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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 11 (December 1), 1999:
pp. 3678-3682
Lipoprotein (a) and Genetic Polymorphisms of Clotting Factor V,
Prothrombin, and Methylenetetrahydrofolate Reductase Are Risk Factors
of Spontaneous Ischemic Stroke in Childhood
By
Ulrike Nowak-Göttl,
Ronald Sträter,
Achim Heinecke,
Ralf Junker,
Hans-Georg Koch,
Gerhard Schuierer, and
Arnold von
Eckardstein for the Childhood Stroke Study Group
From the Department of Paediatrics, Institute of Clinical Chemistry
and Laboratory Medicine and Institute of Arteriosclerosis Research,
Institute of Medical Statistics, and Institute of Clinical Radiology,
Westphalian Wilhelms-University Münster, Münster, Germany.
 |
ABSTRACT |
Ischemic stroke is a rare event in childhood. In approximately one
third of cases no obvious underlying cause or disorder can be detected.
We investigated the importance of genetic risk factors of venous
thromboembolism in childhood or stroke in adulthood as risk factors for
spontaneous ischemic stroke in children. One hundred forty-eight
Caucasian infants and children (aged 0.5 to 16 years) with stroke and
296 age-matched controls from the same geographic areas as the patients
were analyzed for increased lipoprotein (a) [Lp(a)] levels >30
mg/dL; for the presence of the factor V (FV) G1691A mutation, the
prothrombin (PT) G20210A variant, and the TT677 genotype of
methylenetetrahydrofolate reductase (MTHFR); and deficiencies of
protein C, protein S, and antithrombin. The following frequencies
(patients v controls), odds ratios (ORs), and confidence
intervals (CIs) of single risk factors were found: Lp(a) >30 mg/dL
(26.4% v 4.7%; OR/CI, 7.2/3.8 to 13.8; P < .0001), FV G1691A (20.2% v 4%; OR/CI, 6/2.97 to 12.1; P < .0001), protein C deficiency (6% v 0.67%; OR/CI, 9.5/2 to
44.6; P = .001), PT G20210A (6% v 1.3%; OR/CI,
4.7/1.4 to 15.6; P = .01), and the MTHFR TT677 genotype
(23.6% v 10.4%; OR/CI, 2.4/1.53 to 4.5; P < .0001).
A combination of the heterozygous FV G1691A mutation with increased
Lp(a) (n = 11) or the MTHFR TT677 genotype (n = 5) was found in
10.8% of cases, but only 0.3% of controls (OR/CI, 35.75/4.7 to 272;
P < .0001). Increased Lp (a) levels, the FV G1691A mutation,
protein C deficiency, the prothrombin G20210A variant, and the MTHFR
TT677 are important risk factors for spontaneous ischemic stroke in childhood.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
IN CHILDREN, cerebrovascular events, half
of which are ischemic strokes, occur at an estimated incidence of about
2 per 100,000 per year.1,2 Risk factors of cerebrovascular accidents in children include congenital heart malformations, vascular
abnormalities, endothelial damage, infectious diseases, and collagen
tissue diseases, as well as some rare inborn errors of metabolism like
Fabry's disease, homocystinuria, organic acid disorders, ornithine
transcarbamylase deficiency, carbohydrate-deficient glycoprotein
syndrome, and mitochondrial myopathy, encephalopathy, lactic acidosis,
and stroke-like episodes (MELAS).1-4 However, in about one
third of affected children, no obvious cause or underlying disorder can
be detected.1-3 Hypercoagulable states may represent a risk
factor for stroke in childhood. For example, deficiencies of natural
anticoagulants such as antithrombin, protein C, and protein S have been
found in rare cases of childhood stroke.5-14
There is also evidence that activated protein C resistance or its
underlying genetic defect, the factor V (FV) G1691A mutation, plays a
role in the early onset of childhood ischemic stroke,15-19 which is in contrast to data obtained in adult
populations.20,21 The 20210A allele within the
3`-untranslated region of the prothrombin (PT) gene, which is a common
but mild risk factor of venous thrombosis in the CNS,22,23
has also been controversially discussed as a risk factor for arterial
thrombosis, ie, myocardial infarction or stroke.24-27
Elevated lipoprotein(a) [Lp(a)] has been identified as a genetically
determined risk factor for stroke in young adults, but only preliminary
data are available on its role as a risk factor for ischemic stroke in
infants and children.28-30 Finally, in adult patients, the
C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene,
which causes a thermolabile variant of this enzyme and appears to
facilitate the manifestation of hyperhomocysteinemia especially in
individuals with undernutrition with folic acid, has been discussed as
a genetic risk factor for vascular disease and stroke.31-33
The present multicenter case-control study was undertaken to unravel
the role of genetic prothrombotic risk factors, elevated Lp(a), and
homocysteinemia as risk factors of ischemic stroke in children who do
not show additionally identifiable clinical risk factors.
