Analysis of the apolipoprotein(a) size polymorphism in patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is characterized by an increased incidence of vascular disease which is only partially explained by traditional risk factors. Previous reports suggested that the level of lipoprotein(a) [Lp(a)], a particle linked to atherothrombotic disorders, is increased in patients with SLE. However, whether there are any differences in the distribution of apolipoprotein(a) [apo(a)] phenotypes between SLE patients and healthy controls remain to be determined. To address this issue, Lp(a) levels and apo(a) isoform size were analyzed in a total of 54 patients with SLE and in 108 age- and gender-matched healthy controls. SLE patients showed Lp(a) levels [median (interquartile range): 25.3 (6.5-51.0) vs. 9.5 (4.6-25.9) mg/dl, P=0.0109)] and a percentage of subjects with at least one small-sized apo(a) isoform (< or =25 K-IV repeats) significantly higher than controls (44.44% vs. 25.92%, P=0.0277). Multiple regression analysis adjusting for age, gender, disease duration, kidney involvement, the presence of active disease, as well as the carriage of at least one small apo(a) isoform revealed that only small apo(a) phenotypes were significant predictors of Lp(a) levels in SLE patients (P=0.0001). We conclude that genetic factors related to apo(a) size are a major determinant of elevated Lp(a) levels in patients with SLE. As small apo(a) phenotypes have been related to adverse vascular effects, it is feasible that small apo(a) isoforms may be a useful biological marker in the assessment of vascular risk in patients with SLE.     

冠心病家族史青少年载脂蛋白E、B的基因多态性

目的 探讨青少年载脂蛋白E(apolipoprotein E，apoE)、apoB基因多态性对冠心病的遗传易感性。方法 应用聚合酶链反应—限制性片段长度多态性技术，对244名健康汉族大学生(冠心病家族史阳性者109人，阴性者135人)的apoE、apoB XbaI、apoB 3’可变数目串联重复序列(variable number of tandem repeat ，VNTR)基因型进行分析。结果 阳性组的e4、x^ 、VNTR—B(hypervariable element，HVE＞38)等位基因频率显著高于阴性组(P＜0．05)，且与血总胆固醇、低密度脂蛋白—胆固醇、aPoBl00水平升高有显著相关(P＜0．05)。结论 apoE的e4、apoB Xba I的x^ 、apoB3’VNTR的VNTR—B可能为冠心病的重要遗传标记。     

Apolipoprotein E phenotype and lipoprotein(a) in familial hypercholesterolaemia implication for lipoprotein(a) metabolism

The mechanisms regulating plasma levels of lipoprotein(a) [Lp(a)] are largely unknown. A two- to three-fold increase in Lp(a) levels in patients with familial hypercholesterolaemia (FH) has implied that LDL receptor activity may be an important factor in determining plasma Lp(a) levels, as it is in determining low-density lipoprotein (LDL) cholesterol concentration. Common apolipoprotein E (apoE) variants also affect plasma LDL cholesterol levels. We therefore examined the effect of the common apoE variants on plasma Lp(a) levels in 149 patients with heterozygous FH. Patients with the apoE₂ allele (n = 11) had significantly higher plasma levels of LDL cholesterol compared to those with a apoE₃E₃ phenotype, while patients with the apoE₄ isoform had similar levels. However, there was a significant effect of the apoE₂ allele in lowering Lp(a) levels, compared to the apoE₃E₃ group. The median Lp(a) concentration in patients possessing an apoE₂ isoform was 13.1 mg/dl below the median, while in those with an apoE₄ allele the median Lp(a) levels were 4.13 mg/dl higher. There was a marked inverse correlation between plasma Lp(a) and LDL cholesterol concentration in the FH patients carrying the apoE₂ allele. Our data imply that difference in Lp(a) levels observed between FH patients with different apoE isoforms does not result from altered clearance of Lp(a) via the LDL receptor pathway, and suggest that apoE mediated hepatic up-take, or conversion, of remnant particles may be determining Lp(a) production rate.Abbreviations apo apoprotein - CHD coronary heart disease - FH familial hypercholesterolaemia - HDL high-density lipoprotein - LDL low-density lipoprotein - Lp(a) lipoprotein(a)     

Effects of apoE gene polymorphism on Lp(a) concentrations depend on the size of apo(a): a study of 466 white men

