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• W2313206757 abstract "The high degree of size heterogeneity of apo(a), the distinct protein component of lipoprotein (a) [Lp(a)], renders the development and selection of specific antibodies directed to apo(a) more difficult and poses significant challenges to the development of immunoassays to measure its concentration in plasma or serum samples. Apo(a) is extremely variable in size not only between but also within individuals because of the presence of two different, genetically determined apo(a) isoform sizes. Therefore, the antigenic determinants per particle available to interact with the antibodies will vary in the samples and the calibrators, thus contributing to apo(a) size-dependent inaccuracy of different methods. The lack of rigorous validation of the immunoassays and common means of expressing Lp(a) concentrations hinder the harmonization of results obtained by different studies and contribute to the lack of common cut points for identification of individuals at risk for coronary artery disease or for interventions aimed at reducing Lp(a) levels. The aim of our review is to present and critically evaluate the issues surrounding the measurements of Lp(a), their impact on the clinical interpretation of the data, and the obstacles we need to overcome to achieve the standardization of Lp(a) measurements. The high degree of size heterogeneity of apo(a), the distinct protein component of lipoprotein (a) [Lp(a)], renders the development and selection of specific antibodies directed to apo(a) more difficult and poses significant challenges to the development of immunoassays to measure its concentration in plasma or serum samples. Apo(a) is extremely variable in size not only between but also within individuals because of the presence of two different, genetically determined apo(a) isoform sizes. Therefore, the antigenic determinants per particle available to interact with the antibodies will vary in the samples and the calibrators, thus contributing to apo(a) size-dependent inaccuracy of different methods. The lack of rigorous validation of the immunoassays and common means of expressing Lp(a) concentrations hinder the harmonization of results obtained by different studies and contribute to the lack of common cut points for identification of individuals at risk for coronary artery disease or for interventions aimed at reducing Lp(a) levels. The aim of our review is to present and critically evaluate the issues surrounding the measurements of Lp(a), their impact on the clinical interpretation of the data, and the obstacles we need to overcome to achieve the standardization of Lp(a) measurements. Lipoprotein (a) [Lp(a)], is the most complex and polymorphic of the lipoprotein particles. Despite more than 50 years of intense research that has elucidated many aspects of Lp(a)'s structure and biochemistry, its physiological and pathological roles are still poorly understood. Lp(a) is composed of a lipoprotein particle quite similar in protein and lipid composition to LDL, containing one molecule of apoB wrapped around a particle that has primarily a core of cholesteryl ester and triglyceride with phospholipids and unesterified cholesterol at its surface. The presence of a unique hydrophilic, highly glycosylated protein referred to as apo(a), covalently attached to apoB-100 by a single disulfide bridge, differentiates Lp(a) from LDL (1Brunner C. Kraft H.G. Utermann G. Muller H.J. Cys4057 of apolipoprotein(a) is essential for lipoprotein(a) assembly.Proc. Natl. Acad. Sci. USA. 1993; 90: 11643-11647Crossref PubMed Scopus (147) Google Scholar, 2Koschinsky M.L. Côté G.P. Gabel B. van der Hoek Y.Y. Identification of the cysteine residue in apolipoprotein(a) that mediates extracellular coupling with apolipoprotein B-100.J. Biol. Chem. 1993; 268: 19819-19825Abstract Full Text PDF PubMed Google Scholar). Apo(a) is part of the plasminogen gene superfamily, and its presence imparts distinctive synthetic and catabolic properties to Lp(a) along with a marked size heterogeneity (3van der Hoek Y.Y. Wittekoek M.E. Beisiegel U. Kastelein J.J. Koschinsky M.L. The apolipoprotein(a) kringle IV repeats which differ from the major repeat kringle are present in variably-sized isoforms.Hum. Mol. Genet. 