Download PDF
Thromb Haemost 1999; 82(01): 121-127
DOI: 10.1055/s-0037-1614640
Rapid Communication
Schattauer GmbH

Evidence that Modifications of Lp(a) In Vivo Inhibit Plasmin Formation on Fibrin

A Study with Individual Plasmas Presenting Natural Variations of Lp(a)
Thierry Soulat
1   From Inserm U.143, Hôpital de Bicêtre, Reims, France
,
Stéphane Loyau
1   From Inserm U.143, Hôpital de Bicêtre, Reims, France
,
Veronique Baudouin
2   Pediatric Nephrologic Department, Hòpital Robert Debré, Paris, France
,
Vincent Durlach
3   Medical Clinic and Biochemistry Department, Hôpital Robert Debré, Reims, France
,
Philippe Gillery
3   Medical Clinic and Biochemistry Department, Hôpital Robert Debré, Reims, France
,
Roselyne Garnotel
3   Medical Clinic and Biochemistry Department, Hôpital Robert Debré, Reims, France
,
Chantal Loirat
2   Pediatric Nephrologic Department, Hòpital Robert Debré, Paris, France
,
Eduardo Anglés-Cano
1   From Inserm U.143, Hôpital de Bicêtre, Reims, France
› Author AffiliationsThis study was supported in part by the INSERM and by grant N°CRC940189 from Assistance Publique-Hopitaux de Paris. We are indepted to N. Schlegel and M. F. Hurtaud-Roux for their help with the determination of t-PA and PAI-1 in plasma.
Further Information

Publication History

Received 09 December 1998

Accepted after resubmission 22 April 1999

Publication Date:
11 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

In the present study we have investigated the effect of individual variations in the concentration of Lp(a) on plasmin formation at the surface of fibrin. The plasma Lp(a) concentrations from 20 nephrotic children were high at flare-up of the disease (0.43 ± 0.45 g/l) and decreased progressively with remission at both 6 weeks (0.28 ± 0.24 g/l) and 6 months (0.24 ± 0.288 g/l). In contrast, the concentration of plasminogen showed an inverse variation, with low values at flareup (1.27 ± 0.34 μM) and normal values at remission (1.66 ± 0.17 μM at 6 weeks and 1.99 ± 0.21 μM at 6 months). An increase in plasmin formation (from 0.62 ± 0.49 to 0.73 ± 0.61, and 0.84 ± 0.75 pmol/well) and a decrease in apo(a) binding (from 5.45 ± 2.42 to 4.54 ± 2.12, and 3.93 ± 1.51 fmol/well) on the surface of fibrin, were concomitantly observed from flare-up to remission at 6 weeks and at 6 months, respectively. Values for plasmin formation parallel the amount of plasminogen bound. The low concentration of plasminogen found at flare-up may also have contributed to the increased binding of Lp(a) as indicated by a decrease in the maximal amount of Lp(a) bound (Bmax) to fibrin as a function of plasma plasminogen concentrations. Bmax was 1.51 fmol in the absence of plasminogen and decreased to 1.1 fmol and 0.93 fmol at respectively 1 and 2 μM of plasminogen. Altogether, these data constitute the first quantitative evidence indicating that plas-min formed at the surface of fibrin may vary with modifications of the concentration of Lp(a) in vivo.

 

