Physiology of Plasminogen: With Special Reference to Activation and Degradation

Abstract

Plasminogen is said to be synthesized in many organs, but the major source of its production is considered to be the liver. The production of plasminogen is observed in fetal life, but its plasma level is low in new born infants, rising rapidly to attain adult levels in about 13 weeks. The plasma levels do not change much with age. Although the fibrinolytic enzyme system is influenced by many factors such as hormones, exercise, emotion, age, sex, nutritional states etc., the plasma levels of plasminogen are relatively stable. In this presentation we would like to discuss three important subjects related to the physiology of plasminogen. The first subject is the activation pathway of the native form of plasminogen (Glu-plg) by various activators in the plasma or clotted plasma. Glu-plg was not easily activated by activators such as urokinase (UK) or tissue plasminogen activator (t-PA), but activated very easily in the presence of fibrin clot. In the presence of purified clot, Glu-plg was partly activated by activators to Glu-plasmin, but also converted to Lys-plg by preformed plasmin, subsequently being activated to plasmin. Glu-plg I (containing two carbohydrate chains) changed conformation more easily upon interaction with fibrin than Glu-plg II (containing one carbohydrate chain) and Glu-plg I was also more easily activated by activators than Glu-plg II. Although Glu-plg was hardly activated by activators in the plasma, Glu-plg was activated easily in the presence of plasma clot. Results of immunoblotting experiments indicated that Glu-plg was mainly activated by activators directly to plasmin, not via Lys-plg in contrast to purified systems. The second subject is the degradation of plasminogen by elastase. Plasminogen may be degraded by proteolytic enzymes such as cathepsin or elastase. The degradation of plasminogen by elastase is shown to give rise to K1 to K3, K4, and mini-pig (containing K5). We have shown that the degradation rate to Glu-plg by elastase increased in the presence of tranexamic acid, indicating that the conformational change of Glu-plg in the presence of tranexamic acid resulted in the exposure of the hydrophobic regions connecting K3, K4 and K5, thus making them accessible to elastase. Consequently, Lys-plg or conformationally altered Glu-plg (possibly bound to fibrin or FDP) is more easily degraded in vivo. The last subject is relationship between plasma plasminogen levels and fibrinolytic activity in various ages. Although plasma plasminogen levels do not change with age, the fibrinolytic activity lowers. We found that t-PA antigen levels increased, PA inhibitor levels decreased, and PA activity decreased with age. These results suggest that the major factor influencing the activity of fibrinolytic system is not plasminogen but other components such as PA, PA inhibitors or inhibitors of plasmin.

Regulation of Plasmin Activity by Annexin II Tetramer

“…At various timed intervals, an aliquot of the reaction mixture was removed and either subjected to SDS-PAGE (inset) or assayed for plasmin activity after dilution in plasmin assay buffer. Inset: The reaction was conducted in the absence (odd numbers) or presence of AIIt (even numbers) for 0.5 min (1, 2), 10 min (3, 4), 30 min (5,6) or 60 min (7,8). HPm, LPm, Pg, and Pm refer to the plasmin heavy chain, the plasmin light chain, [Glu]-plasminogen, and plasmin, respectively.…”

Plasminogen replacement therapy for the treatment of children and adults with congenital plasminogen deficiency

“…13,14 There are 2 main forms of native plasminogen, one with glutamic acid at its N terminus (Glu-plasminogen) and one with lysine at its N terminus (Lys-plasminogen). 15 Glu-plasminogen has a longer half-life than Lys-plasminogen (2 to 2.5 days vs 0.8 days, respectively, in healthy subjects) and is the predominant (.95%) form of circulating native plasminogen. 12 Upon binding to a fibrin clot, Glu-plasminogen is cleaved and converted into the more readily activated Lys-plasminogen.…”

Microparticle-enhanced nephelometric immunoassay of human plasminogen

“…Plasminogen, a glycoprotein of 90,000 Da synthesized by the liver, is the zymogen of plasmin (1,2). Implication of the plasminogen-plasmin system in fibrinolysis (3,4) and tumoral invasion (5,6) has led to the development of numerous human plasminogen (hPIg) assays.…”