 Polymorphisms in the genes for the low-density lipoprotein (LDL) receptor ligands, apolipoprotein E (apoE), and apolipoprotein B (apoB) are associated with variation in plasma levels of LDL cholesterol. Lp(a) lipoprotein(a) [Lp(a)] is LDL in which apoB is attached to a glycoprotein called apolipoprotein(a) [apo(a)]. Apo(a) has several genetically determined isoforms differing in molecular weight, which are inversely correlated with Lp(a) concentrations in blood. The interaction of apo(a) with triglyceride-rich lipoproteins differs with the size of apo(a), and therefore the effects of apoE gene polymorphism on Lp(a) levels could also depend on apo(a) size. We have investigated the possible effect of genetic variation in the apoE and apoB genes on plasma Lp(a) concentrations in 466 white men with different apo(a) phenotypes. Overall there was no significant association between the common apoE polymorphism and Lp(a), but in the subgroup with apo(a)-S4, concentrations of Lp(a) differed significantly among the apoE genotypes (P=0.05). Lp(a) was highest in the apoE genotypes ɛ₂ɛ₃ and ɛ₃ɛ₃ and lowest in genotype ɛ₃ɛ₄, and the apoE polymorphism was estimated to account for about 2.4% of the variation in Lp(a). In contrast, in the subgroup with apo(a)-S2 Lp(a) was significantly lower (P=0.04) in apoE genotype ɛ₂ɛ₃ than in genotype ɛ₃ɛ₃. Lp(a) concentrations did not differ among the XbaI (P=0.65) or SP 24/27 (P=0.26) polymorphisms of the apoB gene. The expected effects of both apoE and apoB polymorphism on LDL levels were significant in the whole population sample and in subjects with large-sized apo(a) isoforms (P<0.01), whereas no effect was seen in those with low molecular weight apo(a) isoforms. We conclude that the influence of apoE genotypes on Lp(a) concentrations depends on the size of the apo(a) molecule in Lp(a), possibly because both apo(a)-S4 and apoE4 have high affinity for triglyceride-rich lipoproteins and may be taken up and degraded rapidly by remnant receptors. Received: 12 January 1995 / Accepted: 12 July 1996     

Apolipoprotein(a) isoform-specific changes of lipoprotein(a) after kidney transplantation

The atherogenic lipoprotein(a) (Lp(a)) is significantly increased in patients with kidney disease. Some studies in hemodialysis patients described this increase to be dependent on the genetic apolipoprotein(a) (apo(a)) isoforms. Only patients who express high molecular weight (HMW) apo(a) isoforms but not those with low molecular weight (LMW) isoforms show a relative increase of Lp(a) when compared to healthy controls matched for apo(a) isoforms. However, this was not confirmed by all studies. We therefore prospectively investigated the changes of Lp(a) deriving from each apo(a) isoform in heterozygotes following kidney transplantation. Lp(a) concentrations were measured by ELISA. To calculate the isoform-specific concentrations and the changes of Lp(a) deriving from each isoform, we densitometrically scanned the apo(a) bands from immunoblots before and after transplantation in 20 patients expressing two apo(a) isoforms. Of these, 10 patients expressed both an LMW and an HMW apo(a) isoform. The other 10 patients expressed only HMW isoforms. Densitometric scanning of apo(a) bands and calculation of isoform-derived Lp(a) concentrations clearly demonstrated that the decrease of Lp(a) following kidney transplantation is caused by changes in the expression of HMW apo(a) isoforms. In some patients, we observed an almost complete disappearance of the HMW apo(a) isoform after transplantation. This study clearly demonstrates that the changes of Lp(a) plasma concentrations in kidney disease depend on the genetically determined size of apo(a). This provides evidence for an interaction of apo(a) genetic variability and kidney function on Lp(a) concentrations.     