  • References

  • 1 Dalhen GH, Guyotn JR, Attar M, Farmer JA, Kautz JA, Gotto AM. Association of levels of lipoprotein Lp(a), plasma lipids and other lipoproteins with coronary artery disease documented by angiography. Circulation 1986; 74: 758-65.
    CrossrefPubMedGoogle Scholar
  • 2 Sandkamp M, Funke H, Schulte H, Kohler E, Assmann G. Lipoprotein(a) is an independent risk factor for myocardial infarction at a young age. Clin Chem 1990; 36: 20-3.
    PubMedGoogle Scholar
  • 3 Eaton DL, Fless GM, Kohr WJ, McLean JW, Xu QT, Miller CG, Lawn RM, Scanu AM. Partial amino acid sequence of apolipoprotein(a) shows that it is homologous to plasminogen. Biochemistry 1987; 84: 3224-8.
    PubMedGoogle Scholar
  • 4 McLean JW, Tomlinson JE, Kuang WJ, Eaton DL, Chen EY, Fless GM, Scanu AM, Lawn RM. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature 1987; 300: 132-7.
    PubMedGoogle Scholar
  • 5 Boerwinckle E, Leffert CC, Lin JP, Lackner C, Chiesa G, Hobbs HH. Apolipoprotein(a) gene accounts for greater than 90-percent of the variation in plasma lipoprotein(a) concentrations. J Clin Invest 1992; 90: 52-60.
    CrossrefPubMedGoogle Scholar
  • 6 Marcovina SM, Zhang ZH, Gaur VP, Albers JJ. Identification of 34 apolipoprotein(a) isoforms: differential expression of apolipoprotein(a) alleles between american blacks and whites. Biochem Biophys Res Comm 1993; 191 (03) 1192-6.
    CrossrefPubMedGoogle Scholar
  • 7 Boonmark NW, Lou XJ, Yang ZJ, Schwartz K, Zhang JL, Rubin EM. Modification of apolipoprotein(a) lysine binding site reduces atherosclerosis in transgenic mice. J Clin Invest 1997; 100: 558-64.
    CrossrefPubMedGoogle Scholar
  • 8 Hughes SD, Lou XJ, Ighani S, Verstuyft J, Grainger DJ, Lawn RM. Lipo-protein(a) vascular accumulation in mice. In vivo analysis of the role of lysine binding site using recombinant adenovirus. J Clin Invest 1997; 100: 1493-500.
    CrossrefPubMedGoogle Scholar
  • 9 Rouy D, Koschinsky ML, Chapman J, Anglés-Cano E. Apolipoprotein(a) and plasminogen interactions with fibrin: a study with recombinant apolipoprotein(a) and isolated plasminogen fragments. Biochemistry 1992; 31 (27) 6333-9.
    CrossrefPubMedGoogle Scholar
  • 10 Harpel PC, Gordon BR, Parker TS. Plasmin catalyses binding of lipoprotein(a) to immobilized fibrinogen and fibrin. Proc Natl Acad Sci USA 1989; 86: 3847-51.
    CrossrefPubMedGoogle Scholar
  • 11 Hajjar KA, Gavish D, Breslow JL, Nachman RL. Lipoprotein(a) modulation cell surface fibrinolysis and its potential role in atherosclerosis. Nature 1989; 339: 303-5.
    CrossrefPubMedGoogle Scholar
  • 12 Miles LA, Dahlberg ACM, Plescia J, Felez J, Kato K, Plow EF. Role of cell-surface lysines in plasminogen binding to cells: identification of α-enolase as a candidate plasminogen receptor. Biochemistry 1991; 30: 1682-91.
    CrossrefPubMedGoogle Scholar
  • 13 Loscalzo J, Weinfeld M, Fless GM, Scanu AM. Lipoprotein(a), fibrin binding and plasminogen activation. Atherosclerosis 1990; 10: 240-5.
    PubMedGoogle Scholar
  • 14 Kang C, Durlach V, Soulat T, Fournier C, Anglés-Cano E. Lipoprotein(a) isoforms display differences in affinity for plasminogen-like binding to human mononuclear cells. Arterioscler Thromb Vasc Biol 1997; 17: 2036-43.
    CrossrefPubMedGoogle Scholar
  • 15 Falco C, Estellés A, Dalmau J, Espana F, Aznar J. Influence of lipoprotein(a) levels and isoforms on fibrinolytic activity – Study in families with high lipoprotein(a) levels. Thromb Haemost 1998; 79: 818-23.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Rouy D, Grailhe P, Nigon F, Chapman J, Anglés-Cano E. Lipoprotein(a) impairs generation of plasmin by fibrin-bound tissue-type plasminogen activator. Arterioscler Thromb 1991; 11: 629-38.
