New data on the interactions between lipoprotein (a) [Lp(a)] and the coagulation-fibrinolytic system, which emphasize the importance of the activity of lysine-binding sites on apolipoprotein (a) [apo(a)], provide an increasingly strong basis for the role of Lp(a) in thrombosis. Further insights into the genetic control of Lp(a) levels show that inherited factors other than the size of the apo(a) gene are important. The clinical relationship between Lp(a) and coronary heart disease has been more firmly established by two further large prospective cohort studies. The consensus that the concentration of Lp(a) does not predict the outcome of thrombolytic therapy still holds, although Lp(a) does affect endogenous fibrinolysis after myocardial infarction. The effect of Lp(a) on mortality should soon be known.
FusterVBadimonLBadimonJJChesebroJH: The pathogenesis of coronary artery disease and the acute coronary syndromesN Engl J Med1992, 326:243–250, 311–317.
2.
StaryHC: Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adultsAtherosclerosis1989, 99 (suppl 1):119–132.
3.
BergK: A new serum type system in man: The Lp systemActa Pathol Microbiol Scand1963, 59:211–220.
4.
DahlenGH: Lp(a) lipoprotein in cardiovascular diseaseAtherosclerosis1994, 108:111–126. Awide-ranging review by one of the authors who, along with Berg, first published a paper on Lp(a). The author includes an idiosyncratic and interesting hypothesis that Lp(a) might be related to the autoimmune process.
5.
RabbiniLELoscalzoJ: Recent observations on the role of haemostatic determinants in the development of the atherothrombotic plaqueAtherosclerosis1994, 105:1–7. Abrief but thoughtful review on the relationship between atherosclerosis and thrombosis including the role of Lp(a).
6.
MacLeanJWTomlisonJEKuangWJEatonDLChenEYFlessGM: Cdna Sequence of human apolipoprotein (a) is homologous to plasminogenNature1987, 330:132–137.
7.
KarridiIKostnerGMGriesANimpfJRomicsLMalleE: Lipoprotein (a) and plasminogen are immunochemically relatedBiochem Biophys Acta1988, 960:91–97.
8.
HajjarKAGavishDBreslowJLNachmanRL: Lipoprotein (a) modulation of endothelial cell surface fibrinolysis and its potential role in atherosclerosisNature1989, 339:303–305.
9.
MilesLAFlessGMLevinEGScanuAMPlowEF: A potential basis for the thrombotic risks associated with lipoprotein (a)Nature1989, 339:301–303.
10.
LoscalzoJWeinfieldMFlessGMScanuAM: Lipoprotein (a), fibrin binding, and plasminogen activationArteriosclerosis1990, 10:240–246.
11.
SimonDIFlessGMScanuAMLoscalzoJ: Tissue-type plasminogen activator binds to and is inhibited by surface-bound lipoprotein (a) and low-density lipoproteinBiochemistry1991, 30:6671–6677.
12.
Angles-CanoE: Overview on fibrinolysis: Plasminogen activation pathways on fibrin and cell surfacesChem Phys Lipids1994, 67/68:353–362. Anicely illustrated analysis of the importance of structure-surface interactions in fibrinolysis by an author pre-eminent in this experimental field.
13.
Angles-CanoEHervioLRouyDFournierCChapmanJLapaudM: Effects of lipoprotein (a) on the binding of plasminogen to fibrin and its activation by fibrin-bound tissue-type plasminogen activatorChem Phys Lipids1994, 67/68:369–380. Ina thorough study using a sensitive solid-phase fibrin system, the authors investigated the effects of Lp(a) on the binding of plasminogen and its activation by fibrin-bound t-PA.
14.
GawAHobbsHH: Molecular genetics of lipoprotein (a): New pieces to the puzzleCurr Opin Lipidol1994, 5:149–155. Anexcellent review of the molecular genetics of Lp(a) that brings the original work by MacLean et al. [6] in 1987 up to date.
15.
LacknerCEBoerwinkleCCLeffertTRahmigTHobbsHH: Molecular basis of apolipoprotein (a) isoform size heterogeneity as revealed by pulse field gel electrophoresisJ Clin Invest1991, 87:2153–2161.
16.
Hoover-PlowJLMilesLAFlessGMScanuAMPlowEF: Comparison of the lysine binding functions of lipoprotein (a) and plasminogenBiochemistry1993, 32:13681–13687.
LiuACLawnRM: Vascular interactions of lipoprotein (a)Curr Opin Lipidol1994, 5:269–273. Auseful review from two aficionados of apo(a) interactions.
19.
