Promotion and Subsequent Inhibition of Plasminogen Activation after Administration of Intravenous Endotoxin to Normal Subjects

Abstract

To evaluate the effect of endotoxin on the fibrinolytic response, we administered Escherichia coli endotoxin (4 ng per kilogram of body weight) intravenously to 19 healthy volunteers and measured fibrinolytic proteins, protease inhibitors, neutrophil elastase, and von Willebrand factor in serial blood samples obtained over 24 hours. One hour after endotoxin administration, the level of tissue plasminogen activator (t-PA) antigen rose from 10 to 23 ng per milliliter, peaking at 52 ng per milliliter at three hours. The level of alpha 2-plasmin inhibitor-plasmin complexes increased sevenfold, peaking at three hours. Plasminogen-activator inhibitor-1 activity rose more slowly, from 7 U per milliliter to a maximum of 49 U per milliliter at five hours. The concentrations of neutrophil elastase and von Willebrand antigen were unchanged at one hour, increased approximately threefold by 3 hours, and remained elevated at 24 hours. None of these measures changed in a control group (n = 5) given intravenous saline instead of endotoxin. We studied t-PA functional activity in four subjects. The level of activity rose rapidly, from 1.2 ng per milliliter at base line to 8.3 ng per milliliter at one hour and 13.9 ng per milliliter at two hours; it was undetectable at three hours. This increase in plasminogen activator activity was abolished in vitro by incubation of t-PA with an antiserum specific for human t-PA, suggesting that t-PA may be directly responsible for plasmin generation in the response to endotoxin. We conclude from this study of healthy subjects that endotoxin activates the fibrinolytic system, beginning with release of t-PA in the blood within one hour. The early activation of plasmin by endotoxin may prevent thrombosis, and the increase in fibrinolysis is then offset by the release of plasminogen activator inhibitor.