Tissue plasminogen activator, plasminogen activator inhibitor-1, and tissue plasminogen activator/plasminogen activator inhibitor-1 complex as risk factors for the development of a first stroke

Background and Purpose-Abnormalities in the fibrinolytic system have been a ssociated with an increased risk for stroke in a few studies. This study wa s designed to test whether plasma levels of tissue plasminogen activator (t PA), plasminogen activator inhibitor-1 (PAI-1), and tPA/PAI-1 complex could predict a first-ever stroke. Methods-The study was an incident case-control study nested within the Vast erbotten Intervention Program and the Northern Sweden Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) cohorts. In this study 108 first-ever stroke cases were defined according to the MONICA classificatio n, and 216 controls from the same cohort were randomly selected and matched for age, sex, sampling time, and geographic region. Results-Stroke occurred on average 30 months after the blood sampling date. The mean plasma concentration of tPA/PAI-1 complex was higher for the stro ke cases than for the controls (3.9 versus 3.0 mu g/L). In univariate regre ssion analysis, significantly higher odds ratios were found for the tPA/PAI -1 complex as continuous variable. When divided into quartiles, the odds ra tio was 2.74 for the highest: quartile compared with the lowest. In the mul tivariate model, the tPA/PAI-1 complex remained an independent predictor fo r stroke. Additionally, tPA mass: concentration quartiles 3 and 4 showed a significant association with all stroke as outcome. No association was foun d, however, for PAI-1. In subgroup analysis of cerebral hemorrhage (n=18), the mean tPA/PAI-1 complex level was higher for the cases than for the cont rols (4.8 versus 3.0 mu g/L), and in multivariate analysis: including all c ontrols (n=216), only tPA/PAI-1 complex remained significant. Conclusions-This prospective study shows that tPA/PAI-1 complex, a novel fi brinolytic marker, is independentry associated with the development of a fi rst-ever stroke, especially hemorrhagic stroke. This finding supports the h ypothesis that disturbances in fibrinolysis precede a cerebrovascular event .