SorensenKECelermajerDSGeorgakopoulosDHatcherGBetteridgeDJDeanfieldJE: Impairment of endothelium-dependent dilatation is an early event in children with familial hypercholesterolaemia and is related to the lipoprotein (a) levelJ Clin Invest1994, 93:50–55. Flow-mediated vasodilatation was measured using ultrasound in the femoral artery of children with familial hypercholesterolaemia. Impairment of vasodilatation was found to correlate with the serum Lp(a) concentration but not with other parameters.
20.
EzrattyASimonDILoscalzoJ: Lipoprotein (a) binds to human platelets and attenuates plasminogen binding and activationBiochemistry1993, 32:4628–4633.
21.
LiuJHarpelPCPannellRGurewichV: Lipoprotein (a): A kinetic study of its influence on fibrin-dependent plasminogen activation by prourokinase or tissue plasminogen activatorBiochemistry1993, 32:9694–9700.
22.
HamstenAErikssonPKarpeFSilveiraA: Relationship of thrombosis and fibrinolysis to atherosclerosisCurr Opin Lipidol1994, 5:382–389. Awell-referenced review highlighting the importance of both the insulin resistance syndrome, genetic variability and gene-environment interaction in the haemostatic system.
23.
EtinginORHajjarDPHajjarKHarpelPCNachmanRL: Lipoprotein (a) regulates plasminogen activator inhibitor-1 expression in endothelial cells: A potential mechanism of thrombogenesisJ Biol Chem1991, 266:2459–2465.
24.
ScanuAMMilesLAFlessGMPfaffingerDEisenbartJJacksonE: Rhesus monkey lipoprotein (a) binds to lysine sepharose and U937 monocytoid cells less efficiently than human lipoprotein (a). Evidence for the dominant role of kringle 4(37)J Clin Invest1993, 91:283–291.
25.
HervioLMChapmanJThilletJLoyauSAngles-CanoE: Does apolipoprotein (a) heterogeneity influence lipoprotein (a): Effects of fibrinolysis?Blood1993, 82:392–397.
26.
LiuJHarpelPCGuerwichV: Fibrin-bound lipoprotein (a) promotes plasminogen binding but inhibits fibrin degradation by plasminBiochemistry1994, 33:2554–2560. Adetailed study including an explanation of some of the conflicting results on the effects of Lp(a) on plasminogen binding to fibrin and fibrin-dependent activation by t-PA.
27.
GraingerDJKrichenohrHLMetcalfeJCWeissbergPLWadeDPLawnRM: Proliferation of human smooth muscle cells promoted by lipoprotein (a)Science1993, 260:1655–1658.
28.
GraingerDJKempPRLiuACLawnRMMetcalfeJC: Activation of transforming growth factor-β is inhibited in transgenic apolipoprotein (a) miceNature1994, 370:460–463. Themodel proposed by Grainger et al. [27] of plasminogen and TGF-β inhibition by apo(a), with subsequent stimulation of smooth muscle cells, is extended in vivo by measurements of these parameters in the vessel walls of apo(a) transgenic mice.
29.
PerombelonNFSoutarAKKnightBL: Variation in lipoprotein (a) concentration associated with different apolipoprotein (a) allelesJ Clin Invest1994, 93:1481–1492. Acareful and thorough family study that shows convincingly that inherited factors other than the size of the apo(a) gene are related to the plasma Lp(a) concentration.
30.
ZysowBRLindahlGEWadeDPKnightBLLawnR: C/T polymorphism in the 5′ untranslated region of the apolipoprotein (a) gene introduces an upstream ATG and reduces in-vitro translationArterioscler Thromb1995, 15:58–67. Astimulating study describing a further genetic marker of apo(a) expression and thence of Lp(a) concentration.
31.
WilliamsJKBellingerDANicholsTCGriggsTRBumolTFFoutsRL: Occlusive arterial thrombosis in cynomologus monkeys with varying plasma concentrations of lipoprotein (a)Arterioscler Thromb1993, 13:548–554.
32.
RosengrenAWilhelmsenLErikssonERisbergBWiedelH: Lipoprotein (a) and coronary heart disease: A prospective case-control study in a general population sample of middle-aged menBMJ1991, 301:1248–1251.
33.
JauhiainenMKoskinenPEhnholmCFrickMHMantariMManninenV: Lipoprotein (a) and coronary heart disease risk: A nested case-control study of the Helsinki Heart Study participantsAtherosclerosis1991, 89:59–67.
34.
RidkerRMHennekensCHStampferMJ: A prospective study of lipoprotein (a) and risk of myocardial infarctionJAMA1993, 270:2195–2199.
35.
SchaeferEJLamon-FavaSJannerJMcNamaraJROrdovasJMDavisCE: Lipoprotein (a) levels and risk of coronary heart disease in men. Lipid Research Clinics Primary Prevention TrialJAMA1994, 271:999–1003. Amethodologically sound analysis covering 7–10 years of follow-up that confirms Lp(a) as a risk factor for fatal and non-fatal myocardial infarction in white male study participants with elevated levels of LDL.
