Inhibitor-Resistant Tissue-Type plasminogen activator: An improved thrombolytic agent in vitro

R. V. Shohet, S. Spitzer, E. L. Madison, R. Bassel-Duby, M. J. Gething, J. F. Sambrook

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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 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.

Original languageEnglish (US)
Pages (from-to)124-128
Number of pages5
JournalThrombosis and Haemostasis
Volume71
Issue number1
StatePublished - Jan 1 1994

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ASJC Scopus subject areas

  • Hematology

Cite this

Shohet, R. V., Spitzer, S., Madison, E. L., Bassel-Duby, R., Gething, M. J., & Sambrook, J. F. (1994). Inhibitor-Resistant Tissue-Type plasminogen activator: An improved thrombolytic agent in vitro. Thrombosis and Haemostasis, 71(1), 124-128.