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Thromb Haemost 1998; 79(04): 818-823
DOI: 10.1055/s-0037-1615071
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Schattauer GmbH

Influence of Lipoprotein (a) Levels and Isoforms on Fibrinolytic Activity – Study in Families with High Lipoprotein (a) Levels

Cristina Falcó
1   From the Research Center, Valencia, Spain
,
Amparo Estellés
1   From the Research Center, Valencia, Spain
,
Jaime Dalmau
2   From the Children’s Hospital, Valencia, Spain
,
Francisco España
1   From the Research Center, Valencia, Spain
,
Justo Aznar
3   From the Department of Clinical Pathology, La Fe University Hospital, Valencia, Spain
› Author Affiliations
Further Information

Publication History

Received 03 July 1997

Accepted after resubmission 14 November 1997

Publication Date:
07 December 2017 (online)

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Summary

Increased levels of lipoprotein (a) [Lp(a)] have been considered an independent risk factor for cardiovascular disease, but the mechanism behind this relationship is not completely understood. A high concentration of Lp(a) may interfere with fibrinolysis because of the structural similarity between apo(a) and plasminogen. The aim of the present study was to examine the influence of apo(a) levels and isoforms on fibrinolytic activity in 82 subjects from 24 families in which the Lp(a) levels were ≥30 mg/dl in at least one child and one parent. Several fibrinolytic parameters, including plasmin generation by fibrin-bound tissue plasminogen activator, the lipid profile and apo(a) isoforms were studied. Subjects with high circulating Lp(a) levels (n = 44) had significantly reduced plasmin generation compared with their relatives with normal Lp(a) levels (n = 38). A significant inverse correlation between Lp(a) levels and plasmin generation was observed. The individuals with a combination of high levels of plasma Lp(a) and a major apo(a) isoform ≤580 kD molecular weight show the lowest fibrinolytic activity. A high correlation was found between the levels of apo(a) isoforms in children and the levels of the corresponding parental apo(a) iso-forms. We conclude that the antifibrinolytic effect of Lp(a) in subjects with two apo(a) isoforms may depend not only on the total plasma level of Lp(a) but also on the relative concentration of the small apo(a) isoform.

 