36.
ArmstrongVWCremerPEberleEMankeASchulzEFWielandH: The association between serum Lp(a) concentration and angiographically assessed coronary atherosclerosis: Dependence on serum LDL levelsAtherosclerosis1986, 62:249–257.
37.
WaldNJLawMWattHCWuTBaileyAJohnsonM: Apolipoproteins and ischaemic heart disease: Implications for screeningLancet1994, 343:75–79.
38.
CremerPNagelDLabrotBMannHMuchePElsterH: Lipoprotein Lp(a) as predictor of myocardial infarction in comparison to fibrinogen, LDL cholesterol and other risk factors: Results from the prospective Gottingen Risk Incidence and Prevalence Study (GRIPS)Eur J Clin Invest1994, 24:444–453. Aprospective cohort study following 6000 men over 5 years in which Lp(a) ranked fifth as a risk factor with almost identical status to elevated fibrinogen and low HDL levels for fatal and non-fatal myocardial infarction.
39.
SeedMStubbsPO'ConnorBDohertyEGreenwoodTW: Variations in Lp(a) concentrations in acute coronary ischaemia: Myocardial infarction and unstable angina [abstract]Proceedings of the International Atherosclerosis Society1994, 109:286.
40.
MaherVBrownGBMarcovinaSMSaccoDLiuJTHillgerLA: Adverse effect of Lp(a) on coronary atherosclerosis and clinical events is eliminated by substantially lowering LDL-cholesterol [abstract]. J Am Coll Cardiol1994:739.
41.
ThompsonGRMaherVGMMathewsSKitnaoYNeuworthCShortMB: The Familial Hypercholesterolaemia Regression Study: A randomised trial of LDL apheresisLancet1995, 345:811–816. Anangiographic comparison of 39 patients with familial hypercholesterolaemia undergoing LDL apheresis or oral therapy (40 mg simvastatin, 20 g cholestipol) to reduce LDL and Lp(a) levels or LDL levels alone, respectively. The mean LDL level during treatment was 3.3 mmol/l. In these circumstances, the Lp(a) concentration had no impact on angiographic change.
42.
BowdenJFPritchardPHHillJSFrolichJJ: Lipoprotein (a) concentration and apolipoprotein (a) isoform size: Relation to the presence of CAD in familial hypercholesterolaemiaArterioscler Thromb1994, 14:1561–1568. Somewhatsurprising data from Vancouver patients with familial hypercholesterolaemia and controls showing a poor correlation between the Lp(a) concentration and apo(a) isoform size. Furthermore, no correlation was found between coronary artery disease and Lp(a) concentration in the patients with familial hypercholesterolaemia. The authors felt this might have been a reflection of the study population's genetic heterogeneity.
43.
SeedMHopplicherMDReaveleyDMcCarthySThompsonGRBoerwinkleE: Relation of serum lipoprotein (a) concentration and apolipoprotein (a) phenotype to coronary heart disease in patients with familial hypercholesterolaemiaN Engl J Med1990, 322:1492–1499.
44.
WiklundOAngelinBLolfssonSOErikssonMFagerGBerglandL: Apolipoprotein (a) and ischaemic heart disease in familial hypercholesterolaemiaLancet1990, 335:1360–1363.
45.
FarrerMGameFLAlbersCNeilAWWinocourPHLakerMF: Coronary artery disease is associated with increased lipoprotein (a) concentrations independent of the size of circulating apolipoprotein (a) isoformsArterioscler Thromb1994, 14:1272–1283. Alarge study of 826 people, Caucasian controls and those with coronary artery disease, that showed that the Lp(a) concentration but not the apo(a) isoform was related to the presence of coronary artery disease.
CambillauMSimonAAmarJGiralPHAtgerVSegondP, And the PCVMETRA Group: Serum Lp(a) as a discriminant marker of early atherosclerotic plaque at three extracoronary sites in hypercholesterolemic menArterioscler Thromb1992, 12:1346–1352.
48.
MolgaardJKlauserICLassvikCFaergemanOGerdesLOOlssonAG: Significant association between low-molecular-weight apoprotein (a) isoforms and intermittent claudicationArterioscler Thromb1992, 12:895–901.
49.
BrownSAMorrisettJDBoerwinkleEHutchinsonRPatschW: The relation of lipoprotein (a) concentrations and apolipoprotein (a) phenotypes with asymptomatic atherosclerosis in subjects of the Atherosclerosis Risk in Communities (ARIC) StudyArterioscler Thromb1993, 13:1558–1566.
50.
JennerJLOrdovasJMLamon-FavaS: Effects of age, sex and menopausal status on plasma lipoprotein (a) levelsCirculation1993, 87:1135–1141.
51.
