The Transition G to A at Position 20210 in the 3′-Untranslated Region of the Prothrombin Gene Is Not Associated With Cerebral Ischemia

To the Editor:

A large population-based case-control study, the Leiden Thrombophilia Study, has shown the association of two different inherited coagulation defects with venous thromboembolism: a mutation in the factor V gene (factor V:Q506), that renders activated factor V partially resistant to the inactivation by activated protein C¹ and, more recently, a mutation in the 3′-untranslated region of prothrombin (G to A at position 20210), that leads to high levels of prothrombin in plasma.2 Carriers of either defect are at increased risk for venous thromboembolism, estimated to be up to sevenfold for factor V:Q5061 and threefold for the 20210 AG genotype.1 The prevalence of factor V:Q506 among healthy individuals was twice higher than that of the 20210 AG genotype (5% and 2.3%).

No association between factor V:Q506 and arterial thrombosis (stroke and acute myocardial infarction) was found in a large prospective cohort study of men over 40 years of age.3 Lack of association was also demonstrated for cerebral ischemia in the young (aged 45 years or less), even though the possibility of a pathogenetic role of the mutation in a subgroup of patients with stroke of undetermined cause cannot be ruled out.4 Preliminary data on the association between the 20210 AG genotype and manifestations of arterial thrombosis such as acute myocardial infarction5 and peripheral arterial disease6 would suggest that carriers of the mutation are at an increased risk of developing arterial disease. To establish whether or not the 20210 AG genotype is associated with cerebral ischemia, and to see whether there is interaction between this mutation and factor V:Q506, we performed a retrospective case-control study on 155 consecutive patients with stroke or transient ischemic attacks (men/women: 85/70; mean age ± SD, 43 ± 13) and 155 healthy subjects matched by sex and age (±5 years). The study was designed as to have a power of 80% to detect an odds ratio of 4.0. All the patients with focal cerebral ischemia had been examined by an expert neurologist who evaluated their history, clinical documentation, and the presence of cerebrovascular risk factors. Previous thrombotic episodes were excluded in healthy subjects using a structured validated questionnaire.7 The prevalence of the 20210 AG genotype was 3.8% in patients and 3.2% in controls (odds ratio [OR], 1.2; 95% confidence interval [CI], 0.4 to 4.0), and that of factor V:Q506 was 3.2% in patients and 1.3% in controls (OR, 2.5; 95% CI, 0.5 to 13.4). The prevalence did not substantially change considering the 96 patients who developed cerebral ischemia at a young age (4.2% for both the 20210 AG genotype and factor V:Q506; OR 1.3, 95% CI 0.3 to 5.0 for the 20210 AG genotype, and OR 3.3, 95% CI 0.6 to 18.5 for factor V:Q506) and the remaining 59 patients in whom the disease developed at an older age (3.4%, OR 1.1, 95% CI 0.2 to 5.6 for the 20210 AG genotype, and 1.7%, OR 1.3, 95% CI 0.1 to 14.8 for factor V:Q506). In only two patients with the 20210 AG genotype (one third of the carriers) cerebral ischemia was of undetermined cause. There were no patients or controls carrying both the mutations. In conclusion, our data show the lack of association between the transition G to A at position 20210 of the prothrombin gene and cerebral ischemia. As for factor V:Q506, the prevalence of the 20210 AG genotype was similar in patients and in healthy individuals, suggesting that at no age the newly identified inherited prothrombotic defect is associated with an increased risk of the disease.