1993; 2: 361-366Crossref PubMed Scopus (172) Google Scholar). Treatment of purified Lp(a) with a reducing agent dissociates apo(a) from the particle yielding a lipoprotein particle that is similar to LDL in physical and chemical properties. However, Lp(a) particles have been reported to associate noncovalently with triglyceride-rich lipoproteins in hypertriglyceridemic individuals or after a fatty meal (4Gaubatz J.W. Hoogeveen R.C. Hoffman A.S. Ghazzaly K.G. Pownall H.J. Guevara Jr., J. Koschinsky M.L. Morrisett J.D. Isolation, quantitation, and characterization of a stable complex formed by Lp(a) binding to triglyceride-rich lipoproteins.J. Lipid Res. 2001; 42: 2058-2068Abstract Full Text Full Text PDF PubMed Google Scholar). This association may result in overestimation of Lp(a) measured by ELISA methods based on the apo(a) capture/apoB detection approach. Apo(a), shares a high amino acid sequence homology to several regions of the serine protease zymogen plasminogen, including the protease domain, and the so-called kringle 4 (K4) and 5 domains, which are tri-loop polypeptides stabilized by three internal disulfide bridges. Apo(a) is thus formed by an inactive carboxy-terminal protease-like domain and by a kringle 5 domain, both of which exhibit ∼85% homology with plasminogen, and multiple copies of the plasminogen-like K4 domain (Fig. 1). Based on amino acid sequence differences, the K4 domain of apo(a) is divided into 10 similar but distinct K4 types (1 through 10), having 75% to 85% amino acid homology with the K4 of plasminogen (5McLean J.W. Tomlinson J.E. Kuang W.J. Eaton D.L. Chen E.Y. Fless G.M. Scanu A.M. Lawn R.M. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen.Nature. 1987; 330: 132-137Crossref PubMed Scopus (1590) Google Scholar, 6Guevara Jr., J. Knapp R.D. Honda S. Northup S.R. Morrisett J.D. A structural assessment of the apo(a) protein of human lipoprotein(a).Proteins. 1992; 12: 188-199Crossref PubMed Scopus (65) Google Scholar). Each of the K4 types, except K4 type 2, is present as a single copy, whereas the identical K4 type 2 repeats vary from a minimum of 3 to as many as 40 (3van der Hoek Y.Y. Wittekoek M.E. Beisiegel U. Kastelein J.J. Koschinsky M.L. The apolipoprotein(a) kringle IV repeats which differ from the major repeat kringle are present in variably-sized isoforms.Hum. Mol. Genet. 1993; 2: 361-366Crossref PubMed Scopus (172) Google Scholar, 7Lackner C. Cohen J.C. Hobbs H.H. Molecular definition of the extreme size polymorphism in apolipoprotein(a).Hum. Mol. Genet. 1993; 2: 933-940Crossref PubMed Scopus (313) Google Scholar). As a consequence, apo(a) has the unique characteristic of being highly polymorphic in size, and the variable numbers of the K4 type 2 domains are primarily responsible for the size heterogeneity of Lp(a). Apo(a) is also heterogeneous in its glycosylation, which occurs both within the core of K4 motifs and within the linker sequences that join individual kringles (8Scanu A.M. Edelstein C. Learning about the structure and biology of human lipoprotein(a) through dissection by enzymes of the elastase family: facts and speculations.J. Lipid Res. 1997; 38: 2193-2206Abstract Full Text PDF PubMed Google Scholar), thus additionally contributing to the size heterogeneity of Lp(a). A variety of immunochemical methods, such as ELISA, nephelometry, immunoturbidimetry, and dissociation-enhanced lanthanide fluorescent immunoassay, are used to measure Lp(a) in human plasma or sera. The peculiar structural characteristics of Lp(a), including the high degree of size heterogeneity, the covalent association of apo(a) with apoB in the Lp(a) macromolecular complex, and the high sequence homology between apo(a) and plasminogen, constitute a significant challenge to the development of suitable immunoassays for the accurate measurement of Lp(a). The first hurdle is to develop suitable antibodies that are specific for apo(a) in the Lp(a) molecular complex. One possible approach is to make antibodies against purified apo(a), obtained by dissociating it from Lp(a) with a reducing agent. However, antibodies against apo(a) prepared in this manner generally react poorly with apo(a) in Lp(a), presumably because the reducing agent not only cleaves the disulfide bond between apoB and apo(a), but also cleaves the three intrachain disulfide bonds in each of the kringle domains, contributing to altered apo(a) conformation and to changes in its immunoreactivity. An alternate approach is to raise antibodies against purified Lp(a). Polyclonal antibodies produced by this approach would require absorptive removal of antibodies reacting with apoB and plasminogen. Similarly, monoclonal antibodies (MAbs) made against Lp(a) need to be selected for antigenic determinants specific for apo(a) and therefore not present in plasminogen