IslamSGutinBSmithCTreiberFKambohI: Association of apolipoprotein (a) phenotypes in children with family history of premature coronary artery diseaseArterioscler Thromb1994, 14:1609–1616. Ina small study of 46 children categorized according to their family history of premature coronary artery disease, small apo(a) isoforms were more prevalent in both blacks and whites with a positive family history.
52.
ShintaniSKikuchiSHamaguchiHShiigaiT: High serum lipoprotein (a) levels are an independent risk factor for cerebral infarctionStroke1993, 24:965–969.
53.
SandkampMFunkeHSchulteHKohlerEAssmannG: Lipoprotein (a) is an independent risk factor for myocardial infarction at a young ageClin Chem1990, 36:20–23.
54.
BuddeTFechtrupCBosenbergEVielhauerCEnbergsASchulteH: Plasma Lp(a) levels correlate with number, severity, and length-extension of coronary lesions in male patients undergoing coronary arteriography for clinically suspected coronary atherosclerosisArterioscler Thromb1994, 14:1730–1736. Acareful cross-sectional study of risk factors associated with coronary pathology in men suggesting that Lp(a) is related to the early pathogenesis of coronary artery disease.
55.
CressmanMDAboodDO'NeilJHoffHF: Lp(a) and premature mortality during chronic haemodialysisChem Phys Lipids1994, 67/68:419–427. Lp(a) proved to be an independent risk factor for fatal cardiovascular disease over a 4-year follow-up period in patients with treated end-stage renal failure.
56.
OremADegerOMemisOCaliskanKCimsitG: High endogenous Lp(a) levels as a thrombogenic risk factor in Behçet's diseaseAnn Rheumatol1994, 53:351–352.
57.
YamazakiMAsakauraHJokajiHSaitoMUotaniCKumabashiriI: Plasma levels of lipoprotein (a) are elevated in patients with the antiphospholipid antibody syndromeThromb Haemost1994, 71:424–427.
58.
QuiSTherouxPGenestJSolymossBCRobilaillEDMarcilM: Lipoprotein (a) blood levels in unstable angina pectoris, acute myocardial infarction and after thrombolytic therapyAm J Cardiol1991, 67:1175–1179.
59.
MbewuADDurringtonPNMacknessMIHuntLTurkieWHCreamerJE: Serum Lp(a) lipoprotein concentration and outcome of thrombolytic treatment for myocardial infarctionBr Heart J1994, 71:316–321. Thebest and most painstaking of the studies examining the relationship between the outcome of thrombolysis and Lp(a) concentration (indicated by electrocardiographic change 3 h after thrombolysis). The study supports the view that Lp(a) predicts myocardial infarction but not thrombolytic outcome.
60.
BrugemannJvan der MeerJHillegeHLvan BovenAJvan DoormaalJJde GraeffPA: Lipoprotein (a) levels in patients with myocardial infarction treated with anistreplase: No prediction of efficacy but inverse correlation with plasminogen activation in non-patencyInt J Cardiol1994, 24:109–113. Aninteresting study whose main contribution lies in its analysis of the relationship between Lp(a) and plasminogen in post-infarction vessels that did not recanalize after thrombolysis.
61.
MoliternoDJLangeRAMeidellRSWillartJELeffeetCCGerardRD: Relation of plasma lipoprotein (a) to infarct artery patency in survivors of myocardial infarctionCirculation1993, 88:935–940.
62.
SchreinerPMorrisettJDSharrettRPatschWTyrolerHAWuK: Lipoprotein (a) as a risk factor for preclinical atherosclerosisArterioscler Thromb1993, 13:826–833.
63.
LawnRMWadeDPHammerREChieseGVerstuyftJGRubinEM: Atherogenesis in transgenic mice expressing human apolipoprotein (a)Nature1992, 360:670–672.
64.
PalabricaTMLiuACAronovitzMJFurieBLawnRMFurieBC: Antifibrinolytic activity of apolipoprotein (a) in vivo: Human apolipoprotein (a) transgenic mice are resistant to tissue plasminogen activator-mediated thrombolysisNature Medicine1995, 1:256–259. Thefirst and most convincing in-vivo study showing the effect of apo(a) on fibrinolysis.
65.
LacknerCCohenJCHobbsHH: Molecular definition of the extreme size polymorphism in apolipoprotein (a)Hum Mol Genet1993, 2:922–940.
66.
LintonMFFarereRVChiseaGGrassDSChinPHammerRE: Transgenic mice expressing high plasma concentrations of human apolipoprotein B100 and lipoprotein (a)J Clin Invest1993, 92:3029–3037.
67.
PhillipsMLLembertasAVSchumakerVNLawnRMShireSJZioncheckF: Physical properties of recombinant apolipoprotein (a) and its association with LDL to form an Lp(a)-like complexBiochemistry1993, 32:3722–3728.
