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Acute myocardial infarction (AMI) is a major cause of death in the Western World (Table 1). One of the main precipitating events in AMI is the formation of an occluding thrombus in a coronary artery. The thrombus prevents blood flow to the myocardium thus reducing oxygen supply which in turn leads to an, often fatal, infarction. It is now widely accepted that early removal of the blood clot, by dissolution of the fibrin network which holds it together, is of major benefit in reducing morbidity and mortality.1 A number of fibrinolytic proteins are now in use in the clinic. One of these is tissue-type plasminogen activator (t-PA).2 t-PA is a serine protease; however, it does not dissolve fibrin directly, instead it activates plasminogen, a plasma protein, by cleaving the arg561-val562 peptide bond thus revealing the active enzyme, plasmin. Plasmin in turn dissolves fibrin and lyses the thrombus. The primary structure of t-PA was only established after cloning the mRNA as cDNA (Fig. 1).3,4 The 527 amino acid protein, like many serine proteases, consists of two chains (A and B) linked by a protease-susceptible peptide bond. The B chain carries the catalytic centre, but somewhat unusually for a serine protease, t-PA appears to be active in both single and two-chain forms. The A chain is believed to be divided into four structural domains (the finger, the growth factor and two kringles). |
