Inherited thrombophilia and polygenic risk scores in venous thromboembolism: from classical testing to genomic risk...

Venous thromboembolism (VTE) is caused by the interaction between genetic, individually acquired, and environmental factors. The aim of this narrative review is to summarize advances in the research on genetic susceptibility to VTE and its recurrence, focusing on genome‑wide association study (GWAS)-derived polygenic risk scores (PRSs) and sequencing‑based approaches, and to discuss current barriers to their clinical implementation. Testing for the classical inherited thrombophilias, such as the deficiencies of natural anticoagulants (antithrombin, proteins C and S, the factor V Leiden variant, and the G20210A mutation of factor II) could improve risk stratification and therapeutic decision‑making in VTE, although their role in VTE management remains controversial. Over the last 2 decades, knowledge on genetic susceptibility to VTE progressed beyond the classical thrombophilias, thanks to the evolution from single‑gene Sanger sequencing to genome‑wide sequencing and next‑generation sequencing. GWASs have enabled the creation of PRSs combining the effects of multiple single‑nucleotide polymorphisms. PRSs could significantly improve VTE risk prediction beyond clinical factors. Integration of genetic and clinical data could improve predictive accuracy. In addition, combining GWAS with transcriptome‑wide association studies and Mendelian randomization has shown that genetic risk may change across different clinical presentations of VTE, and that recurrent VTE differs genetically and biologically from the initial event, being associated with genetic variants, such as those of kininogen 1 and fibrinogen. PRSs can stratify VTE risk beyond traditional factors in European‑ancestry cohorts; recurrence may have a partially distinct genetic / proteomic architecture. However, prospective clinical utility of these novel approaches to VTE risk stratification remains to be established, and integrating this advanced knowledge into clinical practice remains a future challenge in VTE management.