  • References

  • 1 Berg K. A new serum type in man: the Lp system. Acta Pathol Microbiol Scand 1963; 59: 369-82.
    CrossrefPubMedGoogle Scholar
  • 2 Utermann G, Weber W. Protein composition of Lp(a) lipoprotein from human plasma. FEBS Lett 1983; 154: 357-61.
    CrossrefPubMedGoogle Scholar
  • 3 Dahlen GH, Guyton 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
  • 4 Rosengren A, Wilhelmsen L, Eriksson E, Risberg B, Wedel H. Lipoprotein(a) and coronary heart disease: a prospective case control study in a general population sample of middle aged men. Br Med J 1990; 301: 1248-51.
    CrossrefPubMedGoogle Scholar
  • 5 McLean JW, Tomlinson JE, Kuang W, Eaton DL, Chen EY, Fless GM, Scanu AM, Lawn RM. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature 1987; 330: 132-7.
    CrossrefPubMedGoogle Scholar
  • 6 Miles LA, Fless GM, Levin EG, Scanu AM, Plow EF. A potential basis for the thrombotic risks associated with lipoprotein(a). Nature 1989; 339: 301-3.
    CrossrefPubMedGoogle Scholar
  • 7 Hajjar KA, Gavish D, Breslow JL, Nachman RL. Lipoprotein(a) modulation of endothelial cell surface fibrinolysis and its potential role in atherosclerosis. Nature 1989; 339: 303-5.
    CrossrefPubMedGoogle Scholar
  • 8 Harpel PC, Gordon BR, Parker TS. Plasmin catalyzes binding of lipoprotein(a) to immobilized fibrinogen an fibrin. Proc Natl Acad Sci USA 1989; 86: 3847-51.
    CrossrefPubMedGoogle Scholar
  • 9 Edelberg JM, Gonzalez-Gronow M, Pizzo SV. Lipoprotein(a) inhibits streptokinase-mediated activation of human plasminogen. Biochemistry 1989; 28: 2370-4.
    CrossrefPubMedGoogle Scholar
  • 10 Loscalzo J, Weinfeld M, Fless GM, Scanu AM. Lipoprotein(a) fibrin binding, and plasminogen activation. Arteriosclerosis 1990; 10: 240-5.
    CrossrefPubMedGoogle Scholar
  • 11 Miles LA, Plow EF. Lp(a): an interloper into the fibrinolytic system?. Thromb Haemost 1990; 63: 331-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Rouy D, Grailhe P, Nigon F, Chapman J, Angles-Cano E. Lipoprotein (a) impairs the generation of plasmin by fibrin-bound t-PA: In vitro studies in a plasma milieu. Arterioscler Thromb 1991; 11: 629-38.
    CrossrefPubMedGoogle Scholar
  • 13 Rouy D, Koschinsky ML, Fleury V, Chapman J, Angles-Cano E. Apolipo-protein (a) and plasminogen interaction with fibrin: A study with recombinant apolipoprotein (a) and isolated plasminogen fragments. Biochemistry 1992; 31: 6333-9.
    CrossrefPubMedGoogle Scholar
  • 14 Edelberg JM, Pizzo SV. Lipoprotein(a): the link between impaired fibrinolysis and atherosclerosis. Fibrinolysis 1991; 5: 135-43.
    PubMedGoogle Scholar
  • 15 Hervio LH, Durlach V, Girard-Globa A, Anglés-Cano E. Multiple binding with identical linkage: A mechanism that explain the effect of lipoprotein(a) on fibrinolysis. Biochemistry 1995; 34: 13353-8.
    CrossrefPubMedGoogle Scholar
  • 16 Utermann G, Kraft HG, Menzel HJ, Hopferwieser T, Seitz C. Genetics of the quantitative Lp(a) lipoprotein trait. I. Relation of Lp(a) glycoprotein phenotypes to Lp(a) lipoprotein concentrations in plasma. Hum Genet 1988; 78: 41-6.
    CrossrefPubMedGoogle Scholar
  • 17 Utermann G, Duba C, Menzel HJ. Genetics of the quantitative Lp(a) lipo-protein trait. II. Inheritance of Lp(a) glycoprotein phenotypes. Hum Genet 1988; 78: 47-50.
    CrossrefPubMedGoogle Scholar
  • 18 Kamboh MI, Ferrel RE, Kottke BA. Expressed hypervariable polymorphism of apolipoprotein(a). Am J Hum Genet 1991; 49: 1063-74.
    PubMedGoogle Scholar
  • 19 Gavish D, Azrolan N, Breslow JL. Plasma Lp(a) concentration is inversely correlated with the ratio of kringle IV/kringle V encoding domains in the apo(a) gene. J Clin Invest 1989; 84: 2021-7.
