Association of recurrent venous thromboembolism and circulating microRNAs

Abstract

Background Patients with unprovoked first venous thromboembolism (VTE) are at a high risk of recurrence. Although circulating microRNAs (miRNAs) have been found to be associated with VTE and are markers of hypercoagulability, this study is the first to examine whether circulating miRNAs are associated with the risk of VTE recurrence. Results A nested case-control study design was used where plasma samples were obtained from 78 patients with unprovoked VTE from the Malmö Thrombophilia Study (MATS). A total of 39 VTE patients with recurrent VTE (cases) were matched with 39 VTE patients without recurrent VTE (controls) defined by age and sex (MATS population). Plasma levels of 179 different miRNAs were evaluated in the 78 samples (after anticoagulant treatment was stopped) using qPCR. A total of 110 miRNAs were detected in all samples. Among those, 12 miRNAs (miR-15b-5p, miR-106a-5p, miR-197-3p, miR-652-3p, miR-361-5p, miR-222-3p, miR-26b-5p, miR-532-5p, miR-27b-3p, miR-21-5p, miR-103a-3p, and miR-30c-5p) were found to be associated with recurrent VTE after multiple correction test and conditional logistic regression analysis. A further analysis showed that miR-15b-5p, miR-197-3p, miR-27b-3p, and miR-30c-5p exhibited a trend over time, with a larger difference in miRNA levels between cases and controls for earlier recurrence. Of these 12 miRNAs, 8 miRNAs significantly correlated with circulating transforming growth factor β1/2 (TGFβ1/2). Three of them correlated with platelet count. Conclusion We have identified 12 plasma miRNAs that may have the potential to serve as novel, non-invasive predictive biomarkers for VTE recurrence. Electronic supplementary material The online version of this article (10.1186/s13148-019-0627-z) contains supplementary material, which is available to authorized users.

Role of microRNAs in Venous Thromboembolism

“…Three years later, Sun et al (2020) [52] demonstrated that over-expression of miR-103a-3p by viral construct resulted in decreased venous thrombus formation in experimental DVT. Such finding reinforces the potential role of miR-103a-3p in the pathogenesis of VTE, since this miRNA has also been found to be downregulated in VTE patients in three different studies [52,54,55] as previously described (Table 2). Zhang et al (2020) [53] reported that intravenous administration of miR-338-5p mimics resulted in decreased interleukin-6 expression and venous thrombus formation.…”

“…It is noteworthy that among all miRNAs characterized in the fourteen studies described in Table 2, only six miRNAs were identified in more than one study. In the context of VTE, miR-532 [44,55], miR-320a [51,54], miR-320b [51,54], and miR-424-5p [45,54] were found to be upregulated, miR-103a-3p [52,54,55] was downregulated, and miR-27b yielded conflicting results, as it was up-and downregulated [50,55]. Several factors may account for the poor reproducibility among studies such as differences in clinical characteristics of participants, time from the occurrence of the thrombotic event to blood sampling, conditions of sample collection, sample processing (e.g., centrifugation speed and time) and storage, protocol used for RNA isolation, and methods for miRNA quantification and data normalization [20,58].…”

“…The study revealed that 5 miRNAs were upregulated, and 4 miRNAs were downregulated in VTE patients versus controls ( Table 2). Wang et al (2019) [55] were the first to examine whether circulating miRNAs were associated with recurrent VTE. The authors used a nested case-control study derived from the Malmö Thrombophilia Study, where the expression of miRNAs was quantified in plasma of 78 patients with unprovoked VTE two weeks after discontinuation of anticoagulation.…”

A Foundational Study for Normal F8-Containing Mouse Models for the miRNA Regulation of Hemophilia A: Identification and Analysis of Mouse miRNAs that Downregulate the Murine F8 Gene

“…A growing body of research studies have highlighted the important role of miRNAs in hemostasis and thrombosis [16][17][18][19]. Our previous studies have also demonstrated the dysregulation of some miRNAs in blood samples of HA patients compared to healthy controls and their direct interaction with human F8-mRNA [4,5].…”

Venous thromboembolism research priorities: A scientific statement from the American Heart Association and the International Society on Thrombosis and Haemostasis

“…16 Unbiased "omics" approaches that measure circulating microRNAs has identified candidates that are associated with VTE recurrence. 17 Metabolic screening has also shown potential to identify new biomarkers that influence VTE. 18,19 In sum, personalized approaches to treatment that integrate thrombus pathophysiology, circulating biomarkers, patient characteristics, and patient preferences require study.…”