Modulation of the fibrinolytic system by major peripheral ischemia

A rat model was developed to investigate the effects of acute peripheral ischemia on the components of the fibrinolytic system.

Laparotomy was performed and ischemia was introduced by total aortic clamping at a subrenal position. Control animals underwent sham laparotomy alone. Plasma and tissue samples were collected for analysis at 30, 60, 90, and 120 minutes after operation.

Functional assays of rat plasma revealed a dramatic and transient increase in tissue-type plasminogen activator (tPA) activity within 30 minutes of the onset of ischemia. A simultaneous decline in plasminogen activator inhibitor activity was observed. Immunohistochemical analysis suggested this initial increase in tPA activity resulted primarily from the release of stored tPA from ischemic vascular tissues. Northern blot analysis revealed that both tPA and plasminogen activator inhibitor-1 messenger RNA levels were elevated at 60 to 120 minutes in well-perfused tissues distant from the ischemic insult.

Collectively, these data demonstrate that acute peripheral ischemia results in a rapid and transient increase in plasma fibrinolytic activity, concomitant with the early release of stored tPA from ischemic vascular tissues. In addition, peripheral ischemia appears to stimulate both tPA and plasminogen activator inhibitor-1 gene expression in well-perfused tissues at later time points, consistent with the existence of humoral mediators.