PEDIATRICS Vol. 99 No. 6 June 1997, pp. e11 (doi:10.1542/peds.99.6.e11)
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nowak-Göttl, U.
Right arrow Articles by Vielhaber, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nowak-Göttl, U.
Right arrow Articles by Vielhaber, H.
Related Collections
Right arrow Nutrition & Metabolism

PEDIATRICS Vol. 99 No. 6 June 1997, p. e11
Copyright ©1997 by the American Academy of Pediatrics

ELECTRONIC ARTICLE:
Lipoprotein (a): Its Role in Childhood Thromboembolism

Ulrike Nowak-Göttl, Ottfried Debus, Martina Findeisen, Reiner Kassenböhmer, Hans Georg Koch, Harmut Pollmann, Christiane Postler, Peter Weber, and Heinrich Vielhaber

From the Department of Paediatrics, University Hospital, Münster, Germany.

ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGMENTS
ABBREVIATIONS
REFERENCES

ABSTRACT

Purpose.  Elevated lipoprotein (a) [LP (a)] concentrations are independent risk factors of coronary heart disease or stroke in young adults. To clarify its role in childhood thromboembolism, Lp (a) was measured in 72 children with thromboembolism.

Methods.  In addition to Lp (a), defects of the protein C anticoagulant system, antithrombin, and antiphospholipid antibodies were investigated in children with arterial (n = 36) or venous (n = 36) thrombosis.

Results.  Enhanced Lp (a) >50 mg/dL was diagnosed in 8 out of 36 children with arterial and 5 out of 36 patients with venous thrombosis. Of the 72 children, 25 showed the factor V Leiden mutation, 10 showed protein C deficiency, 2 showed antithrombin deficiency, and 4 showed primary antiphospholipid syndrome. Three children with increased Lp (a) were heterozygous for the factor V Leiden mutation, and 1 girl showed additional protein C deficiency.

Conclusions.  Data of this study indicate that increased concentrations of Lp (a) play an important role in childhood thrombosis. childhood thrombosis, lipoprotein (a), factor V Leiden, protein C.

INTRODUCTION

Lipoprotein (a) [Lp (a)] is a cholesterol-rich plasma lipoprotein with a lipid composition similar to that of low-density lipoproteins (LDL). The protein composition is different from that of LDL, consisting of two major proteins, apolipoprotein (apo) B and apo (a).1,2 Lp (a) levels vary from person to person but are genetically determined as a dominant trait, minimally affected by race, age, and sex.3,4 Numerous groups agree in their findings that individuals with increased concentrations of Lp (a) have a higher risk of premature coronary heart disease,5 unrelated to the remaining lipoproteins. In addition, the risk of stroke3,8 as well as for restenosis after coronary artery bypass surgery13,14 correlates highly with increased Lp (a) concentrations. Little is known, however, about the relation between increased Lp (a) concentrations and childhood thrombosis at various sites. We used a commercially available enzyme-linked immunosorbent assay to measure Lp (a) in a population of children with arterial or venous thrombosis.

METHODS

Seventy-two infants and children aged from birth to 18 years consecutively recruited between 1992 and 1996 and primarily treated for arterial (n = 36) or venous (n = 36) thrombosis were enrolled in this study. In the majority of cases arterial thrombosis occurred in the central nervous system. Sixteen of 36 infants developed embolic stroke or multiple thrombosis in the neonatal period (attributable to the uncertainty in differentiating between embolic and local stroke in the majority of cases investigated, all children with initial symptoms of stroke were categorized in the arterial group). In addition, 11 children >1 year of age suffered an ischemic embolic, local, or lacunar stroke. Left intracardial thrombus formation was diagnosed in 4 of 36 patients, the femoral artery was occluded in two children and aortic thrombosis was found in two infants. Venous thromboses were found in the femoral vein (n = 10), renal veins (n = 8), superior caval vein (n = 6), central nervous system (n = 7), and portal vein (n = 5), respectively. In the majority of cases, underlying diseases triggering the thromboembolic event were diagnosed. As in previous reports, asphyxia, systemic infections, dehydration, congenital heart disease, and central lines were commonly associated with the vascular occlusion reported.15

Fasting venous blood samples for coagulation studies were obtained in the acute phase of the vascular accident and at least 6 months after the thrombotic episode when the children were free of anticoagulant medication. In infants and children with suspected inherited thrombophilia the final diagnosis was made when DNA-based assays confirmed the diagnosis (Arg506 to Gln mutation of the factor V gene) or when repeatedly measured plasma concentrations were outside the age-appropriate reference range and family screening confirmed the suspected inherited coagulation defect.20 Although the mean ± 2 standard deviation of the plasma values in the control children was 25 mg/dL, we chose the markedly elevated cut-off level of Lp (a) >50 mg/dL (2 × 25 mg/dL) according to Margaglione et al12 in the present study. In addition, bearing in mind the importance of Lp (a) as a risk factor of familial thrombophilia, family data are included in this report.