or apoB. To correctly frame the issues related to the measurement of Lp(a), it is appropriate to provide some basic information on the use of immunoassays to measure the concentration of different proteins in human samples. Measurements by immunoassay are based on the antibody-antigen reaction whereby the measurement of a signal is generated by the formation of the antigen-antibody complex. A value is obtained by comparison of the signal in samples with that generated by a standard containing a known concentration of the analyte. For an assay to be accurate, 1) the antibody needs to be specific for the analyte being measured, 2) the analyte being measured in the sample should have the same structural characteristics as the analyte in the assay calibrator to achieve the same degree of immunoreactivity per particle, 3) an accuracy-based target value should be assigned to the assay calibrators using an appropriate reference material to guarantee consistency and comparability of results, and 4) common protocols should be available for transferring an accurate value from the reference material to the assay calibrators and to verify that accurate results are obtained on test samples. Considering the intra- and interindividual high degree of size variation in apo(a) due to the variable number of K4 type 2 repeats, it is practically impossible to select assay calibrators with the same apo(a) size present in individual samples to be analyzed. Because a greater number of antibodies directed to K4 type 2 will react with the larger than the smaller Lp(a) particles, Lp(a) molecules in the samples larger than those in the calibrator will give a higher signal than that of the calibrator, resulting in overestimation of Lp(a) values. In contrast, in the samples with Lp(a) molecules smaller than those in the calibrator, Lp(a) values will be underestimated. Therefore, the mass of the measured particles will not reflect the number of Lp(a) particles. Furthermore, the degree of inaccuracy in the samples will vary depending on the choice of the apo(a) sizes in the assay calibrators, their lot-to-lot changes, and the different approaches taken to assign their target value. Considering that calibrators of turbidimetric and immunonephelometric assays are usually selected to have high Lp(a) levels, the isoforms present in the calibrators may be predominantly constituted by small apo(a) sizes with the consequence that the majority of samples will have apo(a) isoforms larger than those in the calibrator resulting in overestimation of Lp(a) values. The different approaches taken to assign the target value to the assay calibrators and to express the Lp(a) values are other major factors contributing to Lp(a) method inaccuracy and to the lack of comparability of values obtained by commercially available methods. In the early 1970s, the first immunochemical methods developed to measure Lp(a) concentrations were based on antibodies generated using purified Lp(a), and the values assigned to the calibrators and consequently to the samples were expressed in milligrams per deciliter of the total lipoprotein mass obtained by summation of the major components of Lp(a) preparations purified from plasma (9Albers J.J. Hazzard W.R. Immunochemical quantification of human plasma Lp(a) lipoprotein.Lipids. 1974; 9: 15-26Crossref PubMed Scopus (161) Google Scholar, 10Albers J.J. Adolphson J.L. Hazzard W.R. Radioim­munoassay of human plasma Lp(a) lipoprotein.J. Lipid Res. 1977; 18: 331-338Abstract Full Text PDF PubMed Google Scholar). The majority of the assays subsequently developed expressed Lp(a) values in milligrams per deciliter of the total lipoprotein particle even though no common approaches were followed by manufacturers or research laboratories to assign the target values to the assay calibrators. Even though using modern immunoassays, Lp(a) levels are measured using antibodies specific to apo(a), the distinct protein component of Lp(a), many commercial methods and research laboratories continue to use standards with values assigned in milligrams per deciliter or grams per liter of the total mass of Lp(a) using different and poorly defined “master calibrators.” However, it is not possible to accurately determine the total mass of the heterogeneous Lp(a) particle because it requires the quantification of all the independent Lp(a) constituents, not only the protein but also the multiple lipid and carbohydrate components. Even if all the Lp(a) components could be accurately measured and the summation value of the components