Study of lipoprotein (a) phenotypes in Ivorian subject

The objective of this study was to identify the apo (a) phenotypes and to find a correlation between apo (a) isoform size and Lp (a) plasma level in Ivorian subjects. This study involved 30 healthy subjects (11 females and 19 males) aged of 35 +/- 2 years. Lp (a) plasma levels have been determined by technical ELISA, while phenotypes of apo (a) have been identified by agarose high resolution electrophoresis followed by Western blot. The Lp (a) plasma level in our population was 329 +/- 291 mg/l and 30% of our population's Lp (a) plasma levels were above 300 mg/l. 70% of our subjects have homozygous phenotype and 30% have heterozygous phenotype. Three apo (a) isoforms (S2, S3, S4) have been identified in homozygous subjects whereas four apo (a) isoforms (B, S2, S3, S4) have been detected in heterozygous subjects. Their sizes varied from 13 to 33 kringle 4.77% of our subjects had apo (a) isoforms whose sizes were above 22 kringle 4. No correlation has been observed between the size of apo (a) isoforms and the Lp (a) plasma level in homozygous subjects. Our results highlight apo (a) polymorphism in Ivorians. Homozygous phenotypes and large size apo (a) isoforms predominate in this population.     

Polymorphisms in human apolipoprotein(a) kringle IV-10 and coronary artery disease: relationship to allele size, plasma lipoprotein(a) concentration, and lysine binding site activity

Elevated plasma levels of lipoprotein(a) [Lp(a)] represent a major independent risk factor for the development of atherosclerosis. The kringle IV type 10 of apolipoprotein(a) [apo(a)] is the primary lysine binding site (LBS) of Lp(a) and is associated with lesion formation in transgenic mice. The purpose of this study was to search for mutations in the apo(a) kringle IV type 10 which could alter the LBS activity of Lp(a) from patients with coronary artery disease. We found the DNA region of kringle IV type 10 of apo(a) to be mutable but relatively well preserved in the Spanish population. We identified a novel mutation which probably leads to a truncated form of apo(a) in a patient heterozygous for the mutation and with low lysine binding activity and low plasma Lp(a) concentration. Two other mutations have been previously identified in humans, the substitutions W81R and M75T. The W81R was not found in our sample, but the M75T mutation was present in 43% of patients with coronary artery disease and 23% of age-matched controls. The genotype TT conferred a significant risk for myocardial infarction (odds ratio 2.53). This association was not due to linkage disequilibrium with kringle IV repeats. The M75T polymorphism was not associated with the LBS function of apo(a), but it influenced plasma Lp(a) concentration.     

A common nonsense mutation in the repetitive Kringle IV-2 domain of human apolipoprotein(a) results in a truncated protein and low plasma Lp(a)

LPA, the gene coding for apolipoprotein(a) [apo(a)], is the major determinant of lipoprotein(a) [Lp(a)] plasma levels, which are associated with risk for coronary heart disease (CHD) and stroke. It is not completely understood how variation in LPA relates to Lp(a) concentrations. One type of variation related to Lp(a) levels is the number of Kringle (K) IV-2 (g.61C>T; GenBank L14005.1) repeats in LPA, but sequence variation may also contribute. Human apo(a) contains from two to >40 nearly identical K IV-2 repeats of genomic size 5.5 kb, which makes it difficult to detect mutations. To elucidate the genetic variation of the apo(a) K IV-2 domain, we isolated a single "nonexpressing" apo(a) allele with 26 K IV-2 repeats, followed by PCR, cloning and sequencing of 96 clones, resulting in an average coverage of each K IV-2 repeat of approximately four-fold. The previously described K IV types 2A and 2B (K IV-2A and K IV-2B) were detected in 74% of the clones. In addition, a new type designated 2C (K IV-2C) was present. A nonsense mutation in the first exon of K IV-2 (g.61C>T) predicted to result in a truncated protein (p.R21X) was found in nine clones on a K IV-2A background. The presence of this mutation was confirmed by analysis of genomic DNA and was shown to represent the rare allele (frequency 0.02) of a SNP. Immunoblot analysis of apo(a) from plasma confirmed the presence of a truncated apo(a) isoform in the index individual and family members. Our data show that SNPs affecting Lp(a) plasma concentrations also exist in the apo(a) K IV-2 domain.     

Review of risk factors for cardiovascular diseases

Traditional risk factors for coronary heart disease (CHD) include only the patient's age and family history and whether there is evidence of hypertension, elevated LDL, low HDL, diabetes or history of smoking. In recent years, considerable progress has been made in identifying a new generation of risk factors, including Lp(a). triglycerides, subfractions of HDL and LDL, modified LDL, apo E pheno/genotype, homocysteine and fibrinogen. At the same time, studies have broadened our knowledge of traditional markers. These advances have enabled physicians to make a better assessment of patient risk for CHD and to prescribe more appropriate treatment.     

