title: Inhibitor-resistant tissue-type plasminogen activator: an improved thrombolytic agent in vitro.
abstract: 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.
authors.affiliation: Department of Internal Medicine, University of Texas, Southwestern Medical School, Dallas 75235-8573.
authors.forename: R V
authors.initials: RV
authors.lastname: Shohet
authors.forename: S
authors.initials: S
authors.lastname: Spitzer
authors.forename: E L
authors.initials: EL
authors.lastname: Madison
authors.forename: R
authors.initials: R
authors.lastname: Bassel-Duby
authors.forename: M J
authors.initials: MJ
authors.lastname: Gething
authors.forename: J F
authors.initials: JF
authors.lastname: Sambrook
mesh_terms: 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
chemical_list: D005343:Fibrinolytic Agents; D017395:Plasminogen Activator Inhibitor 1; D011993:Recombinant Fusion Proteins; D010959:Tissue Plasminogen Activator