| |
MATERIALS AND METHODS |
Ethics.
The present prospective multicenter case-control study was performed in
accordance with the ethical standards laid down in a relevant version
of the 1964 Declaration of Helsinki and approved by the Medical Ethics
Committee at the Westfälische Wilhelms-University, Münster, Germany.
Inclusion criteria.
Infants and children aged 6 months to 16 years with first onset of
spontaneous ischemic stroke were included.
Exclusion criteria.
Neonates and infants less than 6 months of age (n = 32), and childhood
stroke patients with known underlying diseases, ie, congenital or
acquired heart diseases (n = 49), cerebral vascular abnormalities
(fibromuscular dysplasia, n = 12; Moyamoya, n = 4),
endothelial damage (trauma or dissection, n = 12), infectious diseases
(n = 31), collagen tissue diseases and metabolic disorders (n = 5) were
not enrolled in the present study.
Study period.
From October 1995 to October 1998, 148 consecutive Caucasian patients
(median age at first thrombotic onset, 4.5 years; range, 6 months to 16 years; male/female distribution, 1:1.1) with spontaneous ischemic
stroke were recruited from different geographic areas of Germany: 65%
from the Northern and Western part of Germany, ie, catchment areas of
Hamburg (10%), Münster (17%), Halle (8%), Bielefeld (5%),
Düsseldorf (7%), and Frankfurt/Main (18%), and 35% of the
Southern regions of Germany, the overall catchment area of Munich, respectively.
Imaging methods.
Diagnoses of ischemic stroke were confirmed by an external
neuroradiologist, who was unaware of the laboratory test results, upon
the results of computed tomography (CT), magnetic resonance (MR)
imaging, and MR angiography according to criteria previously published
by Ringelstein et al.34
Clinical data of the patients studied.
At acute onset of spontaneous ischemic stroke, the majority of
patients presented with hemiparesis (n = 134) combined with aphasia (n = 22) or coma (n = 28); impairment of vision or
infratentorial symptoms, ie, ataxia, was the initial symptom in the
remaining 14 patients. The corresponding brain lesions with territorial infarction were predominantly found in the left medial artery (n = 89),
right medial artery (n = 45), or vertebrobasilar system (n = 14).
Control population.
A total of 296 age- and sex-matched Caucasian controls (potential bone
marrow donors undergoing elective surgery; median age, 5 years; range,
6 months to 16 years; male/female distribution, 1:1.1) from the same
geographic areas as the patients were investigated with parental consent.
Blood samples.
With informed parental consent, 6 weeks to 3 months after the acute
stroke event, blood samples were collected by peripheral venipuncture
into plastic tubes containing 1/10 by volume of 3.8% trisodium citrate
(Sarstedt, Nümbrecht, Germany), and placed immediately on melting
ice. Platelet-poor plasma was prepared by centrifugation at 3,000g
for 20 minutes at 4°C, aliquoted in polystyrene tubes, stored
at  70°C, and thawed immediately before the assay procedure.
The laboratory staff was unaware of whether the blood samples were
those of a patient or a control.
For genetic analysis, we obtained venous blood in EDTA-treated sample
tubes (Sarstedt, Nümbrecht, Germany), from which cells were
separated by centrifugation at 3,000g for 15 minutes. The buffy-coat layer was then removed and stored at 70°C pending DNA extraction by standard techniques.
