Expanding the genetic landscape of hereditary thrombophilia: classical defects, novel variants, and genomic perspectives. A narrative review

Hereditary thrombophilia encompasses a spectrum of genetic conditions predisposing to venous thromboembolism (VTE). Traditionally, it has been attributed to a limited number of well-defined defects, including deficiencies of natural anticoagulants—antithrombin, protein C, and protein S—and two common gain-of-function mutations, Factor V Leiden and prothrombin G20210A. These classical abnormalities remain clinically relevant but explain only a minority of early-onset, recurrent, or familial cases. Advances in molecular genetics have uncovered a broader landscape of inherited susceptibility. Next-generation sequencing, whole-exome sequencing, and genome-wide association studies have identified rare and population-specific variants in genes such as SERPINC1, PROS1, F2, and F5, as well as regulatory and intronic changes influencing coagulation pathways. Additional contributors include elevated factor VIII, IX, or XI levels, fibrinogen structural variants, and abnormalities in fibrinolytic regulators such as TAFI and PAI-1. Beyond single-gene defects, evidence supports a polygenic model in which multiple low-effect alleles and modifier genes act synergistically with environmental triggers to determine thrombotic risk. This expanding genetic and functional complexity challenges the traditional binary concept of thrombophilia. Integrating genomic tools into clinical evaluation—while avoiding indiscriminate testing—may improve risk stratification in selected patients, particularly those with strong family history or unusual thrombotic phenotypes. Hereditary thrombophilia should therefore be regarded as a continuum of genetic predisposition rather than a categorical disorder, calling for a refined, personalized approach to prevention and management of VTE in the genomic era.