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

for the Regeneron Genetics Center, Eric Manderstedt, Christina Lind-Halldén, Christer Halldén, Johan Elf, Peter J. Svensson, Björn Dahlbäck, Gunnar Engström, Olle Melander, Aris Baras, Luca A. Lotta, Bengt Zöller

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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 PROC (protein C), PROS1 (protein S), and SERPINC1 (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 PROC, PROS1, and SERPINC1 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 PROC, PROS1, and SERPINC1 genes were more common than the rs1799963 variant but the conferred genetic risk was comparable with the rs6025 and rs1799963 variants.

Original languageEnglish
Article numbere023018
Pages (from-to)1-27
JournalJournal of the American Heart Association
Issue number4
Publication statusPublished - 2022-Feb-15

Swedish Standard Keywords

  • Cardiac and Cardiovascular Systems (30206)


  • epidemiology
  • genetics
  • natural anticoagulants
  • thrombophilia
  • venous thromboembolism
  • Anticoagulants
  • Protein C/genetics
  • Humans
  • Middle Aged
  • Risk Factors
  • Male
  • Protein S/genetics
  • Venous Thromboembolism/diagnosis
  • Thrombosis/complications
  • Antithrombins
  • Prothrombin
  • Female
  • Aged
  • Mutation
  • Thrombophilia/complications
  • Factor V/genetics
  • Cohort Studies


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