Plasma Levels of Tissue Plasminogen Activator/Plasminogen Activator Inhibitor-1 Complex and von Willebrand Factor Are Significant Risk Markers for Recurrent Myocardial Infarction in the Stockholm Heart Epidemiology Program (SHEEP) Study

Abstract

Abstract-An impaired fibrinolytic function due to elevated plasma levels of plasminogen activator inhibitor (PAI)-1 activity or tissue plasminogen activator (tPA) antigen is correlated with the development of myocardial infarction (MI) in patients with manifest coronary heart disease. Recently, methods for determining the specific tPA/inhibitor complexes constituting tPA antigen in plasma have become available. In the Stockholm Heart Epidemiology Program (SHEEP) study, 86 of 1212 MI patients, subjected to blood sampling in a metabolically stable period, suffered reinfarction before the end of 1996. These individuals have been compared with an approximately equal number of matched MI patients without recurrence and a group of matched healthy control subjects regarding the plasma concentrations of some hemostatic factors. The hemostatic compounds studied (fibrinogen, von Willebrand factor, tPA antigen, PAI-1, and the tPA/PAI-1 complex) were typically higher in the groups (men and women) with recurrence of MI compared with those without. The plasma concentrations were also typically higher in the pooled groups of patients compared with the groups of healthy control subjects. The largest between-group differences were found for the plasma tPA/PAI-1 complex. The crude odds ratio for reinfarction associated with higher concentration (Ն75th percentile among the control subjects) of tPA/PAI-1 was 1.8 (95% CI 1.1 to 3.1); the corresponding crude odds ratio for von Willebrand factor was 2.3 (1.3 to 4.0). The tPA/PAI-1 complex correlated strongly with PAI-1 and tPA antigen in all groups and with serum triglycerides and body mass index in all groups except for women with reinfarction. An increased plasma level of tPA/PAI-1 complex is a novel risk marker for recurrent MI in men and women. Most likely, increased plasma levels of tPA/PAI-1 complex reflect impaired fibrinolysis, because the correlation with PAI-1 is strong. Further support is obtained indicating that the plasma concentration of von Willebrand factor is also an important risk marker for recurrent MI. Key Words: fibrinolysis Ⅲ hemostasis Ⅲ myocardial infarction Ⅲ risk markers A decreased fibrinolytic activity, which is either due to an increased plasma concentration of plasminogen activator inhibitor (PAI)-1 1-4 or an impaired function to release tissue plasminogen activator (tPA) on exercise, 3 has been demonstrated to be connected to an increased risk of myocardial infarction in studies with prospective designs. The plasma concentration of tPA antigen, which typically correlates well with PAI-1 activity rather than with tPA activity, has turned out to be an even stronger predictor of myocardial infarction. 3,5,6 Only a minor portion of the tPA in plasma is functionally active. The major portion involves tPA in complex with various inhibitors, such as PAI-1, anti-plasmin, and C1 inhibitor. We have recently developed 2-site ELISA methods to specifically measure these complexes in plasma. 7 It was found that tPA antigen correlated strongly with the tPA/PAI-1 compl...

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