Inhibition of Clot Lysis and Decreased Binding of Tissue-Type Plasminogen Activator as a Consequence of Clot Retraction

Tissue-type plasminogen activator (t-PA) is less active in vivo and in vitro against clots that are enriched in platelets, even at therapeutic concentrations. The release of radioactivity from ‘El-fibrin-labeled clots was decreased by 47% 6 hours after the addition of t-PA 400 U/mL when formed in plateletrich versus platelet-poor plasma. This difference was not due to the release of plasminogen activator inhibitor-I (PAI-1) by platelets. Thus, the fibrinolytic activity of t-PA in the supernatant was similar in the two preparations and fibrin autography demonstrated only a minor degree of t-PA-PAL1 complex formation. Furthermore, a similar platelet-dependent reduction in clot lysis was seen with a t-PA mutant resistant to inhibition by PAI-1. The reduction in t-PA activity correlated with a decrease in t-PA binding to platelet-enriched clot