Lipoprotein (a): Its Role in Childhood Thromboembolism
Ulrike Nowak-Göttl, MD; Ottfried Debus, MD; Martina Findeisen, MD; Reiner Kassenböhmer, MD;
Hans Georg Koch, MD; Harmut Pollmann, MD; Christiane Postler, MD; Peter Weber, MD; and
Heinrich Vielhaber, MD
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 5 36) or venous (n 5 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. Pediatrics 1997;99(6). URL: http://
www.pediatrics.org/cgi/content/full/99/6/e11; childhood
thrombosis, lipoprotein (a), factor V Leiden, protein C.
ABBREVIATIONS. Lp (a), lipoprotein (a); LDL, low-density lipoprotein; apo, apolipoprotein.
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,5–7 unrelated to
the remaining lipoproteins. In addition, the risk of
stroke3,8 –12 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 variFrom the Department of Paediatrics, University Hospital, Münster, Germany.
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.
PEDIATRICS (ISSN 0031 4005). Copyright © 1997 by the American Academy of Pediatrics.
ous 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 5 36) or venous (n 5 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 5 10), renal veins
(n 5 8), superior caval vein (n 5 6), central nervous system (n 5
7), and portal vein (n 5 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.15–19
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 –22 Although the mean 6 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 3 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 270°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.
http://www.pediatrics.org/cgi/content/full/99/6/e11
PEDIATRICS Vol. 99 No. 6 June 1997
Downloaded from by guest on June 14, 2017
1 of 3
TABLE 1.
Incidence of Genetic Risk Factors for Thrombophilia in Children With Arterial or Venous Thromboembolism
Arterial Thrombosis
(n 5 36)
Genetic risk factors
Lipoprotein (a)
Factor V Leiden
Protein C deficiency type I
Antithrombin deficiency type I
VenousThrombosis
(n 5 36)
21/36 (58 %)
8/36 (22 %)
11/36 (30 %)
2/36 (5.5%)
0/36
29/36 (80 %)
5/36 (14 %)
14/36 (38 %)
8/36 (22 %)
2/36 (5.5%)
TABLE 2.
Lp (a) Concentration, Thrombus Location, and Affected Family Members in Children With Familially Increased Lp(a) and
Thromboembolism
Patient
Location
Lp (a)
mg/dL
Female, neonate
Male, neonate
Male, 5 mo
Male, 3 y
Male, 5 y
Male, 6 y
Female, 8 y
Female, 13 y
Male, neonate
Male, 3 y
Male, 4 y
Male, 10 y
Male, 13 y
Arterial
Arterial
Arterial
Arterial
Arterial
Arterial
Arterial
Arterial
Venous
Venous
Venous
Venous
Venous
70
145
70
110
90
80
90
85
90
65
92
165
98
Additional Genetic
Risk
Factor V Leiden
Affected Family
Member
Lp (a): mg/dL
Family Member
Grandparent
Grandparent
Father
Father, grandparent
Mother
NA*
NA
90
80/120
85
Factor V Leiden
Protein C deficiency
Grandparent
Grandparent
Factor V Leiden
Father
Grandparents
Mother
Father, grandparent
NA
120
80
NA
150
120/150
* NA 5 Not available.
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 ageand 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 6 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.
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 infarc2 of 3
tion (n 5 6), stroke (n 5 4), or venous thrombosis
(n 5 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 b-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
LIPOPROTEIN (A): ITS ROLE IN CHILDHOOD THROMBOEMBOLISM
Downloaded from by guest on June 14, 2017
grandparents.29 –31 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
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).
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
2. Seman LJ, Breckenridge WC. Isolation and partial characterization of
apolipoprotein (a) from human lipoprotein (a). Biochem Cell Biol. 1986;
64:999 –1009
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
4. Albers JJ, Hazzard WR. Immunochemical quantification of human
plasma Lp (a) lipoprotein. Lipids. 1974;9:15–26
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
6. Seed M, Hoppichler F, Reaveley D, et al. 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
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
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
9. Nagayama M, Shinohara Y, Nagayama T. Lipoprotein (a) and ischemic
cerebrovascular disease in young adults. Stroke. 1994;25:74 –78
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
11. Woo J, Lau E, Lamm CWK, et al. Hypertension, lipoprotein (a), and
apolipoprotein A-I as risk factors for stroke in the Chinese. Stroke.
1991;22:203–208
12. Margaglione M, Di Minno G, Grandone E, et al. Plasma lipoprotein (a)
levels in subjects attending a metabolic ward. Arterioscler Thromb Vasc
Biol. 1996;16:120 –128
13. Hoff HF, Beck GJ, Skibinski CI, et al. Serum Lp (a) levels as a predictor
of vein graft stenosis after coronary artery bypass surgery in patients.
Circulation. 1988;77:1238 –1244
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
16. Kohlhase B, Vielhaber H, Kehl HG, Kececioglu D, Koch HG, NowakGöttl U. Thromboembolism and resistance to activated protein C in
children with underlying cardiac disease. J Pediatr. 1996;129:677– 679
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
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
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
23. Nowak-Göttl U, Koch HG, Aschka I, et al. Resistance to activated
protein C (APCR) in children with venous or arterial thromboembolism.
Br J Haematol. 1996;92:992–998
24. Berg K. A new serum type system in man—the Lp-system. Acta Pathol
Microbiol Scand. 1963;59:369 –383
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
27. Utermann G. The mysteries of lipoprotein (a). Science. 1989;246:904 –910
28. Cambillau M, Simon A, Amar J, et al. Serum Lp (a) as a discriminant
marker of early atherosclerotic plaques at three extracoronary sites in
hypercholestrolemic men. Arterioscl Thromb. 1992;12:1346 –1352
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
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
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
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
http://www.pediatrics.org/cgi/content/full/99/6/e11
Downloaded from by guest on June 14, 2017
3 of 3
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
Pediatrics 1997;99;e11
DOI: 10.1542/peds.99.6.e11
Updated Information &
Services
including high resolution figures, can be found at:
/content/99/6/e11.full.html
References
This article cites 30 articles, 11 of which can be accessed free
at:
/content/99/6/e11.full.html#ref-list-1
Citations
This article has been cited by 1 HighWire-hosted articles:
/content/99/6/e11.full.html#related-urls
Permissions & Licensing
Information about reproducing this article in parts (figures,
tables) or in its entirety can be found online at:
/site/misc/Permissions.xhtml
Reprints
Information about ordering reprints can be found online:
/site/misc/reprints.xhtml
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and
trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove
Village, Illinois, 60007. Copyright © 1997 by the American Academy of Pediatrics. All rights
reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from by guest on June 14, 2017
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
Pediatrics 1997;99;e11
DOI: 10.1542/peds.99.6.e11
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/99/6/e11.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 1997 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from by guest on June 14, 2017