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The 1691 G-->A mutation in the factor V gene: relationship to activated protein C (APC) resistance and thrombosis in
C Leroy-Matheron1, M Levent, J M Pignon
1Unité d'Hémostase et de Thrombose, Centre Hospitalier et Universitaire Henri Mondor, Créteil, France.
Insights
The factor V 1691 G-->A mutation is linked to thrombosis, but its association with activated protein C (APC) resistance is incomplete. Homozygosity for this mutation presents a milder thrombotic risk compared to deficiencies in protein C or S.
Area of Science:
- Genetics
- Hematology
- Thrombosis
Background:
- The 1691 G-->A mutation in the factor V gene is a known risk factor for thrombosis.
- Activated protein C (APC) resistance is often associated with this mutation, but the relationship is not fully understood.
Purpose of the Study:
- To investigate the relationship between the factor V 1691 G-->A mutation, APC resistance, and thrombosis.
- To compare the clinical manifestations and thrombotic risk associated with this mutation to deficiencies in protein C (PC) and protein S (PS).
Main Methods:
- Screening 450 subjects for the factor V 1691 G-->A mutation.
- Assessing APC resistance in subjects with and without the mutation.
- Measuring prothrombin fragment 1 + 2 and D-dimers to evaluate thrombin generation.
- Comparing clinical data of mutation carriers with PC- and PS-deficient patients.
Main Results:
- The mutation was found in 65 of 450 subjects (14.4%), with a 13% prevalence in thrombotic patients.
- Incomplete cosegregation of heterozygosity for the mutation with APC resistance was observed.
- Elevated prothrombin fragment 1 + 2 and D-dimers indicated increased thrombin generation in mutation carriers.
- Heterozygous subjects experienced their first thrombotic event later than PC- or PS-deficient patients.
- Homozygosity for the mutation appeared to be a less severe thrombotic condition than homozygous PC or PS deficiencies.
Conclusions:
- The factor V 1691 G-->A mutation is prevalent in patients with unexplained thrombosis.
- Functional APC resistance assays alone are insufficient for diagnosing the condition due to incomplete cosegregation.
- The mutation is associated with increased thrombin generation and a thrombotic risk profile distinct from PC/PS deficiencies.
- Homozygosity for the factor V mutation represents a relatively benign thrombotic disorder.
Abstract:
Four hundred fifty subjects were screened for the 1691 G-->A mutation in the factor V gene. Two hundred ninety-seven patients were referred to us for unexplained thrombosis, 133 were family members of these patients and 20 were normal subjects. We studied the relationships between the mutation, resistance to APC and thrombosis. Among the 450 subjects tested, 65 belonging to 42 families were found to have the 1691 G-->A mutation in one (n = 61) or both alleles (n = 4). The prevalence of the mutation in the thrombotic patients was 13%. Resistance to APC was tested for in 247 subjects not on anticoagulant treatment (4 homozygous and 44 heterozygous for the mutation, and 199 individuals without the mutation). Incomplete cosegregation of heterozygosity for the 1691 G-->A mutation with APC resistance (APC-SR < 2.4 or n-APC-SR < 0.75) was observed, showing that the functional assay alone is insufficient for a firm diagnosis. In patients carrying the mutation, elevated levels of prothrombin fragment 1 + 2 and D-dimers pointed to increased thrombin generation in vivo. Clinical manifestations in the heterozygous subjects were very similar to those reported in heterozygous PC or PS deficiencies, but the first thrombotic event occurred later than in PC- or PS-deficient patients. Homozygosity for the factor V gene mutation appears to be a far more benign thrombotic disorder than homozygous PC and PS deficiencies.