Historical Review: More Than Two Decades Understanding The Genetic Architecture of Hemostasis and Thrombosis

Authors: Sabater-Lleal, M; Thibord, F; Vries, PS de; Huffman, J; Wolberg, AS; Lowenstein, CJ; Morrison, AC; Johnson, AD; Smith, NL

Affiliations: Unit of genomics of Complex Disease, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona,Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; Cardiology Unit, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden. University of Bordeaux, INSERM, Bordeaux Population Health Research Center (UMR 1219), Bordeaux, France. Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA. Palo Alto VA Institute for Research, VA Palo Alto Heath Care System, Palo Alto, CA; MAVERIC, VA Boston Healthcare System, Boston, MA. Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina at Chapel Hill, NC, USA. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA. National Heart Lung and Blood Institute, Division of Intramural Research, Population Sciences Branch, The Framingham Heart Study, Framingham, MA, USA. Department of Epidemiology, University of Washington, Seattle, WA, USA; Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA, USA; Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, WA, USA.

Publication: Journal of thrombosis and haemostasis : JTH ; 2025

ABSTRACT: From the beginning of the millennium and the development of genome-wide analyses, the technical advances and remarkable increase in research sample sizes have led to an escalating number of discoveries revealing genetic determinants of levels of the main factors regulating hemostasis and thrombosis, and demonstrating a clear polygenic complex regulation of most coagulation factors. These discoveries have been useful to understand the biology underlying hemostasis regulation, and to understand risk of associated thrombotic disease, such as venous thromboembolism, coronary artery disease, and ischemic stroke. In this historical review, we outline the main discoveries in genetic studies of coagulation factors (fibrinogen and its alternatively spliced γ’ isoform, D-dimer, factor V, factor VII, factor VIII, von Willebrand factor, and factor XI), the main natural anticoagulants (protein C, protein S, antithrombin), components of fibrinolysis (tissue plasminogen activator [tPA, plasminogen activator inhibitor-1 [PAI-1]), and global coagulation tests (prothrombin time [PT], activated partial thromboplastin time [aPTT]). We explore the clinical implications of these discoveries and suggest new avenues for future investigation.