Assays for genotyping.
The C677T polymorphism in the MTHFR gene, the G1691A polymorphism in
the FV gene, and the G20210A polymorphism in the PT gene were blindly
detected in patients and controls by polymerase chain reaction (PCR)
amplification and digestion with HinfI,31
MnlI,35 and HindIII,22
respectively, as previously reported.
Assays for the quantification of plasma proteins and metabolites.
Activities of protein C and antithrombin were measured using
the chromogenic substrates S-2366 and S-2765, respectively (Chromogenix, Mölndal, Sweden).36 Free protein S
antigen,36 protein C antigen, and Lp(a) 28 were
quantified by enzyme-linked immunosorbent assay (ELISA) (Asserachrom:
free protein S, protein C; Diagnostica Stago, Ansieres-sur-Seine,
France) and (COALIZA Lp(a); Chromogenix, Mölndal, Sweden:
intraassay and interassay coefficients of variation [CVs] were <4%
at 10 mg/dL and <7% at 40 mg/dL), respectively. In a subgroup of 60 randomly selected patients of all study centers and controls, fasting
plasma homocysteine concentrations were measured by high-performance
liquid chromatography (HPLC) using reagents and standards from Immuno
(Vienna, Austria: CVs within/between days are 2.2%/3.5%).
Classification of risk cut-offs.
Heterozygous protein C deficiency type I was diagnosed when functional
plasma activity and immunologic antigen concentration of the protein
were below the lower age-related limit.37,38 A type II
deficiency was diagnosed when functional activity was repeatedly found
to be low along with normal antigen concentrations. The diagnosis of
protein S deficiency was based on reduced free protein S antigen levels
combined with decreased or normal total protein S antigen
concentrations, respectively. Criteria for the hereditary nature of a
hemostatic defect were its presence in at least 1 further first- or
second-degree family member and/or the identification of a causative
gene mutation.36
The critical cut-off level for Lp(a) concentrations was defined at 30 mg/dL, previously identified by us as the risk threshold value for
venous thrombosis in childhood.39 Moreover, this value is
also widely accepted as the cut-off in the assessment of increased risk
for cerebrovascular and cardiovascular events in adults.40
Statistics.
Because of their non-Gaussian frequency distribution, continuous data
are presented as medians and ranges and evaluated by nonparametric
statistics using the Wilcoxon-Mann-Whitney, and 1-way analysis of
variance (ANOVA) with subsequent paired comparison according to
Scheffe. Prevalences of prothrombotic risk factors in patients and
controls were compared by  2 analysis or, if necessary,
Fisher's exact test. The significance level was set at .05. With
respect to the number of different tests applied, a correction
according to Bonferroni was performed. The critical cut-off
2 values for P less than .05 were 6.6 and .01 (Fisher's exact test), respectively. In addition, odds ratios (ORs)
and 95% confidence intervals (CIs) were calculated. All statistical
analyses were performed using the MedCalc software package (MedCalc,
Mariakerke, Belgium).
| |
RESULTS |
Results are summarized in Table 1.
Lp(a).
Caucasian children with a history of ischemic stroke had significantly
higher (P < .0001) concentrations of Lp(a) (median, 21 mg/d;
range, 0 to 162) compared with controls (median, 5 mg/dL; range, 0 to
115). Lp(a) levels greater than 30 mg/dL were found in 26.4% of cases,
but only 4.7% of controls (OR/CI, 7.2/3.8 to 13.8; P < .0001; 2 = 41.8).
Factor V G1691A gene mutation.
Heterozygosity for the FV G1691A mutation was diagnosed in 20.2% of
cases compared with 4% of controls (OR/CI, 6/2.97 to 12.1; P < .0001; 2 = 28.4).
Protein C deficiency.
Six percent of patients and 0.67% of controls had protein C type I
deficiency (OR/CI, 9.6/2 to 44.6; P = .001).
PT G20210A gene mutation.
Six percent of children with stroke but only 1.3% of controls carried
the PT G20210A variant (OR/CI, 4.7/1.43 to 15.6; P = .01).