Lipoprotein(a): identification of subjects with a superbinding capacity for fibrinogen

We have previously shown that the binding of lipoprotein (a) [Lp(a)] to immobilized fibrinogen involves the domain located in kringles IV-5 to IV-8, but not kringle IV-10. In extending those studies to subjects living in Chicago and in the island of Sardinia, we found that about 6% of them had an Lp(a) with Bmax values of 27.7 + 6.0 fmol, which were about 5–8-fold higher than those of controls (3.4 + 2.8 fmol) and in the range of those observed for free apo(a) derived from the Lp(a) of controls (36.6 + 2.9 fmol). This superbinding phenotype was unaffected by age, sex, type of lipid disorder and hypolipidemic agents, and also had a familial incidence. We are currently exploring the hypothesis that this fibrinogen superbinding phenotype is due to conformational changes of apolipoprotein(a) [apo(a)] resulting from the lipid content and composition of the Lp(a) particle and/or sequence anomalies in the kringle domain IV-5 to IV-8.     

Apolipoprotein(a) phenotypes and lipoprotein(a) concentrations in patients with hyperthyroidism

Lipoprotein(a) [Lp(a)] is a low-density lipoprotein (LDL) particle in which apolipoprotein B-100 (apoB) is attached to a glycoprotein called apolipoprotein(a) [apo(a)]. Apo(a) has several genetically determined phenotypes differing in molecular weight, to which Lp(a) concentrations in plasma are inversely correlated. High plasma levels of Lp(a) are associated with atherosclerotic diseases. It is therefore of interest to study whether factors other than the apo(a) gene locus are involved in the regulation of Lp(a) concentrations. We measured plasma concentrations of Lp(a) and other lipoproteins and determined apo(a) phenotypes in 31 patients with hyperthyroidism, before and after the patients had become euthyroid by treatment. The mean concentration of LDL cholesterol rose from 2.67 to 3.88 mmol/l (P<0.01), apoB rose from 0.79 to 1.03 g/l (P<0.01), and the median Lp(a) concentration increased from 9.74 to 18.97 mg/dl (P<0.01) on treatment. Lp(a) concentrations were inversely associated to the size of the apo(a) molecule both before (P< 0.01) and after treatment (P<0.01). The increase in Lp(a) was significant patients with high molecular weight apo(a) phenotypes (n = 9; P<0.01) and in patients with low molecular weight apo(a) phenotypes (n=16; P< 0.01), but not in those with apo(a) null types (n = 6; P = 0.5). The low levels LDL cholesterol and apoB in untreated hyperthyroidism may result from increased LDL receptor activity. The increase in Lp(a) levels were not correlated with the increase in LDL cholesterol or apoB. Most other clinical evidence indicates that the LDL receptor is not important in Lp(a) catabolism, and we suggest that the low Lp(a) levels seen in thyroid hormone excess are caused by an inhibition of Lp(a) synthesis.Abbreviations Lp(a) lipoprotein(a) - apo(a) apolipoprotein(a) - apoB apolipoprotein B-100 - LDL low-density lipoprotein - HDL high-density lipoprotein - TG triglycerides - T ₄ thyroxine - T ₃ triiodothyronine - TSH thyrotropin     

载脂蛋白(a)5'调控区(TTTTA)n基因多态性与冠心病及其血清脂质的关系

目的:研究载脂蛋白(a)五核苷酸重复序列(PNR)基因多态性在湖北地区汉族人群冠心病(CHD)患者中的分布特点,进一步探讨其与血脂水平的关系。方法:采用聚合酶链反应结合聚丙烯酰胺凝胶电泳,分析了153例健康人及88例冠心病患者的apo(a)PNR基因型,并测定其血清胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、ApoAⅠ、ApoB及脂蛋白(a)的浓度进行分析。结果:CHD患者LP(a)、TC、TG、LDL-C水平明显高于对照组,HDL-C水平明显低于对照组(P<0.01);ApoAⅠ、ApoB两组间无显著差异;CHD组apo(a)PNR(TTTTA)_5/8基因型频率(0.181)和(TTTTA)₅等位基因频率(0.107)分别显著高于对照组(P＜0.05);(TTTTA)_5/8基因型者血清LP(a)水平高于(TTTTA)_8/8、(TTTTA)_8/9基因型者。结论:apo(a)PNR(TTTTA)₅等位基因可能是湖北地区汉族人群冠心病的危险因子之一。     