Blood samples were drawn from a peripheral vein into premarked 3-mL plastic tubes (citrate 3.8%/blood 1:10; Saarstedt, Nümbrecht, Germany), immediately placed on iced water and centrifuged at 4°C at 3000 g for 20 minutes. Platelet-poor plasma was snap-frozen and stored in plastic tubes at -70°C. Lp (a) concentrations were measured with the enzyme-linked immunosorbent assay technique (COALIZA Lp (a): Chromogenix, Mölndal, Sweden). The detection limit was .5 mg/dL and Lp (a) was quantified between 1 and 100 mg/dL. In addition, the factor V Leiden mutation (DNA prepared from ethylenediamine-tetraacetic acid blood), factor V, protein C, protein S, antithrombin, and antiphospholipid antibodies (immunoglobulin M/immunoglobulin G) were measured as described earlier.23

Calculations of median and ranges and nonparametric statistics (Wilcoxon-Mann-Whitney U test) were performed with the Apple computer Stat view program.

RESULTS

Table 1 shows the overall distribution of genetic risk factors for familial thrombophilia in children with arterial and venous thrombosis. Eight of 36 (22%) patients with arterial vascular insults and 5 of 36 (14%) with venous thrombosis showed Lp (a) concentrations >50 mg/dL. In addition, 244 age- and sex-matched healthy controls showed significantly lower (P < .001) median (range) Lp (a) plasma values of 7 mg/dL (0 to 39) compared with 15 mg/dL (0 to 165) in children with venous thrombosis, and 15 mg/dL (0 to 145) in patients with arterial vascular insults, respectively. However, median (range) Lp (a) concentrations in infants and children with venous vascular occlusion were no different from Lp (a) values in the arterial group. With special regard to the markedly elevated cut-off level of >50 mg/dL chosen in this study, single patient values are given in Table 2.12 However, if we had chosen mean ± 2 SD Lp (a) values of the control children, the vascular accident would also have been classified as Lp (a)-related in 5 of the remaining 28 patients (arterial) and 2 of 31 in the venous group.

Table 1. Incidence of Genetic Risk Factors for Thrombophilia in Children With Arterial or Venous Thromboembolism

[View Table]

Table 2. Lp (a) Concentration, Thrombus Location, and Affected Family Members in Children With Familially Increased Lp(a) and Thromboembolism

[View Table]

In addition, 25 of the 72 children showed the factor V Leiden mutation, 10 protein C type I deficiency, and two antithrombin type I deficiency. Four of the 72 children showed primary antiphospholipid syndrome. Three children with increased Lp (a) were heterozygous for the factor V Leiden mutation, and one girl showed an additional protein C deficiency (Table 2). Eleven of 13 patients with thrombosis and Lp (a) >50 mg/dL had a positive family history of early myocardial infarction (n = 6), stroke (n = 4), or venous thrombosis (n = 1) (Table 2).

No factor V or protein S deficiency was diagnosed in the population studied.

DISCUSSION

Data of this study indicate that 58% of children with arterial thrombosis and 80% of children with venous thrombosis had genetic risk factors of familial thrombophilia. Besides inherited defects in the protein C anticoagulant pathway, recently reported in a smaller group of children,23 increased concentrations of Lp (a) play an important role in the etiology of childhood thromboembolism.

Lp (a) was first described in human plasma by Berg as a genetic variant of beta -lipoprotein.24 Lp (a) levels are reported to be regulated by a gene located on the long arm of chromosome 6 close to the gene for plasminogen. Complementary DNA sequencing of human apo (a) showed it to be closely homologous with plasminogen.25 This fact is assumed to provide a direct link between thrombogenesis and atherosclerosis.26,27 In addition, it has been speculated that high plasma Lp (a) levels might also be a marker of the early presence of atherosclerotic lesions at extracoronary sites.28

Besides increased Lp (a) levels in children with thrombosis, 11 of 13 patients with thrombosis and Lp (a) >50 mg/dL in this study had a positive family history of early myocardial infarction, stroke, or venous thrombosis. These findings confirm literature data claiming that increased levels of Lp (a) in infancy and childhood were significantly associated with thromboembolism in the patients' parents or grandparents.29 However, further studies are needed to evaluate whether general neonatal Lp (a) screening could detect families at risk of vascular accidents or could prevent the early onset of thromboembolism in the families affected.32

FOOTNOTES

Received for publication Sep 17, 1996; accepted Feb 7, 1997.

