analysis software. Analyses were performed for the whole VTE population as well as for unprovoked and provoked VTE cohorts. A sub-analysis of patients with cancer within the provoked cohort was performed. Odds Ratios (OR) with 95% confidence intervals were calculated for individual studies and Forrest plots were generated. Results: We identified 1955 potential publications, of which 28 were relevant. Thirteen studies met inclusion criteria and were included in the final analysis. 4546 patients, mean age 61years, with 3476 events were included. Five studies were prospective studies which recruited patients with only primary VTE, four studies examined secondary VTE only and four studies investigated both primary and secondary VTE. For all patients with VTE, primary and secondary, the presence of RVO was associated with a significantly higher recurrent VTE risk (OR 1.93. 95%CI: 1.29 –2.89, p = 0.001). When analyzed separately for primary VTE, RVO did not demonstrate a statistically significant increased recurrent VTE risk (OR 1.38, 95%CI: 0.87 – 2.08), results consistent with prior observations. When results were analyzed for patients with secondary VTE, the OR was 2.78 (95% CI: 1.4 – 5.5, p= 0.003). However, when patients with cancer were eliminated from the secondary VTE cohort, the OR decreased to 1.73 and was no longer significant (95% CI: 0.82 – 3.66). In contrast, for the two studies with cancer patients, the odds ratio for recurrent VTE given a positive RVO study was 5.14 (95% CI: 1.59 – 16.65 p = 0.006). While RVO studies showed recanalization and/or normalization after 6 months in 93% of post-operative patients, recanalization occurred in only 53% of patients who were treated for cancer, only 20% of patients with active cancer had negative RVO studies. Conclusions: A meta-analysis of 13 studies examining the predictive value of RVO studies did not detect significant utility for patients with primary VTE. RVO predicted recurrence in secondary VTE but subset analysis demonstrated that RVO seems to have predictive value primarily in the subgroup of patients with cancer. Current ACCP and NCCN guidelines for thrombosis in cancer differ in their recommemdation for duration of anticoagulation but both recommend extended anticoagulant therapy. A negative RVO study might reliably predict a group which might not need extended anticoagulation. Further prospective clinical trials are needed determining the utility of RVO in cancer patients with VTE. Disclosures: No relevant conflicts of interest to declare.