(Circulation. 2000;102:e184.)
© 2000 American Heart Association, Inc.
Correspondence |
High Antifibrinolytic Activity of Lipoprotein(a) Containing Small Apolipoprotein(a) Isoforms
INSERM U.143, Hemostasis and Vascular Biology, Hôpital de Bicêtre, 84 rue du General-Léclerc, F-94276-Cedex, Bicêtre, France, angles@infobiogen.fr
To the Editor:
Small apolipoprotein(a) [apo(a)] isoforms are frequently found in patients with coronary heart disease.1 However, the question remains regarding whether short apo(a) isoforms are themselves an atherothrombotic risk factor or if they favor atherogenesis by increasing the concentration of lipoprotein(a) [Lp(a)]. An antifibrinolytic mechanism may explain the pathophysiological effects of Lp(a) through its relationship with both high concentrations of Lp(a) and small apo(a) isoforms.2 3 My colleagues and I clearly showed that the influence of Lp(a) on fibrinolysis depends on the high affinity of small apo(a) isoforms for fibrin and on their concentration relative to plasminogen.2 3 However, in a recent issue of Circulation, Marcovina and Koschinsky4 stated that the higher antifibrinolytic activity of small apo(a) isoforms remains to be tested.
I would like to add the following fact to their careful editorial on the stimulating study by Kronenberg et al1 on the role of Lp(a) and apo(a) phenotype in atherogenesis: the existence of apo(a) functional heterogeneity with regard to antifibrinolytic activity has been demonstrated.2 3 This fact was also clearly indicated by Kronenberg et al1 in the following statement: "Lp(a) particles containing low molecular weight apo(a) isoforms have the most profound influence on fibrinolysis by acting as a prominent competitive antagonist of plasminogen. This mechanism is in agreement with the emergence of low-molecular-weight apo(a) phenotypes as a leading risk condition of advanced stenotic atherosclerosis."
In addition, my colleagues and I recently provided the first quantitative evidence that individual modifications in the concentration of small apo(a) isoforms in vivo efficiently compete with plasminogen and inhibit plasmin formation on fibrin.5 These studiies2 3 5 suggest that high Lp(a) concentrations may be associated with markedly different atherothrombotic risks depending on the apo(a) isoform, and they add a new qualitative functional notion to the quantitative concept of Lp(a) as a cardiovascular risk factor.
References
1.
Kronenberg
F, Kronenberg MF, Kiechl S, et al. Role of lipoprotein(a) and
apolipoprotein(a) phenotype in atherogenesis: prospective results from
the Bruneck study. Circulation. 1999;100:1154–1160.
2.
Hervio L,
Chapman MJ, Thillet J, et al. Does apolipoprotein(a) heterogeneity
influence lipoprotein(a) effects on fibrinolysis?
Blood. 1993;82:392–397.
3. Hervio L, Durlach V, Girard-Globa A, et al. Multiple binding with identical linkage: a mechanism that explains the effect of lipoprotein(a) on fibrinolysis. Biochemistry. 1995;34:13353–13358.[Medline] [Order article via Infotrieve]
4.
Marcovina
SM, Koschinsky ML. Lipoprotein(a) concentration and apolipoprotein(a)
size: a synergistic role in advanced atherosclerosis?
Circulation. 1999;100:1151–1153.
5. Soulat T, Loyau S, Baudouin V, et al. Evidence that modifications of Lp(a) in vivo inhibits plasmin formation on fibrin. Thromb Haemost. 1999;82:121–127.
Response
University of Washington, Northwest Lipid Research Laboratories, 2121 North 35th Street, Seattle, WA 98103, smm@u.washington.edu
Department of Biochemistry, Queen’s University, Room 263 Botterell Hall, Kingston, ON K7L 3N6, Canada
We gladly acknowledge the contribution of Dr Anglés-Cano’s group on the role of lipoprotein(a) [Lp(a)] in the fibrinolytic process. This group reported that Lp(a) containing differently-sized apolipoprotein(a) isoforms exhibited differences with respect to binding to fibrin surfaces in vitro and to the tissue plasminogen activator–mediated plasmin formation stimulated by these surfaces.R1 However, on the basis of the limited number of Lp(a) variants examined in these studies and considering the known heterogeneity of Lp(a) in plasma with respect to binding to lysine or to fibrin, it remains to be definitively demonstrated that variably-sized Lp(a) isoforms possess inherent differences in their ability to bind to fibrin or to inhibit plasmin generation. Furthermore, as we stated in our editorial,R2 the effect of Lp(a) isoform size on the process of fibrinolysis itself has yet to be directly examined experimentally.
It is important to note that many plausible mechanisms by which Lp(a) may promote thrombosis have been reported in addition to the well-documented ability of Lp(a) to inhibit fibrin-dependent tissue plasminogen activator–mediated plasminogen activation. These possible mechanisms include the inhibition of plasminogen activation on platelets and on the surface of endothelial cells, the potentiation of platelet responses, and the stimulation of plasminogen activator inhibitor secretion by endothelial cells. Indeed, it could readily be argued that the binding of Lp(a) to fibrin and the resultant competition for plasminogen binding do not constitute the only mechanism by which Lp(a) inhibits plasminogen activation; we have shown that apolipoprotein(a) and plasminogen can bind in solution and that this complex seems to bind very poorly to fibrin.R3 Overall, on the basis of the clinically suggestive results of Kronenberg et al,R4 it is tempting to speculate that smaller apolipoprotein(a) isoforms possess a greater thrombogenic/antifibrinolytic potential. However, more experimental and clinical studies must be performed to further support this finding.
References
1. Hervio L, Chapman MJ, Thillet J, et al. Does apolipoprotein(a) heterogeneity influence lipoprotein(a) effects on fibrinolysis? Blood. 1993;82:392–397.
2. Marcovina SM, Koschinsky ML. Lipoprotein(a) concentration and apolipoprotein(a) size: a synergistic role in advanced atherosclerosis? Circulation. 1999;100:1151–1153.
3. Sangrar W, Gabel BR, Boffa MB, et al. The solution phase interaction between apolipoprotein(a) and plasminogen inhibits the binding of plasminogen to a plasmin-modified fibrinogen surface. Biochemistry. 1997;36:10353–10363.[Medline] [Order article via Infotrieve]
4. Kronenberg F, Kronenberg MF, Kiechl S, et al. Role of lipoprotein(a) and apolipoprotein(a) phenotype in atherogenesis: prospective results from the Bruneck study. Circulation. 1999;100:1154–1160.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||