Lipoprotein (a): A link between thrombogenesis and atherogenesis

Abstract

It is well known that numerous mechanisms of thrombogenesis can participate in every stage of atherosclerotic disease. The discovery of Lp(a) lipoprotein and its structural similarity with plasminogen suggests another pathogenic link between atherogenesis and thrombogenesis. This lipoprotein is present in the whole human population in a wide range of plasma concentrations. It has numerous different isoforms. Its synthesis occurs in the liver, but it is practically metabolically independent from other lipoproteins. Today, Lp(a) lipoprotein is considered to be an independent risk factor for heart and brain ischemic disease. The primary role of the fibrinolytic mechanism is to prevent thrombus Jormation during circulation and to remove already formed ones. Plasmin has a central role in this process, due to the inactive proenzyme plasminogen. Its basic activators are tissue-type plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA). The most important inhibitors of plasminogen are alpha2-antiplasmin and plasminogen activator inhibitors 1 and 2 (PA-1 and PAI-2). Structural similarity of Lp(a) and plasminogen The apo(a) and plasminogen genes are very closely linked on the long arm of chromosome 6. Because of that they are structuraly very similar and they have a cross immunological reactivity. Their common elements are so-called "kringle" structures. The key difference in structure of Lp(a) and plasminogen is replacement of Arg with Ser at position 560. This prevents splitting of apo(a) by plasminogen activators. Lp(a) lipoprotein inhibits activation of plasminogen by streptokinase. It is also a competitive inhibitor of plasminogen for its binding to plasminogen receptors. Furthermore, it successfully achieves competitive inhibition of plasminogen for binding to tetranectin and thrombospondin. Also, Lp(a) inhibits activation of transforming growth factor alpha (TGF-alpha). It positively correlates with PAI-1 and it is assumed that it promotes release of tissue factor pathway inhibitor (17FPI) from endothelial cell surfaces. In regulation of the hemostatic system via apolipoprotein(a) antifibrinolytic effects, Lp(a) lipoprotein ojfers a molecular solution to the link between thrombogenesis and atherogenesis.