Classic Thrombophilias and Thrombotic Risk Among Middle‐Aged and Older Adults: A Population‐Based Cohort Study

• Published in: Journal of the American Heart Association Vol. 11; no. 4; p. e023018
• Main Authors: Manderstedt, Eric, Lind‐Halldén, Christina, Halldén, Christer, Elf, Johan, Svensson, Peter J., Dahlbäck, Björn, Engström, Gunnar, Melander, Olle, Baras, Aris, Lotta, Luca A., Zöller, Bengt, Abecasis, Goncalo, Cantor, Michael, Coppola, Giovanni, Economides, Aris, Lotta, Luca A, Overton, John D, Reid, Jeffrey G, Shuldiner, Alan, Beechert, Christina, Forsythe, Caitlin, Fuller, Erin D, Gu, Zhenhua, Lattari, Michael, Lopez, Alexander, Schleicher, Thomas D, Padilla, Maria Sotiropoulos, Widom, Louis, Wolf, Sarah E, Pradhan, Manasi, Manoochehri, Kia, Ulloa, Ricardo H, Bai, Xiaodong, Balasubramanian, Suganthi, Blumenfeld, Andrew, Boutkov, Boris, Eom, Gisu, Habegger, Lukas, Hawes, Alicia, Khalid, Shareef, Krasheninina, Olga, Lanche, Rouel, Mansfield, Adam J, Maxwell, Evan K, Nafde, Mrunali, O’Keeffe, Sean, Orelus, Max, Panea, Razvan, Polanco, Tommy, Rasool, Ayesha, Salerno, William, Staples, Jeffrey C, Jones, Marcus B, Mighty, Jason, Mitnaul, Lyndon J
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 15.02.2022; Wiley
• Subjects: Aged; Anticoagulants; Antithrombins; Cardiology and Cardiovascular Disease; Clinical Medicine; Cohort Studies; epidemiology; Factor V - genetics; Female; genetics; Humans; Kardiologi och kardiovaskulära sjukdomar; Klinisk medicin; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Middle Aged; Mutation; natural anticoagulants; Original Research; Protein C - genetics; Protein S - genetics; Prothrombin; Risk Factors; thrombophilia; Thrombophilia - complications; Thrombosis - complications; Thrombosis - epidemiology; Thrombosis - genetics; venous thromboembolism; Venous Thromboembolism - diagnosis; Venous Thromboembolism - epidemiology; Venous Thromboembolism - genetics; epidemiology; thrombophilia; genetics; venous thromboembolism; natural anticoagulants
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.121.023018

Background Five classic thrombophilias have been recognized: factor V Leiden (rs6025), the prothrombin G20210A variant (rs1799963), and protein C, protein S, and antithrombin deficiencies. This study aimed to determine the thrombotic risk of classic thrombophilias in a cohort of middle-aged and older adults. Methods and Results Factor V Leiden, prothrombin G20210A and protein-coding variants in the (protein C), (protein S), and (antithrombin) anticoagulant genes were determined in 29 387 subjects (born 1923-1950, 60% women) who participated in the Malmö Diet and Cancer study (1991-1996). The Human Gene Mutation Database was used to define 68 disease-causing mutations. Patients were followed up from baseline until the first event of venous thromboembolism (VTE), death, or Dec 31, 2018. Carriership (n=908, 3.1%) for disease-causing mutations in the , , and genes was associated with incident VTE: Hazard ratio (HR) was 1.6 (95% CI, 1.3-1.9). Variants not in Human Gene Mutation Database were not linked to VTE (HR, 1.1; 95% CI, 0.8-1.5). Heterozygosity for rs6025 and rs1799963 was associated with incident VTE: HR, 1.8 (95% CI, 1.6-2.0) and HR, 1.6 (95% CI, 1.3-2.0), respectively. The HR for carrying 1 classical thrombophilia variant was 1.7 (95% CI, 1.6-1.9). HR was 3.9 (95% CI, 3.1-5.0) for carriers of ≥2 thrombophilia variants. Conclusions The 5 classic thrombophilias are associated with a dose-graded risk of VTE in middle-aged and older adults. Disease-causing variants in the , , and genes were more common than the rs1799963 variant but the conferred genetic risk was comparable with the rs6025 and rs1799963 variants.