Reprint requests to (U.N.-G.) Westfälische Wilhelms-Universität, Paediatric Haematology and Oncology, Albert-Schweitzer-Str. 33, D-48149 Münster, Germany.

ACKNOWLEDGMENTS

The authors thank Susan Griesbach for editing this manuscript.

Participating investigators, besides the authors, were S. Eckhoff-Donovan (Düsseldorf), T. Frank (Münster), and N. Jorch (Bielefeld).

ABBREVIATIONS

Lp (a), lipoprotein (a). LDL, low-density lipoprotein. apo, apolipoprotein.

REFERENCES

  1. Armstrong VW, Walli AK, Seidel D Isolation, characterization and uptake in human fibroblasts of an apo (a)-free lipoprotein obtained on reduction of lipoprotein (a). J Lipid Res 1985; 26:1314-1323 [Medline][Abstract]
  2. Seman LJ, Breckenridge WC Isolation and partial characterization of apolipoprotein (a) from human lipoprotein (a). Biochem Cell Biol 1986; 64:999-1009 [Medline][Medline]
  3. Zenker G, Költringer P, Bone G, Niederkorn K, Pfeiffer K, Jürgens G Lipoprotein (a) as a strong indicator for cerebrovascular disease. Stroke 1986; 17:942-945 [Medline][Abstract/Free Full Text]
  4. Albers JJ, Hazzard WR Immunochemical quantification of human plasma Lp (a) lipoprotein. Lipids 1974; 9:15-26 [Medline][CrossRef][Medline]
  5. Berg K, Dahlen G, Frick MH Lp (a) lipoprotein and pre-beta 1 lipoprotein in patients with coronary heart disease. Clin Genet 1974; 6:230-235 [Medline][Medline]
  6. Seed M, Hoppichler F, Reaveley D, Relation of serum lipoprotein (a) concentration and apolipoprotein (a) phenotype to coronary heart disease in patients with familial hypercholesterolemia. N Engl J Med 1990; 322:1494-1499 [Medline][Abstract]
  7. Sandkamp M, Funke H, Schulte H, Köhler E, Assmann G Lipoprotein (a) is an independent risk factor for myocardial infarction at a young age. Clin Chem 1990; 36:20-23 [Medline][Abstract/Free Full Text]
  8. Murai A, Miyahara T, Fujimoto N, Matsuda M, Kameyama M Lp (a) lipoprotein as a risk factor for coronary heart disease and cerebral infarction. Atherosclerosis 1986; 59:199-204 [Medline][CrossRef][Medline]
  9. Nagayama M, Shinohara Y, Nagayama T Lipoprotein (a) and ischemic cerebrovascular disease in young adults. Stroke 1994; 25:74-78 [Medline][Abstract]
  10. Jürgens G, Költringer P Cerebrovascular disease and Lp (a): its role in atherosclerotic plaque formation and vessel wall elasticity of the carotid arteries. Chem Phys Lipids 1994; 68:429-434[CrossRef]
  11. Woo J, Lau E, Lamm CWK, Hypertension, lipoprotein (a), and apolipoprotein A-I as risk factors for stroke in the Chinese. Stroke 1991; 22:203-208 [Medline][Abstract/Free Full Text]
  12. Margaglione M, Di Minno G, Grandone E, Plasma lipoprotein (a) levels in subjects attending a metabolic ward. Arterioscler Thromb Vasc Biol 1996; 16:120-128 [Medline][Abstract/Free Full Text]
  13. Hoff HF, Beck GJ, Skibinski CI, Serum Lp (a) levels as a predictor of vein graft stenosis after coronary artery bypass surgery in patients. Circulation 1988; 77:1238-1244 [Medline][Abstract/Free Full Text]
  14. Rath M, Niendorf A, Reblin T, Dietel M, Krebber HJ, Beisiegel U Detection and quantification of lipoprotein (a) in the arterial wall of 107 coronary by-pass patients. Atherosclerosis 1989; 9:579-592
  15. Andrew M Developmental hemostasis: relevance to thromboembolic complications in pediatric patients. Thromb Haemost 1995; 74:415-425 [Medline][Medline]
  16. Kohlhase B, Vielhaber H, Kehl HG, Kececioglu D, Koch HG, Nowak-Göttl U Thromboembolism and resistance to activated protein C in children with underlying cardiac disease. J Pediatr 1996; 129:677-679 [Medline][CrossRef][Medline]
