title: Potential attenuation of fibrinolysis by growth factors released from platelets and their pharmacologic implications.
abstract: Increased concentrations of the fast-acting tissue-type plasminogen activator (t-PA) inhibitor attenuate the fibrinolytic activity of pharmacologically administered activators of the fibrinolytic system such as t-PA. Accordingly, it was hypothesized that augmentation of synthesis and elaboration of inhibitor from the liver, leading to increased concentrations of inhibitor in plasma, or from endothelial cells in the vicinity of thrombi undergoing lysis, leading to increased concentrations locally, may contribute to failure of pharmacologically induced thrombolysis or to early reocclusion. Because platelets are rich in transforming growth factor beta and epidermal growth factor-like activity, it was thought that release of growth factors from platelets activated in vivo could mediate increases of the inhibitor in plasma by stimulating its formation in the liver and its local release from endothelial cells in the vicinity of thrombi. If so, fibrinolysis might be rendered more effective by concomitant prevention of platelet growth factor release. Transforming growth factor beta, a major constituent of platelets, increased concentrations of the t-PA inhibitor messenger ribonucleic acid (mRNA) in human hepatoma cells in a specific and dose-dependent manner. A peak effect was seen with 5 ng/ml and a 10-fold increase in 6 hours. Release of inhibitor protein into conditioned media increased as well. Induction of the inhibitor mRNA increase was elicited by exposure as brief as 30 minutes. Cycloheximide, an inhibitor of protein synthesis, was not inhibitory. The mechanisms responsible differed from those seen with epidermal growth factor, shown previously in the laboratory to increase inhibitor mRNA. In addition, the 2 factors were synergistic. Platelet lysates elicited effects simulating those of the purified growth factors.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: S
authors.initials: S
authors.lastname: Fujii
authors.forename: C L
authors.initials: CL
authors.lastname: Lucore
authors.forename: W E
authors.initials: WE
authors.lastname: Hopkins
authors.forename: J J
authors.initials: JJ
authors.lastname: Billadello
authors.forename: B E
authors.initials: BE
authors.lastname: Sobel
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005342:Fibrinolysis; D006023:Glycoproteins / Q000235:genetics*; D006133:Growth Substances / Q000097:blood / Q000502:physiology*; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D015849:Plasminogen Inactivators; D012333:RNA, Messenger / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015291:Transforming Growth Factors / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D006023:Glycoproteins; D006133:Growth Substances; D015849:Plasminogen Inactivators; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; D015291:Transforming Growth Factors; D010959:Tissue Plasminogen Activator