    CrossrefPubMedGoogle Scholar
  • 17 Julius U, Fritsch W, Rchak E, Fücker K, Leonhardt W, Hanefeld M. Impact of hormone replacement therapy on postprandial lipoproteins and lipoprotein(a) in normolipidemic postmenopausal women. Clin Invest 1994; 72: 502-7.
    PubMedGoogle Scholar
  • 18 Noma A, Abe A, Maeda M, Seishima M, Makino Y, Yano K, Shimokawa K. Lp(a): an acute-phase reactant?. Chem Physic Lipids 1994; 67: 411-7.
    PubMedGoogle Scholar
  • 19 de Bruin TWA, van Barlingen H, van Linde-Sibenius Trip M, van Vuurst de Vries AR, Akveld MJ, Erkelens DW. Lipoprotein(a) and apolipoprotein B plasma concentrations in hypothyroid, euthyroid and hyperthyroid subjects. J Clin Endocrinol Metab 1993; 76: 121-6.
    PubMedGoogle Scholar
  • 20 Garnotel R, Monier F, Lefèvre F, Gillery P. Long-term variability of serum lipoprotein(a) concentrations in healthy fertile women. Clin Chem Lab Med 1998; 36: 317-21.
    PubMedGoogle Scholar
  • 21 Wanner C, Rader D, Bartens W, Krämer J, Brewer HB, Schollmeyer P, Wieland H. Elevated plasma lipoprotein(a) in patients with the nephrotic syndrome. Ann Intern Med 1993; 119: 263-9.
    CrossrefPubMedGoogle Scholar
  • 22 Lau SO, Thachuck JY, Hasegawa DK, Edson JR. Plasminogen and anti-thrombin III deficiencies in the childrood nephrotic syndrome associated with plasminogenuria and antithrombinuria. J Pediatr 1980; 96 (03) 390-2.
    CrossrefPubMedGoogle Scholar
  • 23 Gillery P, Arthuis P, Cuperlier C, Circaud R. A rate nephelometric assay of serum lipoprotein(a). Clin Chem 1993; 39: 503-8.
    PubMedGoogle Scholar
  • 24 Hervio L, Chapman J, Thillet J, Loyau S, Anglés-Cano E. Does apolipo-protein(a) heterogeneity influence lipoprotein(a) effects on fibrinolysis?. Blood 1993; 82: 392-7.
    PubMedGoogle Scholar
  • 25 Laurell CB. Quantitative estimation of proteins by electrophoresis in agarose gel containing antibodies. Anal Biochem 1966; 15: 45-52.
    CrossrefPubMedGoogle Scholar
  • 26 Teger-Nilsson AC, Friberger P, Gyzander E. Determination of a new rapid plasmin inhibitor in human plasma blood by means of a plasmin specific tripeptide substrate. Scand J Clin Lab Invest 1977; 37: 403-9.
    CrossrefPubMedGoogle Scholar
  • 27 Clauss A. Gerinnungsphysiologische Schellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-46.
    CrossrefPubMedGoogle Scholar
  • 28 Deutsch D, Mertz ET. Plasminogen purification from human plasma by affinity chromatography. Science 1970; 170: 1095-6.
    CrossrefPubMedGoogle Scholar
  • 29 Kazal LA, Amsel S, Miller OP, Tocantins LM. The preparation and some properties of fibrinogen precipitated from human plasma by glycine. Proc Soc Exp Biol Med 1963; 113: 989-94.
    CrossrefPubMedGoogle Scholar
  • 30 Fleury V, Anglés-Cano E. Characterization of the binding of plasminogen to fibrin surfaces: the role of carboxy-terminal lysine. Biochemistry 1991; 30: 7630-8.
    CrossrefPubMedGoogle Scholar
  • 31 Grailhe P, Boyer-Neuman C, Haverkate F, Grimgergen J, Larrieu MJ, Anglés-Cano E. The mutation in fibrinogen Bicêtre II (γAsn308-Lys) does not affect the binding of t-PA and plasminogen to fibrin. Blood Coag Fibrinol 1993; 4: 679-87.
    CrossrefPubMedGoogle Scholar
  • 32 Fracker PM, Speck JC. Protein cell membrane iodination with a sparingly soluble chloramide 1,3,4,6-tetrachloro-3α,6α-diphenylglycoluril. Biochem Biophys Res Commun 1978; 80: 849-57.
    CrossrefPubMedGoogle Scholar
  • 33 Kyhse-Andersen J. Electroblotting of multiple gels: a single apparatus without buffer tank for rapid transfer of protein from polyacrylamide to nitrocellulose. J Biophys Biochem Methods 1984; 10: 203-9.
