Summary
Platelet-rich clots are inefficiently lysed by current fibrinolytic agents. Platelets
contain a great deal of plasminogen activator inhibitor 1 (PAI-1), the principal endogenous
inhibitor of tissue-type plasminogen activator (t-PA). We have tested whether PAI-1
resistant t-PAs would be more effective thrombolytic agents in an in vitro model of
platelet rich clots. Clots were formed with recalcified human plasma without or with
the addition of platelets. The lysis of these clots was followed by the release of
incorporated 125I-fibrinogen. Mutant and wild-type t-PA were almost equally effective against clots
lacking platelets but the mutant was twice as effective at lysing platelet-rich clots.
A mechanism for this effect is suggested by the demonstration that a complex between
wild-type t-PA and extruded platelet contents resembles that between purified t-PA
and PAI-1 and that the PAI-1 resistant t-PA does not interfere with formation of this
adduct. Because of its enhanced ability to lyse platelet-rich clots in vitro, further
in vivo work may find that PAI-1 resistant t-PA is a more efficacious therapeutic
agent than wild-type t-PA in situations where platelets contribute to the failure
of thrombolysis.
