Failure of peripheral arterial thrombolysis due to elevated plasminogen activator inhibitor type 1

To reduce the risk of intracerebral hemorrhage during thrombolytic therapy, a lower dose of tissue plasminogen activator (t-PA) or urokinase is used for acute peripheral arterial thrombi versus coronary thrombi. We hypothesized that elevated plasminogen activator inhibitor-1 (PAI-1) activity could neutralize infused t-PA or urokinase, resulting in lysis failure. Active PAI-1, active t-PA and total t-PA antigen were measured in 20 patients receiving t-PA, and active PAI-1 was measured in four patients receiving urokinase for acute peripheral arterial thrombosis. The 18 patients that successfully lysed their thrombi all had low active PAI-1 levels (10 +/- 19 pmol/l) during infusion of thrombolytic therapy, while six patients that failed to lyse their thrombi had high active PAI-1 levels (1533 +/- 1384 pmol/l, P = 0.00007) during infusion. Active t-PA levels during t-PA infusion were higher in the group that lysed their thrombi (536 +/- 423 pmol/l versus 42 +/- 45 pmol/l, P = 0.04) even though total t-PA levels were lower (1240 +/- 493 pmol/l versus 1956 +/- 709 pmol/l, P = 0.03). In the patients that failed to lysed their thrombi, > 95% of infused t-PA was neutralized by PAI-1. We conclude that elevated PAI-1 during acute peripheral arterial thrombolysis is associated with an increased risk of lysis failure due to reduced levels of circulating active t-PA or urokinase.