Association of Circulating Long Noncoding 7S RNA with Deep Vein Thrombosis.

Mitochondrial dysfunction is a recognized factor in the pathogenesis of deep vein thrombosis (DVT). The role of 7S RNA, a long noncoding RNA that plays an important role in mitochondrial function, in DVT remains unclear. In this study, we aimed to investigate the potential use of 7S RNA as a biomarker in DVT. Plasma samples were obtained from 237 patients (aged 16-95 years) with suspected DVT recruited in a prospective multicenter management study (SCORE) where 53 patients were objectively confirmed with a diagnosis of DVT and the rest were diagnosed as non-DVT. 7S RNA was measured using quantitative real-time polymerase chain reaction in plasma samples. The plasma expression of 7S RNA was significantly lower in DVT compared with non-DVT (0.50 vs. 0.95, p = 0.043). With the linear regression analysis, we showed that the association between the plasma expression of 7S RNA and DVT (ß = -0.72, p = 0.007) was independent of potential confounders. Receiver-operating characteristic curve analysis showed the area under the curve values of 0.60 for 7S RNA. The findings of the present study showed a notable association between 7S RNA and DVT. However, further investigations are needed to fully elucidate the exact role of 7S RNA in the pathophysiology of DVT and its diagnostic value.

Diagnosing deep vein thrombosis in cancer patients with suspected symptoms: An individual participant data meta-analysis.

BACKGROUND: A previous individual participant data (IPD) meta-analysis showed that the Wells rule and D-dimer testing cannot exclude suspected deep vein thrombosis (DVT) in cancer patients. OBJECTIVES: To explore reasons for this reduced diagnostic accuracy and to optimize the diagnostic pathway for cancer patients suspected of DVT. PATIENTS AND METHODS: Using IPD from 13 studies in patients with suspected DVT, DVT prevalence and the predictive value of the Wells rule items and D-dimer testing were compared between patients with and without cancer. Next, we developed a prediction model with five variables selected from all available diagnostic predictors. RESULTS: Among the 10 002 suspected DVT patients, there were 834 patients with cancer. The median prevalence of DVT in these patients with cancer was 37.5% (interquartile range [IQR], 30.8-45.5), whereas it was 15.1% (IQR, 11.5-16.7) in patients without cancer. Diagnostic performance of individual Wells rule items and D-dimer testing was similar across patients with and without cancer, except "immobility" and "history of DVT." The newly developed rule showed a pooled c-statistic 0.80 (95% confidence interval [CI], 0.75-0.83) and good calibration. However, using this model, still only 4.3% (95% CI, 3.0-5.7) of the suspected patients with cancer could be identified with a predicted DVT posttest probability of <2%. CONCLUSIONS: Likely because of the high prevalence of DVT, clinical models followed by D-dimer testing fail to rule out DVT efficiently in cancer patients suspected of DVT. Direct referral for compression ultrasonography appears to be the preferred approach for diagnosis of suspected DVT in cancer patients.

Identification of novel diagnostic biomarkers for deep venous thrombosis.

The combination of a negative D-dimer and a Wells score can rule out, but not confirm, a diagnosis of deep venous thrombosis (DVT). We aimed to identify new diagnostic biomarkers for DVT and to investigate their relationship with hypercoagulability markers [D-dimer and activated protein C-protein C inhibitor (APC-PCI) complex]. We screened 92 cardiovascular-specific proteins in plasma samples from 45 confirmed DVT patients and 45 age- and sex-matched non-DVT patients selected from a prospective multicentre diagnostic management study (SCORE) by Proseek Multiplex CVDIII96×96 . Plasma levels of 30 proteins were significantly different between DVT and non-DVT patients. After Bonferroni correction, plasma levels of seven proteins: P-selectin, transferrin receptor protein 1, von Willebrand factor, tissue factor pathway inhibitor, osteopontin (OPN), bleomycin hydrolase and ST2 protein remained significantly different. The area under curve (AUC) for these proteins ranged from 0·70 to 0·84. Furthermore, all seven identified proteins were significantly associated with markers of hypercoagulability. A combination of OPN and APC-PCI had the best ability to discriminate DVT from non-DVT patients (AUC = 0·94; sensitivity = 89% and specificity = s84%). In conclusion, we identified multiple proteins associated with markers of hypercoagulability and with a potential to become novel diagnostic biomarkers for DVT.

Diagnostic potential of plasma microRNA signatures in patients with deep-vein thrombosis.