  17. Nowak-Göttl U, Kries von R, Göbel U. Neonatal symptomatic thromboembolism in Germany: report of a prospective registry. Arch Dis Child. 1997. In press
  18. Nowak-Göttl U, Dübbers A, Kececioglu D, et al. Factor V Leiden, protein C and lipoprotein (a) in catheter-related thrombosis in childhood---a prospective study. J Pediatr. 1997. In press
  19. Schmidt B, Andrew M Neonatal thrombosis: report of a prospective Canadian and international registry. Pediatrics 1995; 96:936-934
  20. Andrew M, Paes B, Milner R, Johnston M Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hematol Oncol 1990; 12:95-104 [Medline][Medline]
  21. Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L Maturation of the hemostatic system during childhood. Blood 1992; 80:1998-2005 [Medline][Abstract/Free Full Text]
  22. Nowak-Göttl U, Funk M, Mosch G, Wegerich B, Kornhuber B, Breddin HK Univariate tolerance regions for fibrinogen, antithrombin III, protein C, protein S, plasminogen and a2-antiplasmin in children using the new automated coagulation laboratory (ACL) method. Klin Padiatr 1994; 206:437-439 [Medline][Medline]
  23. Nowak-Göttl U, Koch HG, Aschka I, Resistance to activated protein C (APCR) in children with venous or arterial thromboembolism. Br J Haematol 1996; 92:992-998 [Medline][CrossRef][Medline]
  24. Berg K A new serum type system in man---the Lp-system. Acta Pathol Microbiol Scand 1963; 59:369-383[Medline]
  25. 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; 300:132-137
  26. Miles LA, Fless GM, Levin EG, Scanu AM, Plow EF A potential basis for the thrombotic risk associated with lipoprotein (a). Nature 1989; 339:301-303 [Medline][CrossRef][Medline]
  27. Utermann G The mysteries of lipoprotein (a). Science 1989; 246:904-910 [Medline][Abstract/Free Full Text]
  28. Cambillau M, Simon A, Amar J, Serum Lp (a) as a discriminant marker of early atherosclerotic plaques at three extracoronary sites in hypercholestrolemic men. Arterioscl Thromb 1992; 12:1346-1352 [Medline][Abstract/Free Full Text]
  29. Wang XL, Wilcken DEL, Dudman NPB Early expression of the apolipoprotein (a) gene: relationship between infants` and their parents` serum apolipoprotein (a) levels. Pediatrics 1992; 89:401-406 [Medline][Abstract/Free Full Text]
  30. Gomez Gerique JA, Porres A, Lopez Martinez D, Alvarez Sala LA, Blazques E, Montoya MT, De Oya M Levels of lipoprotein (a) and plasma lipids in Spanish children aged from 4 to 18 years. Acta Paediatr 1996; 85:38-42[Medline]
  31. Wilcken DEL, Wang XL, Greenwood J, Lynch J Lipoprotein (a) and apoproteins B and A-1 in children and coronary vascular events in their grandparents. J Pediatr 1993; 123:519-526[CrossRef][Medline]
  32. Wang XL, Wicken SEL, Dudman NPB Neonatal apo A-I, apo B and apo (a) levels in dried blood spots in an Australian population. Pediatr Res 1990; 28:496-501 [Medline] [Medline]
Pediatrics (ISSN 0031 4005). Copyright ©1997 by the American Academy of Pediatrics



This article has been cited by other articles:


Home page
 Arch. Dis. Child.Home page
J B Austin, S Selvaraj, D Godden, and G Russell
Deprivation, smoking, and quality of life in asthma
Arch. Dis. Child., March 1, 2005; 90(3): 253 - 257.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nowak-Göttl, U.
Right arrow Articles by Vielhaber, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nowak-Göttl, U.
Right arrow Articles by Vielhaber, H.
Related Collections
Right arrow Nutrition & Metabolism