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Factor V Leiden (FV R506Q) in families with inherited antithrombin deficiency
H H van Boven1, P H Reitsma, F R Rosendaal
1Department of Clinical Epidemiology, University Hospital Leiden, The Netherlands.
Insights
The factor V Leiden mutation significantly increases thrombosis risk in individuals with antithrombin deficiency, especially when inherited together. This combined genetic risk leads to earlier onset of thrombotic events.
Area of Science:
- Genetics
- Hematology
- Molecular Biology
Background:
- Antithrombin deficiency is a known risk factor for thrombosis.
- Activated protein C resistance, caused by the factor V R506Q mutation (factor V Leiden), is another significant thrombophilia risk factor.
- The interplay between these two genetic defects in families with thrombophilia requires further investigation.
Purpose of the Study:
- To investigate the prevalence of the factor V Leiden mutation in families with antithrombin deficiency.
- To determine the inheritance patterns and clinical relevance of combined antithrombin deficiency and factor V Leiden mutation.
- To assess the impact of combined genetic defects on thrombotic risk and age of onset.
Main Methods:
- Genotyping for the factor V R506Q mutation in probands and relatives from families with antithrombin deficiency.
- Segregation analysis of both antithrombin and factor V genes within families.
- Clinical data collection on thrombosis history and age of onset.
Main Results:
- The factor V mutation was identified in 18 out of 128 families with antithrombin deficiency.
- Co-segregation of both defects on the same chromosome was observed in four families, suggesting a strong genetic linkage.
- Individuals with both antithrombin deficiency and factor V Leiden mutation experienced thrombosis at a significantly younger median age (16 years) compared to those with only antithrombin deficiency (26 years).
Conclusions:
- The factor V Leiden mutation is a crucial additional risk factor for thrombosis in individuals with antithrombin deficiency, particularly when thrombosis occurs at a young age.
- Co-segregation of these genetic mutations provides a molecular basis for severe, familial thrombophilia.
- Combinations of genetic risk factors explain variations in thrombotic risk within families.
Abstract:
We investigated the presence of the gene mutation of factor V, FV R506Q or factor V Leiden, responsible for activated protein C resistance, in DNA samples of 127 probands and 188 relatives from 128 families with antithrombin deficiency. The factor V mutation was identified in 18 families. Nine families were available to assess the mode of inheritance and the clinical relevance of combined defects. The factor V and antithrombin genes both map to chromosome 1. Segregation of the defects on opposite chromosomes was observed in three families. Co-segregation with both defects on the same chromosome was demonstrated in four families. In one family a de novo mutation of the antithrombin gene and in another a crossing-over event were the most likely explanations for the observed inheritance patterns. In six families with type I or II antithrombin deficiency (reactive site or pleiotropic effect), 11 of the 12 individuals with both antithrombin deficiency and the factor V mutation developed thrombosis. The median age of their first thrombotic episode was 16 years (range 0-19); this is low compared with a median age of onset of 26 years (range 20-49) in 15 of 30 carriers with only a defect in the antithrombin gene. One of five subjects with only factor V mutation experienced thrombosis at 40 years of age. In three families with type II heparin binding site deficiencies, two of six subjects with combined defects experienced thrombosis; one was homozygous for the heparin binding defect. Our results show that, when thrombosis occurs at a young age in antithrombin deficiency, the factor V mutation is a likely additional risk factor. Co-segregation of mutations in the antithrombin and factor V genes provides a molecular explanation for severe thrombosis in several generations. The findings support that combinations of genetic risk factors underly differences in thrombotic risk in families with thrombophilia.