MODULATION OF THE FIBRINOLYTIC SYSTEM BY MAJOR PERIPHERAL ISCHEMIA

Purpose: A rat model was developed to investigate the effects of acute peripheral ischemia on the components of the fibrinolytic system. Met hods: Laparotomy was performed and ischemia was introduced by total ao rtic clamping at a subrenal position. Control animals underwent sham l aparotomy alone. Plasma and tissue samples were collected for analysis at 30, 60, 90, and 120 minutes after operation. Results: Functional a ssays of rat plasma revealed a dramatic and transient increase in tiss ue-type plasminogen activator (tPA) activity within 30 minutes of the onset of ischemia. A simultaneous decline in plasminogen activator inh ibitor activity was observed. Immunohistochemical analysis suggested t his initial increase in tPA activity resulted primarily from the relea se of stored tPA from ischemic vascular tissues. Northern blot analysi s revealed that both tPA and plasminogen activator inhibitor-1 messeng er RNA levels were elevated at 60 to 120 minutes in well-perfused tiss ues distant from the ischemic insult. Conclusions: Collectively, these data demonstrate that acute peripheral ischemia results in a rapid an d transient increase in plasma fibrinolytic activity, concomitant with the early release of stored tPA from ischemic vascular tissues. In ad dition, peripheral ischemia appears to stimulate both tPA and plasmino gen activator inhibitor-1 gene expression in well-perfused tissues at later time points, consistent with the existence of humoral mediators.