For excluding deep-vein thrombosis (DVT), a negative D-dimer and low clinical probability are used to rule out DVT. Circulating microRNAs (miRNAs) are stably present in the plasma, serum and other body fluids. Their diagnostic function has been investigated in many diseases but not in DVT. The aims of present study were to assess the diagnostic ability of plasma miRNAs in DVT and to examine their correlation with known markers of hypercoagulability, such as D-dimer and APC-PCI complex. Plasma samples were obtained from 238 patients (aged 16-95 years) with suspected DVT included in a prospective multicentre management study (SCORE). We first performed miRNA screening of plasma samples from three plasma pools containing plasma from 12 patients with DVT and three plasma pools containing plasma from 12 patients without DVT using a microRNA Ready-to-use PCR Panel comprising 742 miRNA primer sets. Thirteen miRNAs that differentially expressed were further investigated by quantitative real-time (qRT)-PCR in the entire cohort. The plasma level of miR-424-5p (p=0.01) were significantly higher, whereas the levels of miR-136-5p (p=0.03) were significantly lower in DVT patients compared to patients without DVT. Receiver-operating characteristic curve analysis showed the area under the curve (AUC) values of 0.63 for miR-424-5p and 0.60 for miR-136-5p. The plasma level of miR-424-5p was associated with both D-dimer and APC-PCI complex levels (p<0.0001 and p=0.001, respectively). In conclusions, these findings indicate that certain miRNAs are associated with DVT and markers of hypercoagulability, though their diagnostic abilities are probably too low.

A cost-effectiveness analysis of diagnostic algorithms of deep vein thrombosis at the emergency department.

INTRODUCTION: Suspected cases of deep vein thrombosis are common at emergency departments and they often require extensive and costly diagnostic testing. The objective of this study was to evaluate whether a diagnostic algorithm based upon pre-test probability and D-dimer in diagnosing deep vein thrombosis may be cost-effective from a societal perspective in a Swedish setting. MATERIAL AND METHODS: The cost-effectiveness of two alternative diagnostic algorithms were calculated using decision analysis. An algorithm which out ruled deep vein thrombosis among low probability patients with negative D-dimer was compared to a traditional algorithm including compression ultrasonography and/or contrast venography for all patients. For sensitivity analysis, a third reversed algorithm, where D-dimer was followed by pre-test probability, was analyzed. Estimates of probabilities were obtained from a prospective management study, including 357 outpatients with clinical suspicion of deep vein thrombosis. Direct costs were estimated using prices from Scania, Sweden. Indirect costs were estimated using time spent at the local emergency department and gross average wages in Sweden. RESULTS: The total cost of the pre-test probability and D-dimer algorithm was estimated to euro406 per patient and the traditional algorithm was estimated to euro581 per patient. Reversing the order of the score and test resulted in an estimate of euro421 per patient. CONCLUSION: At no significant difference in diagnostic efficacy the algorithm based upon pre-test probability and D-dimer was cost-effective, while the reversed algorithm and diagnostic imaging for all patients were not.

The diagnostic performance of APC-PCI complex determination compared to D-dimer in the diagnosis of deep vein thrombosis.

UNLABELLED: D-dimer testing is widely used as part of the diagnostic algorithm for the exclusion of deep vein thrombosis (DVT) but is considered of limited in value for ruling DVT in. Since D-dimers are poorly defined, there is no standardization of the assays and this makes reliable comparisons between clinical studies difficult. We report on a performance evaluation of a new marker of activated coagulation (Activated Protein-C in complex with Protein-C inhibitor, APC-PCI complex) compared to two quantitative D-dimer assays (Vidas D-dimer Exclusion and Autodimer). The post-hoc comparison was made on 350 frozen plasma samples from consecutive outpatients suspected of DVT in a multicenter management study including clinical probability score, D-dimer testing, venous ultrasound and contrast venography as part of the diagnostic algorithm. RESULTS: The APC-PCI complex performed inferior to the D-dimer assays in terms of sensitivity: 74 vs. >93%, negative predictive value: 91 vs. >96% and area under the curve: 0.82 vs. 0.9, but showed a significantly higher specificity: 80 vs. 40-60%. Specificity for the APC-PCI complex did not decrease with higher clinical probability score and the positive predictive value was significantly higher than that of the D-dimer assays in the intermediate/high probability cohort (66 vs. <52%). In this probability cohort, high levels of the APC-PCI complex and to a lesser extent, D-dimers, can give positive predictive values of >90% in up to 20% of the patients which indicates important clinical implications. However, for the exclusion of DVT at the pre-specified cut-off level, the APC-PCI complex perform inferior to the D-dimer assays in this study.