Editorial Comment Molecular Biologic Modification of Plasminogen Activators

T he application of molecular biology to medical practice has led to the mass production of otherwise limited biological resources for human use. In cardiology, this principle is best exem-plified by the development of tissue-type plasmino-gen activator (t-PA) and its application to a variety of atherothrombotic disorders, principally acute myo-cardial infarction. The fundamental premise on which the development of t-PA for clinical use was based- namely, that it is more clot selective than other available plasminogen activators- has been shown to be of only modest clinical relevance in that t-PA is, of course, only relatively fibrin selective. At the concentrations required to achieve rapid and efficacious thrombolysis in vivo, significant fibrino-genolysis occurs. Furthermore, although significantly less fibrinogenolysis is produced by t-PA than by streptokinase or two-chain urokinases, no significant difference in hemorrhagic complications between t-PA and these fibrin-nonselective plasminogen acti-vators has been demonstrated. In addition to these shortcomings of thrombolytic therapy with t-PA as currently practiced, two other major problems per-sist: delay in the time to patency noted in many patients (the extreme form of which constitutes resis-tance of the thrombus to lysis), and reocclusion, occurring in as many as 25 % of patients in whom the clot is successfully lysed initially. See p 930 Given these shortcomings and the power of genetic engineering techniques to modify protein structure relatively simply, the cardiology community has anx-iously awaited the development of so-called "third-generation " plasminogen activators that have been molecularly tailored to overcome the ' limitations of standard therapy observed with "second-generation" agents. The article in this issue of Circulation by The opinions expressed in this editorial comment are not neces-sarily those of the editors or of the American Heart Association