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.

1
Koster
T
Rosendaal
FR
de Ronde
H
Briët
E
Vandenbroucke
JP
Bertina
RM
Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study.
Lancet
342
1993
1503
2
Poort
SR
Rosendaal
FR
Reitsma
PH
Bertina
RM
A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.
Blood
88
1996
3698
3
Ridker
PM
Hennekens
CH
Lindpaintner
K
Stampfer
MJ
Eisenberg
PR
Miletich
JP
Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men.
N Engl J Med
332
1995
912
4
Landi G, Cella E, Martinelli I, Tagliabue L, Mannucci PM, Zerbi D: Arg506Gln mutation and cerebral ischemia in the young. Stroke 27:1697, 1996 (letter)
5
Rosendaal FR, Siscovick DS, Schwartz SM, Psaty BM, Raghunathan TE, Vos HL: A common prothrombin variant (20210 G → A) increases the risk of myocardial infarction in young women. Thromb Haemost 78:769, 1997 (abstr, suppl)
6
Franco FR, Trip MD, ten Cate H, Prins MH, Kastelein JJP, Reitsma PH: The prevalence of the 20210 G → A mutation in the 3′-untranslated region of the prothrombin gene in patients with premature coronary artery disease. Thromb Haemost 78:769, 1997 (abstr, suppl)
7
Frezzato
M
Tosetto
A
Rodeghiero
F
Validated questionnaire for the identification of previous personal or familial venous thromboembolism.
Am J Epidemiol
143
1996
1257
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