THE ROLE OF TYPE-1 PLASMINOGEN-ACTIVATOR INHIBITOR IN FAILURE OF THROMBOLYTIC THERAPY WITH RECOMBINANT TISSUE-PLASMINOGEN ACTIVATOR

We investigated the possible role of type-1 plasminogen activator inhi bitor (PAI-1) on success or failure of thrombolytic therapy with recom binant tissue plasminogen activator (rt-PA) in 10 responders and 10 no n-responders with acute myocardial infarction and early initiation of therapy within 2 h of onset using the common infusion scheme (100 mg r t-PA over 3 h). We determined plasma levels of t-PA (activity and anti gen) as well as PAI-1 (activity and antigen) in samples obtained befor e, during and after thrombolytic treatment and compared the course of each of those parameters between responders and non-responders to ther apy. Success or failure of treatment was determined by a combination o f noninvasive methods and proven by coronary angiography within 5 days of initiation of thrombolysis. Thirty, 60, 90, and 120 min after init iation of rt-PA infusion, specific t-PA activities in plasma of respon ders were 0.62, 0.63, 0.62, and 0.57 (IU/ng/ml), respectively, as comp ared to 0.42, 0.42, 0.40, and 0.32 (IU/ng/ml) in nonresponders (p < 0. 001). Between 4 and 8 h after initiation of therapy, a time span known to be critical for thrombotic reocclusion, specific activities were s till significantly elevated in responders as compared to non-responder s (p < 0.01). PAI-1 activity levels, which were not detectable during rt-PA infusion in either group, recovered to pre-treatment values 2 h earlier in non-responders. PAI-1 antigen levels were in responders (17 .9 +/- 1.8 and 15.2 +/- 1.7 ng/ml; x +/- S.E.), 6 and 8 h after initia tion of thrombolysis, significantly higher as compared to nonresponder s (12.9 +/- 1.5 and 10.1 +/- 1.1; ng/ml; x +/- S.E.) (p < 0.05). We co nclude that the lower specific activities in nonresponders might be ca used by the formation of significantly greater amounts of rt-PA/PAI-1 -complexes due to disposable higher amounts of PAI-1 in these patients . Furthermore, increased PAI-1 levels after 6 to 8 h might favor throm botic reocclusion in those patients who originally responded to therap y.