    CrossrefPubMedGoogle Scholar
  • 20 Mooser V, Mancini FP, Bopp S, Pethö-Schramm A, Guerra R, Boerwinkle E, Müller H, Hobbs H. Sequence polymorphisms in the apo(a) gene associated with specific levels of Lp(a) in plasma. Hum Mol Genet. 1995; 4: 173-81.
    CrossrefPubMedGoogle Scholar
  • 21 Utermann G, Menzel HJ, Kraft HG, Duba HC, Kemmler HG, Seitz C. Lp(a) glycoprotein phenotypes: inheritance and relation to Lp(a) lipoprotein concentration in plasma. J Clin Invest 1987; 80: 458-65.
    CrossrefPubMedGoogle Scholar
  • 22 Sandholzer Ch, Boerwinkle E, Saha N, Tong MC, Utermann G. Apolipoprotein(a) phenotypes, Lp(a) concentration and plasma lipid levels in relation to coronary hearth disease in a Chinese population: evidence for the role of the apo(a) gene in coronary heart disease. J Clin Invest 1992; 89: 1040-6.
    CrossrefPubMedGoogle Scholar
  • 23 Bowden JF, Pritchard PH, Hill JS, Frohlich JJ. Lp(a) concentration and apo(a) isoform size. Relation to the presence of coronary artery disease in familial hypercholesterolemia. Arterioscler Thromb 1994; 14: 1561-8.
    CrossrefPubMedGoogle Scholar
  • 24 Carmena R, Lussier-Cacan S, Roy M, Minnich A, Lingenhel A, Kronenberg F, Davignon J. Lp(a) levels and atherosclerotic vascular disease in a sample of patients with familial hypercholesterolemia sharing the same gene defect. Arterioscler Thromb Vasc Biol 1996; 16: 129-36.
    CrossrefPubMedGoogle Scholar
  • 25 Utermann G, Hoppichler F, Dieplinger H, Seed M, Thompson G, Boer-winkle E.. Defects in the low density lipoprotein receptor gene effect lipoprotein(a) levels: multiplicative interaction of two gene loci associated with premature atherosclerosis. Proc Natl Acad Sci USA 1989; 86: 4171-4.
    CrossrefPubMedGoogle Scholar
  • 26 Mbewu AD, Bhatnagar D, Durrington PN, Hunt L, Ishola M, Arrol S, Mackness M, Locklwy P, Miller JP. Serum lipoprotein(a) in patients heterozygous for familial hypercholesterolemia, their relatives, and unrelated control populations. Arterioscler Thromb 1991; 11: 940-6.
    CrossrefPubMedGoogle Scholar
  • 27 Ritter MM, Geiss HC, Richter WO, Schwandt P. Lipoprotein(a) concentrations and phenotypes in controls and patients with hypercholesterolemia or hypertriglyceridemia. Metabolism 1994; 43: 572-8.
    CrossrefPubMedGoogle Scholar
  • 28 Aznar J, Estellés A, Bretó M, España F, Alós T. Euglobulin clot lysis induced by tissue-type plasminogen activator is reduced in subjects with increased levels of lipoprotein(a). Thromb Res 1992; 66: 569-82.
    CrossrefPubMedGoogle Scholar
  • 29 Aznar J, Estellés A, Bretó M, España F. Euglobulin clot lysis induced by tissue-type plasminogen activator in subjects with increased levels and different isoforms of lipoprotein(a). Thromb Res 1993; 72: 459-65.
    CrossrefPubMedGoogle Scholar
  • 30 Szczeklik A, Radwan J, Kubicka A, Libura M, Sacha T, Swadzba J, Undas A, Szczeklik J, Jodlowski J. Plasma fibrinolytic activity in healthy subjects with high and low lipoprotein(a) concentrations. Thromb Res 1992; 66: 391-5.
    CrossrefPubMedGoogle Scholar
  • 31 Terres W, Krewitt M, Hamm CW. Effects of lipoprotein(a) on in vitro lysis of whole blood thrombi from healthy volunteers. Thromb Res 1993; 69: 479-87.
    CrossrefPubMedGoogle Scholar
  • 32 Stegnar M, Ambrozic J, Berger B, Keber I. In vitro plasma and euglobulin clot lysis in subjects with elevated lipoprotein(a). Fibrinolysis 1995; 9: 304-8.
    PubMedGoogle Scholar
