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% CI 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.