MTHFR TT677 genotype.
A total of 23.6% of cases but only 10.4% of controls were homozygous
for the MTHFR TT677 genotype (OR/CI, 2.6/1.53 to 4.5; P < .0001; 2 = 12.5). In the randomly selected subgroup of
60 patients, the fasting homocysteine concentrations in patients with
the MTHFR TT677 genotype were significantly higher compared with the
677CT and CC genotypes (CC677: median, 5.8 µmol/L; range, 3 to 8.6 µmol/L, CT677: median, 7.0 µmol/L; range, 3 to 12 µmol/L; TT677:
median, 12.1 µmol/L; range, 7 to 23 µmol/L; P < .01). As a consequence, fasting homocysteine concentrations were
significantly higher in cases (median, 7 µmol/L; range, 3 to 23 µmol/L) as compared with controls (median, 5.5 µmol/L; range, 3 to
8.4 µmol/L; P = .002).
Combined prothrombotic defects.
A combination of the heterozygous FV G1691A mutation either with
increased Lp(a) (n = 11; 7.4%) or the MTHFR TT genotype (n = 5; 3.3%)
was found in 16 of 148 cases with stroke, but only once among controls
(OR/CI, 35.75/4.7 to 272; P < .0001). No further combinations
of more than 2 defects were found in the population studied.
No protein S deficiency or antithrombin deficiency was found in
patients and controls. In addition, mainly due to the exclusion of
stroke patients with associated infectious diseases, no increased anticardiolipin IgG or IgM antibodies were detected in the population presented here.
Within the 2-year study period, 3 of 148 patients (2%) investigated
had recurrent spontaneous stroke.
| |
DISCUSSION |
In this study we demonstrated that Lp(a) levels greater than 30 mg/dL
(OR, 7.2), protein C deficiency (OR, 9.5), the FV G1691A mutation (OR,
6.0), the PT G20210A genotype (OR, 4.7), and the MTHFR TT677 genotype
(OR, 2.6) are risk factors of spontaneous ischemic stroke in childhood.
It is important to emphasize that the suspected diagnosis of ischemic
stroke was blindly confirmed by an independent neuroradiologist.
Moreover, underlying diseases such as cardiac malformations, including
patent foramen ovale, fibromuscular dysplasia, Moyamoya disease,
trauma, severe bacterial or viral septicemia, malignancy, and rheumatic
diseases,3,4 were prospectively excluded in the study
patients presented here. This suggests that each of the genetic
prothrombotic risk factors studied has an impact on the early onset of
spontaneous cerebrovascular ischemic accidents during infancy and
childhood, independently of predisposing diseases.
In adults, the FV G1691A mutation, protein C deficiency, and the PT
G20210A genotype are established genetic risk factors for venous
thromboembolism, but have little importance as risk factors for
arterial thrombosis, ie, myocardial infarction and stroke.20,21,25,27 In contrast, the data of our study, as well as preliminary data on case reports and small studies, indicate that these variants, mainly present in venous thrombosis, play a role
as risk factors of stroke in childhood and young
adults.14-17,19,24,26 Since the children we
investigated did not present with any underlying morphologic disorders
of the cardiovascular system, it is also important to note that the FV
G1691A mutation has been associated with cryptogenic stroke in young
adults.41 Thus, morphologic anomalies of the cardiovascular
system or other underlying diseases3,4 do not appear
necessary to precipitate stroke in the presence of one of the
prothrombotic defects studied.
In this study, we have shown for the first time the importance of
elevated Lp(a) as a risk factor for spontaneous stroke in childhood.
