Reviews
Vol. 5 No. 3 (2026): In memory of Armando D’Angelo
https://doi.org/10.4081/btvb.2026.427

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

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Published: 28 August 2026
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hereditary thrombophilia, venous thromboembolism, genetic predisposition

Authors

Chiara Simion
chiara.simion@unipd.it
Department of Medicine, University of Padua; First Division of Internal Medicine, University Hospital of Padua, Italy.
Elena Campello
Department of Medicine, University of Padua; First Division of Internal Medicine, University Hospital of Padua, Italy.
Walter Ageno
Department of Medicine, University of Padua; Emergency Medicine Unit, University Hospital of Padua, Italy.
Paolo Simioni
Department of Medicine, University of Padua; First Division of Internal Medicine, University Hospital of Padua, Italy.

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.

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Ethics Approval

Ethical approval was not required for this study, as this article is a narrative review based exclusively on previously published literature and did not involve human participants, animals, or identifiable patient data.

CRediT authorship contribution

CS conceived the review, performed the literature search, drafted the manuscript, and prepared 5 s and graphical abstract. EC and WA contributed to the conceptual framework of the review and critically revised the manuscript. PS supervised the work, contributed to the interpretation of the literature, and critically revised the manuscript. All authors read and approved the final manuscript.

Supporting Agencies

none

Data Availability Statement

No new datasets were generated or analyzed during the current study. All data supporting the findings of this review are available in the cited literature.

How to Cite



1.
Simion C, Campello E, Ageno W, Simioni P. Expanding the genetic landscape of hereditary thrombophilia: classical defects, novel variants, and genomic perspectives. A narrative review. Bleeding Thromb Vasc Biol [Internet]. 2026 Aug. 28 [cited 2026 Aug. 28];5(3). Available from: https://www.btvb.org/btvb/article/view/427
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