Inhibitor-resistant tissue-type plasminogen activator: an improved thrombolytic agent in vitro.
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 interefer 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.
Shohet
R V
RV
Department of Internal Medicine, University of Texas, Southwestern Medical School, Dallas 75235-8573.
Spitzer
S
S
Madison
E L
EL
Bassel-Duby
R
R
Gething
M J
MJ
Sambrook
J F
JF
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D005342:Fibrinolysis / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology*; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors*; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000235:genetics
D005343:Fibrinolytic Agents; D017395:Plasminogen Activator Inhibitor 1; D011993:Recombinant Fusion Proteins; D010959:Tissue Plasminogen Activator