High plasma levels of apo(a) fragments in Caucasians and African-Americans with end-stage renal disease: implications for plasma Lp(a) assay

Apolipoprotein(a) [apo(a)] is a plasma glycoprotein that is highly polymorphic in size due to differences in the number of a tandemly arrayed cysteine-rich repeat called kringle (K)4 at its N-terminus. Most plasma apo(a) is covalently attached to apolipoprotein B-100 and circulates as part of lipoprotein(a) [Lp(a)]. A fraction of apo(a) circulates free of lipoproteins. Almost all of the free apo(a) consists of fragments containing variable numbers of K4 repeats derived from the N-terminal region. Previously we provided evidence suggesting that the apo(a) fragments present in human plasma are the source of the apo(a) fragments in human urine. If this were the case, it would be expected that plasma levels of fragments would be higher in subjects with end-stage renal disease (ESRD). In this paper we quantified the levels of apo(a) fragments and plasma Lp(a) in 26 Caucasian and 26 African-American subjects with ESRD and 52 healthy subjects matched for race, sex and the size of the apo(a) isoforms. The plasma levels of apo(a) fragments and Lp(a) were both higher in the ESRD subjects. In addition, the ratio of apo (a) fragments to total immunodetectable apo(a) was increased in ESRD. To determine how much the increase in the apo(a) fragments contributed to the increase in plasma Lp(a) in ESRD, the plasma Lp(a) levels were measured employing two different anti-apo(a) enzyme-linked immunoabsorption assays (ELISA). One assay detected both free and bound apo(a), whereas the other assay detected only bound apo(a). Although the plasma levels of apo(a) in the ESRD subjects tended to be higher using the assay that detected both fragments and full-length apo(a), the increase was modest. Thus, although a greater proportion of the apo(a) in ESRD plasma circulates as fragments, most of the elevation in plasma levels of Lp(a) associated with renal insufficiency is due to an increase in intact Lp(a).     

Apolipoprotein E gene promoter (–219G/T) polymorphism is associated with premature coronary heart disease

The relationship of two apolipoprotein (apo) E gene polymorphisms and coronary heart disease (CHD) was investigated in 118 Finnish families with premature CHD and in 110 healthy control subjects. Affected siblings and probands with premature CHD had higher frequencies of the T allele of the -219G/T promoter polymorphism and the epsilon 4 allele (genotypes epsilon 4/3 or epsilon 4/4) of the apo epsilon 2/epsilon 3/ epsilon 4 polymorphism than those of healthy control subjects. Additionally, when the two apo E gene polymorphisms were combined, affected siblings and probands had a higher frequency of the -219T allele and the epsilon 4 allele combinations than did healthy controls. The -219T and the epsilon 4 alleles both separately and together were associated with higher levels of 2-h glucose in an oral glucose tolerance test. These results indicate that the two polymorphisms of the apo E gene have similar effects on the risk of coronary atherosclerosis in families with premature CHD. This risk was not explained by the effect of apo E gene polymorphisms on cholesterol metabolism, but their effect on cardiovascular risk factor clustering with insulin resistance may be of importance. We conclude that in addition to the epsilon 4 allele, also the -219G/T promoter polymorphism of the apo E gene is associated with early onset CHD.     

Identification of a 76-year-old patient with compound heterozygous Familial Hypercholesterolemia by haplotype analysis of the LDL receptor gene

Summary In a large family with clinical characteristics of heterozygous familial hypercholesterolemia (FH) seven restriction fragment length polymorphisms (RFLP) were used to determine lowdensity-lipoprotein receptor (LDLR) gene haplotypes. Following the inheritance of the LDL receptor genes characterized by their seven RFLP haplotypes, two different alleles were found to cosegregate with elevated cholesterol levels within this family. In a 76-year-old man both alleles identified as defective were present, thus classifying this individual as heterozygous compound for FH. In five heterozygous family members one allele was associated with 38% higher cholesterol levels when compared to the other mutant allele in two heterozygous family members. Cosegregation of hypercholesterolemia with the apolipoprotein B (apoB) gene and apolipoprotein E (apoE) gene was excluded by genotyping all individuals for the apoB XbaI RFLP and apoE polymorphisms. These findings are consistent with variable phenotypic expression of the mutant LDLR gene alleles.Abbreviations apo B apolipoprotein B - apo E apolipoprotein E - CAD coronary artery disease - FH familial hypercholesterolemia - LDLR low-density-lipoprotein receptor - MI myocardial infarction - RFLP restriction fragment length polymorphisms     