  • 33 Hervio L, Chapman M, Thillet J, Loyau S, Anglés-Cano E. Does apolipoprotein(a) heterogeneity influence lipoprotein(a) effects on fibrinolysis?. Blood 1993; 82: 392-7.
    PubMedGoogle Scholar
  • 34 Hervio L, Girard-Globa A, Durlach V, Anglés-Cano E. The antifibrinolytic effect of lipoprotein(a) in heterozygous subjects is modulated by the relative concentration of each of the apolipoprotein(a) isoforms and their affinity for fibrin. Eur J Clin Invest 1996; 26: 411-7.
    CrossrefPubMedGoogle Scholar
  • 35 Palabrica TM, Liu AC, Aronovitz MJ, Furie B, Lawn RM, Furie BC. 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: 256-9.
    CrossrefPubMedGoogle Scholar
  • 36 Cortner JA, Coates PM, Vallagher PR. Prevalence and expression of familial combined hyperlipidemia in childhood. J Pediat 1990; 116: 514-9.
    CrossrefPubMedGoogle Scholar
  • 37 National cholesterol education program.. Report of the expert panel on blood cholesterol levels in children and adolescents. Pediatrics 1992; 89: 525-84.
    PubMedGoogle Scholar
  • 38 Stroop DM, Glueck CJ, MsCray C, Speirs J, Schumacher HR. Measurement of lipoprotein (a): comparison of Macra™ and Imubind® methods. Ann Clin Lab Sci 1996; 26: 329-39.
    PubMedGoogle Scholar
  • 39 Estellés A, Gilabert J, Aznar J, Loskutoff DJ, Schleef R. Changes in the plasma levels of type 1 and type 2 plasminogen activator inhibitors in normal pregnancy and in patients with severe preeclampsia. Blood 1989; 74: 1332-8.
    PubMedGoogle Scholar
  • 40 Friberger P, Knoss M, Gustavsson S, Aurell L, Claeson G. Methods for determination of plasmin, antiplasmin and plasminogen by means of substrate S-2251. Haemostasis 1978; 7: 138-45.
    PubMedGoogle Scholar
  • 41 Wang XL, Wilcken DEL, Dudman NPB. Early expression of the apolipoprotein(a) gene: relationships between infants’ and their parents’ serum apolipoprotein(a) levels. Pediatrics 1992; 89: 401-6.
    PubMedGoogle Scholar
  • 42 Wilcken DEL, Wang XL, Dudman NPB. The relationship between infant and parent levels. Chem Phys Lipids 1994; 67/68: 299-304.
    CrossrefPubMedGoogle Scholar
  • 43 Schreiner PJ, Heiss G, Tyroler HA, Morrisett JD, Davis CE, Smith R. Race and gender differences in the association of Lp(a) with carotid artery wall thickness. The atherosclerosis risk in communities (ARIC) study. Arterioscler Thromb Vasc Biol 1996; 16: 471-8.
    CrossrefPubMedGoogle Scholar
  • 44 Harpel PC, Hermann A, Zhang X, Ostfeld I, Borth W. Lipoprotein(a), plasmin modulation and atherogenesis. Thrombos Haemost 1995; 74: 382-6.
    PubMedGoogle Scholar
  • 45 Hajjar KA, Nachman RL. The role of lipoprotein(a) in atherogenesis and thrombosis. Ann Rev Med 1996; 47: 423-42.
    CrossrefPubMedGoogle Scholar
  • 46 Ghiselli G, Gaddi A, Barozzi G, Ciarrocchi A, Descovich G. Plasma lipoprotein(a) concentration in familial hypercholesterolemic patients without coronary artery disease. Metabolism 1992; 41: 833-8.
    CrossrefPubMedGoogle Scholar
  • 47 Marquez A, Mendoza S, Carrasco H, Hamer T, Glueck ChJ.. High lipoprotein(a) in children from kindreds with parental premature myocardial infarction. Pediat Res 1993; 34: 670-4.
    CrossrefPubMedGoogle Scholar
  • 48 Bailleul S, Couderc R, Rossignol C, Fermanian J, Boutouchent F, Farnier M-A, Etienne J. Lipoprotein(a) in childhood: Relation with other atherosclerosis risk factors and family history of atherosclerosis. Clin Chem 1995; 41: 241-5.
    PubMedGoogle Scholar
  • 49 Islam S, Gutin B, Clayton S, Treiber F, Kamboh MI. Association of apolipoprotein(a) phenotypes in children with family history of premature coronary artery disease. Arterioscler Thromb 1994; 14: 1609-16.
    CrossrefPubMedGoogle Scholar