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The prevalence of elevated prothrombin (PT) in the absence of the G20210A mutation has not been studied in patients with cerebral ischemia. We carried out a case-control study of PT G20210A and PT activity in 49 adult patients aged 45 years or less, with TIA or ischemic stroke without cardiac embolism or large vessel disease, and 87 controls from a group of blood donors. Five patients were heterozygous for PT 20210A (OR=2.3, 95% CI: 0.6-8.0). Even after exclusion of individuals with the PT gene variant, the PT activity was significantly higher in patients than in controls (1.11 vs. 0.97, P=0.0003). The relative risk of cerebral ischemia in patients within the fourth quartile of PT activity (1.10 U/ml or higher), was 3.2 fold (95% CI: 1.03-9.96), than in patients whose level of PT activity was in the second or third quartile. We conclude that, although PT 20210A may be a weak risk factor for TIA and ischemic stroke in young patients, increased PT activity, which is more frequent than the mutation, appears to be more strongly related to cerebral ischemia.