PAI-1-RESISTANT T-PA - LOW-DOSES PREVENT FIBRIN DEPOSITION IN RABBITSWITH INCREASED PAI-1 ACTIVITY

The present study compared the activities of recombinant tissue-type p lasminogen activator (t-PB) and a plasminogen activator inhibitor-1 (P AI-1)-resistant variant t-PA (Kt-PA, KHRR 296-299 AAAA) in preventing renal fibrin deposition in rabbits with elevated PAI-1 activity. In th is model, all rabbits were infused with endotoxin (10 mu g/kg), follow ed by initiation of thrombin (130 U/kg) 4 hours later, when plasma PAI -1 activity was greater than 200 arbitrary units (AU)/mL (baseline, <3 AU/mL. Thirty minutes after completion of the 1-hour thrombin infusio n, rabbits were killed and the kidneys fixed and stained for identific ation of fibrin deposition. Rabbits received one of the following trea tments initiated 30 minutes before thrombin and continued during the 1 -hour thrombin infusion: (1) saline (n = 7); (2) low-dose t-PA (17 mu g/kg, n = 4); (3) higher-dose t-PA (170 mu g/kg, n = 4); or (4) low-do se Kt-PA (17 mu g/kg, n = 6). Fibrin deposition occurred in 86% and 10 0% of the rabbits receiving saline or low-dose t-PA, respectively. Fib rin deposition did not occur in any of the rabbits receiving low-dose Kt-PA or higher-dose t-PA. Low-dose Kt-PA and higher dose t-PA also ca used a reduction in fibrin deposition when infused after thrombin admi nistration had been completed. The data provide in vivo evidence that Kt-PA is more effective than t-PA in preventing fibrin deposition in a n animal model that combines thrombogenic stimulation with increased P AI-1 activity. This is a US government work. There are no restrictions on its use.