transferred to assay calibrators, the value would not be accurate because most individuals express two forms of Lp(a) that differ in apo(a) size, Lp(a) mass, and composition. The major lipid components include triglycerides, phospholipids, and cholesteryl esters with each containing numerous fatty acid species that vary in molecular mass due to differences in chain length and the degree of saturation. Lp(a) also contains variable types and amounts of sphingolipids and other fat-soluble molecules. The carbohydrate component of Lp(a) is also quite variable. Thus, the Lp(a) mass cannot be accurately computed from its constituent components because of inaccuracies in the determination of the mass of the major components and the failure to measure all components. Lp(a) mass can also be estimated by physical chemical methods such as sedimentation and flotation equilibrium (11Fless G.M. Santiago J.Y. Molecular weight determination of lipoprotein(a) in solutions containing either NaBr or D20: relevance to the number of apolipoprotein(a) subunits in Lp(a).Biochemistry. 1997; 36: 233-238Crossref PubMed Scopus (6) Google Scholar). Unfortunately, estimation of purified Lp(a) mass by physical chemical methods requires a number of assumptions and approximations that contribute to inaccuracy in the molecular mass estimations of the Lp(a) macromolecular complex. Another approach that has been followed is to first determine the mass of the protein components of Lp(a), apo(a), and apoB and then assume that the nonprotein components of Lp(a) are similar to that of LDL. Although the apoB component of Lp(a) presumably contains carbohydrate similar to that of LDL, the apo(a) component contains a considerable amount of additional carbohydrate, and the amount varies with the size of apo(a). Furthermore, no rigorous studies have been performed to evaluate to what extent LDL and Lp(a) may also differ in the highly heterogeneous and variable lipid component. Computation of the mass of Lp(a) requires an accurate quantification of each of the different lipid, protein, and carbohydrate components of Lp(a). Highly specialized analytical approaches, each with its own margin of error, are required to quantify the different Lp(a) constituents. As a result, computation of the mass of Lp(a) is fraught with errors. Also, using conventional purification procedures, the amount of Lp(a) recovered from plasma is usually only ∼30% of the Lp(a) initially present. Therefore, the composition of the Lp(a) particles isolated by these procedures may not be representative of the total Lp(a) particles in plasma, and the relative proportion of the two Lp(a) species present in plasma of heterozygous individuals may not be the same as that in the purified Lp(a) preparation. Detailed physical/chemical analyses of Lp(a) mass purified by more advanced approaches such as immunoaffinity purification are not yet available. In any case, for analytical purposes, even if Lp(a) mass could be accurately determined in a primary standard, the Lp(a) mass and the relative concentration of each of the components would be different from that in the assay calibrators or in the test samples. Additionally, the weight ratio of the protein mass of apo(a) to apoB in Lp(a) varies widely depending on the size of apo(a). For example, an Lp(a) containing 15 apo(a) K4 units has an apo(a)/apoB weight ratio of 0.44, whereas an Lp(a) containing 32 apo(a) K4 units has a weight ratio of 0.85. Thus, it is not possible for the primary standard, secondary reference material, assay calibrators, and human samples to have the same Lp(a) composition. Another major point to consider is that there are no other lipoproteins where the values are expressed in total mass, but instead the values are expressed either in milligrams per deciliter or in SI units on the basis of which lipoprotein component is directly measured, being it a specific protein or a specific lipid. To evaluate the contribution of the apo(a) size polymorphism on the inaccuracy of Lp(a) measurements, a variety of MAbs were generated in our laboratory, selected, and carefully characterized for their apo(a) domain specificity, high affinity, and immunochemical properties (12Marcovina S.M. Albers J.J. Gabel B. Koschinsky M.L. Gaur V.P. Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a).Clin. Chem. 1995; 41: 246-255Crossref PubMed Scopus (272) Google Scholar). Using an ELISA sandwich format, an MAb (MAb a-6) was selected to be coated on the ELISA plate wells. The epi­tope recognized by this antibody is located in apo(a) K4 type 2. As depicted in Fig. 1, the K4 type 2 is present in a variable number of identical repeats, and the selection of this MAb was made to achieve the capture of all Lp(a) particles present in the plasma samples. To mimic the immunochemical properties of polyclonal antibodies, MAb a-5, directed to an epitope present in both K4 type 1 and 2 (Fig. 1), was selected as the detecting antibody in one ELISA format. MAb a-40, specific for a unique apo(a) epitope located in K4 type 9 (Fig. 1), was selected as the detecting antibody in a second ELISA format (12Marcovina S.M. Albers J.J. Gabel B. Koschinsky M.L. Gaur V.P. Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a).Clin. Chem. 1995; 41: 246-255Crossref PubMed Scopus (272) Google Scholar). We have demonstrated that Lp(a) contains 1 mol of apo(a) and 1 mol of apoB (13Albers J.J. Kennedy H. Marcovina S.M. Evidence that Lp(a) contains one molecule of apo(a) and one molecule of apoB: evaluation of amino acid analysis data.J. Lipid Res. 1996; 37: 192-196Abstract Full Text PDF PubMed Google Scholar), and therefore, we determined by amino acid analysis the protein concentration of an Lp(a) preparation isolated from human plasma containing an apo(a) with 21 K4 motifs. This purified Lp(a) was then used as a primary standard. To circumvent the problems of the apo(a) size variability, the Lp(a) protein concentration was calculated and expressed in nanomoles per liter, thus reflecting the number of Lp(a) particles. The value obtained in the primary standard was then transferred to the assay calibrator. This value transfer is performed by using the primary standard to calibrate the assay and by performing multiple analyses of the calibrator over a period of several days. The mean of the values constitutes the assigned value of the assay calibrator. A final check of the accuracy of the value transfer is performed by calibrating the assay with the calibrator material and by analyzing multiple times the primary standard. The value transfer is considered accurate if the mean value obtained on the primary standard is within 2% of the expected value. Samples used in this study were selected from subjects who demonstrated a single apo(a) isoform by a high-resolution phenotype system (14Marcovina S.M. Zhang Z.U. Gaur V.P. Albers J.J. Identification of 34 apolipoprotein(a) isoforms: differential expression of apolipoprotein(a) alleles between American blacks and whites.Biochem. Biophys. Res. Commun. 1993; 191: 1192-1196Crossref PubMed Scopus (218) Google Scholar). We have shown that the log of the number of apo(a) K4-encoding sequences in the apo(a) gene are linearly related to the relative mobility of the apo(a) isoforms on agarose gel, providing the basis for a standardized isoform nomenclature where each isoform is defined by its number of K4 domains (15Marcovina S.M. Hobbs H.H. Albers J.J. Relationship between number of apolipoprotein(a) kringle 4 repeats and mobility of isoforms in agarose gel: basis for a standardized nomenclature.Clin. Chem. 1996; 42: 436-439Crossref PubMed Scopus (111) Google Scholar). The selected 723 samples were analyzed in parallel with the same ELISA conditions using the two different detecting MAbs (12Marcovina S.M. Albers J.J. Gabel B. Koschinsky M.L. Gaur V.P. Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a).Clin. Chem. 1995; 41: 246-255Crossref PubMed Scopus (272) Google Scholar). The average bias between the a-5 MAb and a-40 MAb formats was highly correlated with the number of apo(a) K4 domains in the sample. Thus, Lp(a) values measured using MAb a-5, which mimics the immunochemical reactivity of a polyclonal antibody, were higher than those using MAb a-40 in samples containing >21 K4 units and were lower in samples containing <21 K4 units (Fig. 2). For example, by using MAb a-5, Lp(a) values in samples containing 18 K4 were underestimated by 10%, whereas the values were overestimated by ∼20% in samples containing 25 K4 as compared with the values obtained by MAb a-40. The results of this experiment clearly show that the apo(a) size heterogeneity has a significant impact on the accuracy of the measurement of Lp(a). The 723 samples were also analyzed by the same ELISA conditions, but using a polyclonal antibody against apoB as detecting antibody (12Marcovina S.M. Albers J.J. Gabel B. Koschinsky M.L. Gaur V.P. Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a).Clin. Chem. 1995; 41: 246-255Crossref PubMed Scopus (272) Google Scholar). Very similar Lp(a) values, regardless of apo(a) size, were obtained by using either MAb a-40 or the polyclonal antibody directed against apoB as detecting antibody (Fig. 2). These results clearly indicate that harmonization of Lp(a) values can be achieved using a common calibrator and antibodies unaffected by the size polymorphism of apo(a). More recently, Lp(a) values obtained by the MAb a-40 ELISA method on 80 samples spanning a large range of levels and apo(a) isoform size showed high correlation and excellent agreement of absolute values with an ultraperformance liquid chromatography/mass spectrometry method (16Lassman M.E. McLaughlin T.M. Zhou H. Pan Y. Marcovina S.M. Laterza O. Roddy T.P. Simultaneous quantitation and size characterization of apolipoprotein(a) by ultra-performance liquid chromatography/mass spectrometry.Rapid Commun. Mass Spectrom. 2014; 28: 1101-1106Crossref PubMed Scopus (35) Google Scholar), again confirming that using calibrator values traceable to a common reference material, comparable Lp(a) values can be obtained by different methods not affected by apo(a) size variation. To directly evaluate the impact that method inaccuracy may have on the classification of patients at high risk for CVD based on their Lp(a) levels, we used results of analyses performed on the Framingham offspring cohort during the fifth cycle (17Lamon-Fava S. Marcovina S.M. Albers J.J. Kennedy H. Deluca C. White C.C. Cupples A. McNamara J.R. Seman L.J. Bongard V. et al.Lipoprotein(a) levels, apo(a) isoform size, and coronary heart disease risk in the Framingham Offspring Study.J. Lipid Res. 2011; 52: 1181-1187Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). Lp(a) levels and apo(a) isoforms were determined in our laboratory on 2,940 samples. Lp(a) levels were also determined in another laboratory by a commercially available turbidimetric method on 2,556 samples. Individuals with Lp(a) values above the 75 percentile of the Framingham cohort were considered at an increased risk for CVD. The turbidimetric assay as compared with results obtained by the reference ELISA method misclassified 136 individuals as being at increased risk for CVD (false positive) and 23 individuals as being not at risk (false negative). All the false-positive results obtained by the turbidimetric assay were explained by overestimation of Lp(a) values based on the predominant apo(a) size in the sample (17Lamon-Fava S. Marcovina S.M. Albers J.J. Kennedy H. Deluca C. White C.C. Cupples A. McNamara J.R. Seman L.J. Bongard V. et al.Lipoprotein(a) levels, apo(a) isoform size, and coronary heart disease risk in the Framingham Offspring Study.J. Lipid Res. 2011; 52: 1181-1187Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). These findings are consistent with the fact that the size of apo(a) in the calibrator was quite small and most samples in this population had apo(a) sizes larger than the apo(a) in the calibrator. The few false-negative results by this assay were explained by the relatively few samples with apo(a) smaller than the apo(a) in the calibrator. To further evaluate the impact of Lp(a) method differences on the interpretation of clinical data, Lp(a) levels were measured by the ELISA reference method and by a commercially available nephelometric method on samples from 195 participants in the Physician Health Study who subsequently developed angina and on 195 gender- and age-matched controls (18Rifai N. Ma J. Sacks F.M. Ridker P.M. Hernandez W.J. Stampfer M.J. Marcovina S.M. Apolipoprotein(a) size and lipoprotein(a) concentration and future risk of angina pectoris with evidence of severe coronary atherosclerosis in men: the Physicians' Health Study.Clin. Chem. 2004; 50: 1364-1371Crossref PubMed Scopus (101) Google Scholar). Previously published results from the Physician Health Study found no association between Lp(a) levels, as measured by a nephelometric method, and risk of future myocardial infarction (MI), stroke, or peripheral vascular disease (19Ridker P.M. Hennekens C.H. Stampfer M.J. A prospective study of lipoprotein(a) and the risk of myocardial infarction.J. Am. Med. Assoc. 1993; 270: 2195-2199Crossref PubMed Scopus (461) Google Scholar, 20Ridker P.M. Stampfer M.J. Hennekens C.H. Plasma concentration of lipoprotein(a) and the risk of future stroke.J. Am. Med. Assoc. 1995; 273: 1269-1273Crossref PubMed Scopus (119) Google Scholar, 21Ridker P.M. Stampfer M.J. Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease.J. Am. Med. Assoc. 