Thrombogenesis, and Fibrinolysis

Since epidemiological and clinical studies show a strong relationship between the risk of atherosclerosis and plasma Lp(a) concentrations, attempts have been made to elucidate this relationship at a cellular and molecular level (H2, M28, Nl, R5, R6, S9, S10, S12-S14, S16, S24, S25). 

Support for the theories about a relation between plasma Lp(a) concentration and vascular disease came from the determination of abnormal high concentrations of Lp(a) in coronary bypass vein grafts (C14, R3). 

To explain the relationship between Lp(a) concentrations and risk of atherosclerosis, several hypothesis could be brought forward first, Lp(a) affects the metabolism of cholesterol and LDL secondly, Lp(a) plays a role in foam-cell and plaque formation thirdly, Lp(a) interacts with the activation of plasminogen to plasmin, the key step in the fibrinolytic system (L10, M27). Such activation can occur in two different localizations, i.e., on fibrin and its proteolytic residues, and on the surface of endothelial and monocytic cells. 

Lp(a) binds to the LDL receptor on cultured fibroblasts, although with a lower affinity than LDL itself. Once bound, Lp(a) inhibits 3HMG-CoA reductase, indicating that it is taken up by the cells and by releasing its cholesterol moiety, regulates the de novo synthesis of cholesterol (FI 2). High plasma concentrations of Lp(a) can, by this mechanism, influence cholesterol metabolism. As the LDL/Lp(a) ratio in plasma is about 50-100/1, this influence is marginal. 

Lp(a) will also be targeted to uptake by macrophages by the scavenger receptor pathway. Macrophages, turning into foam cells, play an important role in plaque formation. 

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