Protection by alpha 2-macroglobulin of tissue plasminogen activator against inhibition by plasminogen activator inhibitor-1

Tissue plasminogen activator (tPA) is widely used in the treatment of acute myocardial infarction (MI). However, its thrombolytic efficacy does not correlate with the dose administered. The interactions between tPA, alpha 2-macroglobulin (alpha 2-M), and plasminogen activator inhibitor-1 (PAT-1) were investigated both in vitro and in patients undergoing tPA therapy for ME in an attempt to identify variables that might affect the clinical efficacy of tPA. Purified alpha 2-M (5.4 mg/ml) protected 1.6% or 22.4% of tPA (12.5 IU/ml) activity from inhibition by PAI-1 at 4 or 8 IU/ml in vitro. Of nine patients treated with 5-20 mega IU of tPA for MI, the plasma activity of tPA remained increased for 15-30 min after the cessation of infusion in eight; the patient who failed to exhibit a persistent increase in tPA activity had a low plasma concentration of alpha 2-M. Total tPA activity, derived from the area under the activity-versus-time curve (AUC), showed a significant inverse correlation with the ratio of the plasma PAI-1 activity to the plasma alpha 2-M concentration. Total tPA activity did not correlate with plasma PAI-1 activity or plasma alpha 2-M concentration alone. Results suggest that alpha 2-M, by binding to tPA, protects the latter against inhibition by PAI-1.