    PubMedGoogle Scholar
  • 34 Anglés-Cano E, Loyau S, Cardoso-Saldaña G, Couderc R, Gillery P. A novel kringle-4 number based recombinant apo(a) standard for human apo(a) phenotyping. J Lip Res 1999; 40: 354-9.
    PubMedGoogle Scholar
  • 35 Anglés-Cano E. A spectrophotometric solid-phase-fibrin-tissue plasmino-gen activator activity assay (SOFIA-tPA) for high-fibrin-affinity tissue plasminogen activators. Anal Biochem 1986; 26: 171-6.
    PubMedGoogle Scholar
  • 36 Rouy D, Anglés-Cano E. The mechanism of activation of plasminogen at the fibrin surface by t-PA in a plasma milieu in vitro: role of alpha-2-antiplasmin. Biochem J 1990; 271: 51-7.
    CrossrefPubMedGoogle Scholar
  • 37 Milstone H. A factor in normal blood which participates in streptococcal fibrinolysis. J Immunol 1941; 42: 109-16.
    PubMedGoogle Scholar
  • 38 Fleury V, Gurewich V, Anglés-Cano E. A study of activation of fibrin bound plasminogen by tissue type plasminogen activator, single chain urokinase and sequential combinations of the activators. Fibrinolysis 1993; 7: 87-96.
    PubMedGoogle Scholar
  • 39 Montes R, Paramo JA, Anglés-Cano E, Rocha E. Development and clinical application of a new ELISA assay to determine plasmin-α2-antiplasmin complexes in plasma. British J Haematology 1996; 92: 979-85.
    PubMedGoogle Scholar
  • 40 Gazzaruso C, Garzaniti A, Buscaglia P, Bonetti G, Falcone C, Fratino P, Finardi G, Geroldi D. Apolipoprotein(a) phenotypes and their predictive value for coronary heart disease: identification of an operative cut-off of apolipoprotein(a) polymorphism. J Cardiovasc Risk 1998; 5: 37-42.
    PubMedGoogle Scholar
  • 41 Hoylaerts M, Rijken D, Lijnen HR, Collen D. Kinetics of the activation of plasminogen by human tissue plasminogen activator. J Biol Chem 1982; 257: 2912-9.
    PubMedGoogle Scholar
  • 42 Suenson E, Lutzen O, Thorsen S. Initial plasmin-degradation of fibrin as the basis of a positive feed-back mechanism in fibrinolysis. Eur J Biochem 1984; 140: 51322
    PubMedGoogle Scholar
  • 43 Harpel PC, Chang TS, Verderber E. Tissue plasminogen activator and urokinase mediate the binding of Glu-plasminogen to plasma fibrin I. J Biol Chem 1985; 260: 4432-40.
    PubMedGoogle Scholar
  • 44 Leerink CB, Duif P, Gimpel JA, Kortlandt W, Bouma BN, van Rijn HJM. Lysine-binding heterogeneity of Lp(a): consequences for fibrin binding and inhibition of plasminogen activation. Thromb Haemost 1992; 68 (02) 185-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Sangrar W, Gabel BR, Boffa MB, Walker JB, Hancock MA, Marcovina SM, Horrevoets AJG, Neishem ME, Koschinsky ML. The solution phase interaction between apolipoprotein(a) and plasminogen inhibits the binding of plasminogen to a plasmin-modified fibrinogen surface. Biochemistry 1997; 36 (34) 10353-63.
    CrossrefPubMedGoogle Scholar
  • 46 Palabrica TM, Liu AC, Aronovitz MJ, Furie B, Lawn RM, Furie B. Anti-fibrinolytic activity of apolipoprotein(a) in vivo: human apolipoprotein(a) transgenic mice are resistant to tissue plasminogen activator-mediated thrombolysis. Nature Med 1995; 1 (03) 256-9.
    CrossrefPubMedGoogle Scholar
  • 47 Tavola A, D’Angelo SV, Bandello F, Brancato R, Parlavecchia M, Safa O, D’Angelo A. Central retinal vein and branch artery occlusion associated with inherited plasminogen deficiency and high lipoprotein(a) levels: a case report. Thromb Res 1995; 80: 327-31.
    CrossrefPubMedGoogle Scholar
  • 48 Iijima H, Gohdo T, Tsukahara S. Familial dysplasminogenemia with central retinal vein and cilioretinal artery occlusion. Am J Ophtamol 1998; 128 (02) 312-4.
    PubMedGoogle Scholar