Venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, is a common and potentially fatal condition characterized by a high risk of recurrence after discontinuation of anticoagulant therapy. While anticoagulation effectively reduces early recurrence, prolonged treatment exposes patients to an increased risk of bleeding complications. Determining which patients require extended therapy is therefore a major clinical challenge.
In this study, the authors analyzed the genetic determinants of VTE recurrence using data from eight large international cohorts, totaling more than 6,300 patients, of whom nearly 1,800 experienced a recurrence. Using a GWAS meta-analysis, the researchers identified a genetic locus significantly associated with recurrence risk in the overall population, located in the GPR149/MME gene. This locus is not associated with the risk of a first thromboembolic event, underscoring that the biological mechanisms underlying recurrence partly differ from those involved in the initial onset of the disease.
The researchers also showed that only two genetic loci classically associated with initial VTE (KNG1 and FGG) are also involved in recurrence. This dissociation reinforces the idea that recurrence constitutes a distinct biological phenotype shaped by specific mechanisms.
To further explore these results, the study combined Mendelian randomization analyses targeting hemostatic factors and circulating proteins. These analyses support a causal link between elevated plasma levels of coagulation factors such as Factor XI, Factor VIII, and von Willebrand factor, and an increased risk of recurrence. Conversely, higher levels of pro–interleukin-16 appear to be associated with a protective effect. The involvement of PCSK9, known for its role in lipid metabolism, further suggests unexpected biological mechanisms independent of cholesterol.
A central aspect of the study lies in analyses stratified by clinical subgroups. The authors identified eighteen molecular determinants specific to sex, the provoked or unprovoked nature of the first event, or the type of initial VTE. For example, a variant of the SLC4A1 gene is associated with a markedly increased risk of recurrence in patients who initially presented with pulmonary embolism, but not in those with deep vein thrombosis alone. These findings illustrate the strong biological heterogeneity of the disease and highlight the importance of stratified approaches.
This study provides an unprecedented mapping of the genetic and molecular bases of VTE recurrence. It paves the way for improved predictive models and more personalized patient management, taking into account not only clinical factors but also individual biological profiles.
Contact: jean-françois.deleuze@cea.fr