SUMMARY
Venous thromboembolism (VTE) is a prevalent condition with a significant acute and long-term morbidity and results from a complex interaction between genetic and environmental risk factors. About half of VTE cases are unprovoked, suggesting an underlying thrombophilia. Nevertheless, conventional thrombophilia tests, which assess deficiencies in antithrombin, protein C, and protein S, and the presence of the prothrombotic factor V Leiden and prothrombin G20210A variants, identify an underlying inherited predisposition in about 40% of VTE cases. These tests lack specificity for VTE and mostly fail to guide therapeutic decisions. Over the past decade, multi-gene panels utilising high-throughput sequencing have been developed to rapidly analyse a preselected set of VTE-risk genes of which most are involved in (anti)coagulation. Initial studies show that these panels can identify variants missed by conventional testing in approximately 40% of both patients with positive and negative thrombophilia workups. However, only about 10% of VTE patients carry previously undetected (likely) pathogenic variants that are of immediate relevance for counselling. The high prevalence of variants of uncertain significance (VUS) and oligogenic variants complicate data interpretation. Further research is necessary to characterise and reclassify these VUS and to evaluate the therapeutic implications of multi-gene panel testing.
(BELG J HEMATOL 2025;16(4):146–51)