Lp(a) is a low-density lipoprotein that contains apolipoprotein (a)
[apo(a)] as an additional protein. The primary structure of apo(a)
encompasses a protease domain, a kringle V domain, and a variable
number of kringle IV repeats, which are homologous to the same domains
in the plasminogen molecule and which have been made responsible for
the antifibrinolytic activities of Lp(a) found both in vitro and in
vivo.42,43 The genetically determined number of kringle IV
domains and other polymorphisms in the apo(a) gene account for the
greatest part of interindividual differences in Lp(a) levels. Lp(a) has
previously been identified as an independent risk factor of both
myocardial infarction and atherothrombotic stroke in young
adults.29,30,44-47 Thus, our study extends this role to
childhood patients. In this context, it is interesting to note that
elevated Lp(a) is also a risk factor for venous thrombosis in
childhood, as well as for porencephaly and peripartal stroke in
neonates.18,28,39
The thermolabile variant of MTHFR caused by the TT677 genotype
predisposes to hyperhomocysteinemia, especially if it coincides with a
reduced supply of folic acid.48,49 Despite the
well-established association between hyperhomocysteinemia and the risk
of cerebrovascular and cardiovascular disease,48,49 the
role of this polymorphism as a genetic risk factor of stroke or
myocardial infarction in adults is controversial.31-33 In
our study, both the TT677 genotype of the MTHFR polymorphism and
slightly elevated fasting homocysteine, which interestingly did not
reach homocysteine concentrations of adult stroke patients, turned out
to be risk factors of stroke in childhood. However, we did not record
serum levels of vitamins or daily dietary intake. Thus, the question
remains whether the MTHFR TT677 genotype alone or only in combination
with reduced vitamin supply is responsible for the increase of both
fasting homocysteine and risk of spontaneous stroke in children of
Caucasian origin.
In conclusion, in this multicenter case-control study, we have provided
strong evidence that Lp(a) level greater than 30 mg/dL, protein C
deficiency, the FV G1691A mutation, the PT 20210A variant, and the
MTHFR TT677 genotype are risk factors of spontaneous ischemic stroke in
childhood and early adolescence.
| |
APPENDIX |
Coinvestigators of the Childhood Stroke Study Group were as
follows: N. Jorch (Childrens' Hospital Gilead, Bielefeld), U. Göbel, B. Heinrich (Surveillance Unit for Rrare Paediatric
Disorders in Germany, Heinrich-Heine-University, Düsseldorf) C. Mauz-Körholz (Department of Paediatric Haematology and Oncology,
Heinrich-Heine-University, Düsseldorf), S. Becker, C. Heller, W. Kreuz (Department of Paediatric Haematology and Oncology,
Johann-Wolfgang-Goethe-University, Frankfurt/Main), R. Schoebess
(Department of Paediatric Haematology and Oncology, Martin-Luther-University, Halle), N. Münchow (Department of
Paediatric Haematology and Oncology, University Hospital,
Hamburg-Eppendorf), K. Auberger, H. Vielhaber (Childrens' Hospital,
Ludwig-Maximilians-University, Munich), R. von Kries (Surveillance Unit
for Rare Paediatric Disorders in Germany, Institut für Soziale
Pädiatrie, Ludwig-Maximillians-University, Munich), G. Kurlemann,
P. Nabel, H. Pollmann (Department of Paediatrics, Westphalian
Wilhelms-University, Münster).
| |
ACKNOWLEDGMENT |
This work is dedicated to Prof Herbert Jürgens on the occasion of
his 50th birthday. The authors thank all technicians from the
participating laboratories, in particular, Doris Böckelmann, Margit Käse, and Anke Reinkemeier for excellent technical
assistance. In addition, we thank Susan Griesbach for editing the manuscript.
| |
FOOTNOTES |
Submitted March 30, 1999; accepted July 21, 1999.
U.N.-G. was supported by the Surveillance Unit for Rare Paediatric
Disorders in Germany (ESPED), the "German Society of Thrombosis and
Haemostasis Research (GTH)," and Immuno-Baxter GmbH (Germany). A.v.E. was supported by a grant from the Interdisziplinäres
Zentrum für Klinische Forschung at the Medical Faculty of the
Westphalian Wilhelms-University (Project A3).
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Ulrike Nowak-Göttl,
MD, Department of Paediatric Haematology and Oncology,
Westfälische Wilhelms-Universität Münster, Albert
Schweitzer-Str 33, D-48149 Münster, Germany; e-mail:
leagottl{at}uni-muenster.de.
| |
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