Few haematological or lipid risk factors have been identified for stroke, by contrast with coronary heart disease. To find out whether a marker of endogenous fibrinolytic function might be associated with stroke risk, we measured tissue plasminogen activator (tPA) antigen concentrations in baseline plasma samples from 88 healthy participants in the Physicians' Health Study who subsequently had first-ever strokes (71 thromboembolic,12 haemorrhagic, 5 indeterminate) and from 471 participants who remained free of cardiovascular disease during 5 years of follow-up (controls). Mean baseline tPA concentrations were significantly higher among men who later had strokes than in the controls (11 14 [SE 0·80] vs 9·59 [0·27] ng/mL, p=0 03). The difference was largely due to an excess of abnormally high values among stroke cases. The age-adjusted relative risk for stroke among men with baseline tPA concentrations above the 95th percentile of the control distribution was 3 51 (95% Cl 1 72-7·17, p=0 0006) for total stroke and 3 89 (1·83-8 26, p = 0 0004) for thromboembolic stroke. These findings did not change substantially in analyses that also controlled for stroke risk factors (high blood pressure, body-mass index, smoking, presence of diabetes, and parental history of myocardial infarction) or the plasma lipid profile. This prospective study shows that high concentrations of tPA antigen among apparently healthy men are independently associated with high risks of future stroke, especially thromboembolic stroke. This finding is consistent with the hypothesis that activation of the endogenous fibrinolytic system occurs years in advance of arterial vascular occlusion.
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