Molecular clues to venous thromboembolism recurrence Free

In this issue of Blood, Munsch et al¹ present the largest genomic analysis of venous thromboembolism (VTE) recurrence to date, identifying 28 molecular markers and offering new insight into the molecular drivers of VTE relapse.

Despite major advances in anticoagulant therapy, the prevention of recurrent VTE remains an imprecise science. After a first-time unprovoked VTE event, clinicians are routinely challenged to weigh the bleeding risk associated with continuing anticoagulation against the potential for VTE recurrence, if anticoagulation is stopped. Current guidelines favor extended anticoagulation therapy for unprovoked VTE, sometimes using reduced-dose anticoagulation, yet some patients treated indefinitely may never experience another event.^2,3 Munsch et al present compelling genomic evidence that inherited variants—and the proteins they influence—contribute to the risk of VTE recurrence, laying the groundwork for a more personalized approach to secondary prevention of VTE.

Leveraging data from 6355 individuals with a first VTE—1775 of whom experienced VTE recurrence—the authors conducted a genome-wide association study (GWAS) meta-analysis across 8 prospective cohorts of European ancestry; each cohort consisted of patients with a first VTE who completed a course of anticoagulation of variable duration, then discontinued anticoagulation and were followed for the development of subsequent VTE. In addition to GWAS, the authors supplemented their analysis by transcriptome-wide association studies (TWAS) and Mendelian randomization (MR). Using this multilayered approach, the authors identified 28 molecular markers associated with VTE recurrence, including 1 novel gene locus (GPR149). The authors further utilized MR, a methodology in which genetic variants corresponding to modifiable exposures (eg, biochemical markers or physiological traits) are analyzed with respect to clinical outcomes; the power of MR lies in its ability to test whether such exposures causally influence disease risk, offering a way to move from association to inference.⁴ MR analyses further identified 7 proteins as putative causal mediators of VTE recurrence: elevated levels of factor XI, factor VIII, von Willebrand factor, histo-blood group A transferase (BGAT), and Golgi membrane protein 2 were associated with increased VTE recurrence risk, whereas higher levels of PCSK9 and prointerleukin 16 were associated with reduced VTE risk. These findings offer mechanistic insight and nominate potentially targetable pathways for prevention of recurrent VTE.

The study findings revolutionize our understanding of VTE and VTE recurrence in fundamental ways. Historically, it has long been debated whether inherited genetic thrombophilias (eg, factor V Leiden, prothrombin gene mutation, and deficiencies of antithrombin, protein C, and protein S) are associated with VTE recurrence.⁵ In the study by Munsch et al, a fascinating observation was that among previously established genetic and biochemical markers associated with first VTE, only 2 genetic markers (KNG1 and FGG) and 4 genetically-determined protein levels (factor XI, BGAT, von Willebrand factor, and factor VIII) were also linked to VTE recurrence. This would suggest that the risk of recurrent VTE is genetically and biologically distinct from initial VTE risk, shattering existing paradigms of VTE.

The study also explored how genetic risk may diverge across different clinical presentations of VTE. In subgroup analyses, 18 molecular markers were identified as being associated with VTE recurrence only in specific clinical contexts such as sex, provoked or unprovoked VTE status, or the type of initial VTE. For instance, the exonic variant SLC4A1 p.Glu40Lys was associated with a threefold increased risk of recurrence in patients with pulmonary embolism (PE) but not in those with deep venous thrombosis (DVT)—an intriguing signal that reinforces the emerging notion that PE and DVT may diverge at the molecular level, complementing earlier findings from plasma proteomic analyses of first VTE.⁶ These stratified findings underscore the heterogeneity of VTE recurrence and point to future opportunities for more tailored risk prediction.

Methodologically, the study by Munsch et al stands out for its scale and rigor. By integrating GWAS, TWAS, and MR, the authors move beyond statistical association toward biological inference. With over 6000 participants, this represents the largest GWAS of VTE recurrence to date—a meaningful improvement over prior efforts that were constrained by smaller sample sizes and inconsistent outcome definitions. Their decision to model time to recurrence from anticoagulant discontinuation mirrors real-world clinical decision-making and increases the relevance of their findings.

Still, questions remain about how to translate these findings into clinical practice. Existing tools for predicting VTE recurrence—such as HERDOO2,⁷ DASH,⁸ and L-TRRiP⁹—primarily rely on clinical and laboratory features, incorporating only limited genetic data, often restricted to single variants like factor V Leiden. Incorporating more comprehensive genomic data, either by refining existing tools or by developing new integrative models, may improve individualized risk prediction and future risk assessment strategies, but such approaches will require large-scale prospective validation.

Importantly, the study population was composed entirely of individuals of European ancestry, a limitation the authors acknowledge. Given population-level differences in allele frequencies and linkage disequilibrium structure, the generalizability of these findings is uncertain. Broader efforts to include ancestry-diverse cohorts—such as through the All of Us Research Program or global biobank consortia—will be critical to ensuring equity in the development and application of genomic risk tools.¹⁰ 

Ultimately, Munsch et al bring us closer to an era in which inherited risk informs not just who is at risk for a first clot, but who remains vulnerable after a clot has already occurred.¹ Their findings challenge the conventional wisdom that thrombophilia testing is of limited utility and suggest instead that genetics—when scaled appropriately and interpreted through robust analytic frameworks—can illuminate pathways of disease progression, identify potential therapeutic targets, and guide secondary VTE prevention. As the tools of genomic medicine become more accessible, the question is increasingly not whether we can personalize anticoagulation decisions in VTE, but how best to do so with an expanding landscape of big data.

Conflict-of-interest disclosure: The authors declare no competing financial interests.