Vascular accumulation of Lp(a): in vivo analysis of the role of lysine-binding sites using recombinant adenovirus

Despite the importance of lipoprotein(a) [Lp(a)] as an atherogenic risk factor, very little information, especially from in vivo studies, is available concerning which structural features of apo(a) contribute to the interactions of Lp(a) with the vessel wall and its proatherogenic properties. Nearly all the proposed and proven activities of apolipoprotein(a) [apo(a)] focus on its high degree of sequence homology with plasminogen and the possibility that structural features shared by these two molecules contribute to the atherogenesis associated with high Lp(a) plasma levels in humans. In these studies, we examined the properties of three forms of Lp(a) differing at postulated lysine-binding domains contained in the constituent apo(a). We used the recombinant adenoviral gene delivery system to produce apo(a) in the plasma of human apoB transgenic mice, resulting in high levels of Lp(a) similar to those found in the plasma of humans. By comparison of in vitro lysine-binding properties of these forms of Lp(a) with measurements of Lp(a) vascular accumulation in the mice, we have demonstrated that lysine-binding defective forms of Lp(a) have a diminished capacity for vascular accumulation in vivo.     

Effect of low-density lipoprotein buoyant density and cholesterol content on the formation of lipoprotein(a) particles

Lipoprotein(a) [Lp(a)] is a unique lipoprotein which resembles low-density lipoprotein (LDL) both in lipid composition and the presence of apolipoprotein B-100 (apo B-100). Lp(a) is, however, distinguishable from LDL by the presence of an additional glycoprotein apolipoprotein(a) [apo(a)], which is covalently attached to apo B-100 by a single disulfide bond. It is now generally accepted that Lp(a) assembly is a two-step process in which the initial non covalent interaction between apo(a) and apo B-100 is mediated by the weak lysine binding sites present in kringle IV types 6, 7 and 8 of apo(a). In the present study, we have investigated the effect of LDL heterogeneity on Lp(a) assembly in a group of 111 individuals. The three parameters of LDL composition assessed in this study were the cholesterol content, the apo B content, and the relative flotation rate (a measure of LDL buoyancy and thus size). We found no correlation between the size of LDL particles and the extent of Lp(a) formation; a weak negative correlation was observed between cholesterol content of LDL and Lp(a) formation (P=0.042). This may suggest a role for free (i. e., surface-associated) cholesterol in the ability of LDL to form Lp(a) particles. Received: 1 June 2001 / Accepted: 2 July 2001     

Apolipoprotein(a) isoform size influences binding of lipoprotein(a) to plasmin-modified des-AA-fibrinogen

Lipoprotein(a) (Lp(a)) is a LDL-like particle with an additional glycoprotein, apo(a), linked to apolipoprotein B-100. Apo(a) is highly homologous to parts of the plasminogen molecule, and numerous investigations have shown interference of Lp(a) with functions of plasminogen. In this report we studied the influence of apo(a) phenotype on the binding of Lp(a) to plasmin-modified immobilized des-AA-fibrinogen (desafib-X).Results indicate that Lp(a) binds to desafib-X in a specific and saturable way. There was a strongly significant negative correlation between apo(a) isoform length and maximal number of Lp(a) particles bound to the desafib-X matrix (N=18, r=0.84, p=0.002). There was no relation between apo(a) isoform length and K_d for the binding of Lp(a) to desaflb-X. In two donors (10%) no specific binding to desafib-X was observed, as well as to lysine-sepharose.In conclusion, apo(a) isoform length influences the amount of Lp(a) binding to desaflb-X. This implies that small isoforms apart from their usual higher plasma Lp(a) concentrations also are potentially more thrombogenic. The fact that Lp(a) from two donors did not bind to desafib-X, suggests that mutations may exist in the K4-10 domain of apo(a) abolishing its lysine-binding ability.