2001; 285: 2481-2485Crossref PubMed Scopus (1071) Google Scholar). The results obtained with the reference ELISA indicated that the median Lp(a) concentration was significantly higher in cases as compared with controls and baseline Lp(a) values were predictive of future angina. A 2-fold risk was found in study participants with Lp(a) concentrations in the 80th percentile and a 4-fold risk was found in those with Lp(a) above the 95th percentile. In contrast, when using the results obtained by the nephelometric method, median Lp(a) levels did not differ significantly between cases and controls, and Lp(a) levels were not significantly associated with the development of angina. Based on the results of this study (18), the authors in the discussion concluded that “it seems likely that the Lp(a) method affected by apo(a) size that was previously used in the Physician Health Study may have underestimated or even obscured the true relationship between Lp(a) concentration and CVD.” In an attempt to standardize the measurement of Lp(a), the major aim of the International Federation of Clinical Chemistry (IFCC) working group on Lp(a), was to select and characterize a secondary reference material to be used by manufacturers of commercially available methods to assign an accuracy-based Lp(a) target value to their assay calibrators (22Tate J.R. Berg K. Couderc R. Dati F. Kostner G.M. Marcovina S.M. Rifai N. Sakurabayashi I. Steinmetz A. International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Standardization Project for the measurement of lipoprotein(a). Phase 2: selection and properties of a proposed secondary reference material for lipoprotein(a).Clin. Chem. Lab. Med. 1999; 37: 949-958Crossref PubMed Scopus (49) Google Scholar). Among the different preparations evaluated, a proposed reference material (PRM) was selected to be further characterized. To circumvent the strong limitations in the determination of the total mass of the highly heterogeneous Lp(a) previously discussed and taking into consideration the size polymorphism of apo(a), which is the Lp(a) constituent usually directly measured by the immunoassays, the members of the IFCC working group decided that the target value to PRM be assigned in nanomoles per liter of Lp(a) protein. We have previously demonstrated that there is 1 mol of apo(a) and 1 mol of apoB in" @default.
• W2313206757 created "2016-06-24" @default.
• W2313206757 creator A5019882573 @default.
• W2313206757 creator A5067464347 @default.
• W2313206757 date "2016-04-01" @default.
• W2313206757 modified "2023-10-16" @default.
• W2313206757 title "Lipoprotein (a) measurements for clinical application" @default.
• W2313206757 cites W1549967714 @default.
• W2313206757 cites W1708837772 @default.
• W2313206757 cites W1841330065 @default.
• W2313206757 cites W1876370444 @default.
• W2313206757 cites W1907534963 @default.
• W2313206757 cites W1923408704 @default.
• W2313206757 cites W1967527533 @default.
• W2313206757 cites W1972444318 @default.
• W2313206757 cites W1975051427 @default.
• W2313206757 cites W1976485306 @default.
• W2313206757 cites W1980216884 @default.
• W2313206757 cites W1988163135 @default.
• W2313206757 cites W1989069669 @default.
• W2313206757 cites W1990204315 @default.
• W2313206757 cites W1994699782 @default.
• W2313206757 cites W1995859867 @default.
• W2313206757 cites W2007178040 @default.
• W2313206757 cites W2009191878 @default.
• W2313206757 cites W2016918979 @default.
• W2313206757 cites W2022756739 @default.
• W2313206757 cites W2036170644 @default.
• W2313206757 cites W2044515472 @default.
• W2313206757 cites W2052960152 @default.
• W2313206757 cites W2059128672 @default.
• W2313206757 cites W2065390391 @default.
• W2313206757 cites W2080117257 @default.
• W2313206757 cites W2085058703 @default.
• W2313206757 cites W2085713634 @default.
• W2313206757 cites W2086153196 @default.
• W2313206757 cites W2098890974 @default.
• W2313206757 cites W2104355263 @default.
• W2313206757 cites W2104536891 @default.
• W2313206757 cites W2106036207 @default.
• W2313206757 cites W2108284872 @default.
• W2313206757 cites W2111144965 @default.
• W2313206757 cites W2117264692 @default.
• W2313206757 cites W2118645446 @default.
• W2313206757 cites W2126617498 @default.
• W2313206757 cites W2130053210 @default.
• W2313206757 cites W2130412576 @default.
• W2313206757 cites W2130483103 @default.
• W2313206757 cites W2139983966 @default.
• W2313206757 cites W2144390703 @default.
• W2313206757 cites W2149949008 @default.
• W2313206757 cites W2155822995 @default.
• W2313206757 cites W2160741225 @default.
• W2313206757 cites W2184549447 @default.
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