(Stroke. 2000;31:2437.)
© 2000 American Heart Association, Inc.
Original Contributions |
From the Department of Paediatrics (G.G.), University of Magdeburg, Magdeburg; the Departments of Clinical Chemistry and Laboratory Medicine and of Arteriosclerosis Research (R.J.), and the Department of Paediatrics (R.S., A.K., U.N.-G.), University of Münster, Münster; the Department of Paediatrics (R.S.), University of Halle an der Saale, Halle an der Saale; the Department of Paediatrics (K.K.), University of Munich, Munich; and the Department of Paediatrics (C.H.), University of Frankfurt, Frankfurt, Germany.
Correspondence to Ulrike Nowak-Göttl, MD, Department of Paediatrics, Westfälische Wilhelms-University, Albert-Schweitzer-Strasse 33, D-48149 Münster, Germany. E-mail leagottl{at}uni-muenster.de
| Abstract |
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MethodsLipoprotein (Lp)(a); the factor V (FV) G1691A mutation; the prothrombin (PT) G20210A variant; the methylenetetrahydrofolate reductase (MTHFR) T677T genotype; antithrombin; protein C; protein S; and anticardiolipin antibodies (ACAs) were investigated in 91 consecutively recruited neonatal stroke patients and 182 age- and sex-matched healthy controls.
ResultsSixty-two of 91 stroke patients (68.1%) had at least 1 prothrombotic risk factor compared with 44 control subjects (24.2%) (odds ratio [OR]/95% confidence interval [CI], 6.70/3.84 to 11.67). An increased Lp(a) level (>30 mg/dL) was found in 20 patients and 10 controls (OR/95% CI, 4.84/2.16 to 10.86); FV G1691A was present in 17 patients and 10 controls (OR/95% CI, 3.95/1.72 to 9.0); the PT G20210A variant was detected in 4 patients and 4 controls (OR/95% CI, 2.04/0.49 to 8.3); the MTHFR TT677 genotype was found in 15 patients and 20 controls (OR/95% CI, 1.59/0.77 to 3.29); and protein C type I deficiency was found in 6 neonates. Neither antithrombin deficiency nor protein S deficiency was found in the neonatal patients studied. Acquired IgG ACAs were found in 3 cases. Additional triggering factors, ie, asphyxia, septicemia, maternal diabetes, and perinatally acquired renal venous thrombosis, were reported in 54.0% of patients.
ConclusionsBesides acquired triggering factors, the data presented here suggest that genetic prothrombotic risk factors play a role in symptomatic neonatal stroke.
Key Words: factor V lipoproteins neonate prothrombin risk factors stroke
| Introduction |
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1 per 100 000 per
year.5 6 7 Nongenetic risk factors of arterial
cerebrovascular accidents in children and adolescents include
congenital heart malformations, vascular abnormalities,
endothelial damage, infectious diseases, and some rare
congenital metabolic dysfunctions.7 8 The role of congenital thrombophilic states such as activated protein C resistance,9 in the majority of cases due to the factor V (FV) G1691A gene mutation10 11 ; antithrombin, protein C, or protein S deficiency1 ; the 20210A allele within the 3'-untranslated region of the prothrombin (PT) gene12 ; and an increased lipoprotein (Lp)(a) level has also been discussed with reference to the common risk factors for venous thrombosis in children and adolescents.13 14 However, information on these hemostatic defects in symptomatic patients with ischemic stroke during infancy and childhood is limited and controversial. Results of available studies differ, mainly because of differences in the study populations, age groups, or study designs.15 16 17 18 19 20 21 22 23 24 25
Very recently, we have shown that an increased Lp(a) level, the FV G1691A mutation, the PT 20210A allele, and the homozygous C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene are significant risk factors for spontaneous stroke in childhood.23 That study, however, did not include neonatal and child patients with additional acquired risk factors.
In this article, we present the results of a stroke subgroup analysis. It includes symptomatic, full-term neonatal stroke patients only, with respect to inherited prothrombotic risk factors23 and prospectively defined triggering factors.7 8 26 27 28 29
| Subjects and Methods |
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Inclusion Criteria for Subgroup Analysis
Full-term neonates with a first onset of symptomatic
ischemic stroke occurring spontaneously or associated with
perinatal asphyxia, dehydration, septicemia, patent foramen ovale,
birth trauma, maternal diabetes, maternal drug abuse, or infection
composed the patient group.7 8 26 27 28 29 In all cases,
suspected vascular accidents were confirmed by standard imaging methods
(cranial sonography, CT, or MRI) by an independent neuroradiologist as
previously described.23
Patients
From October 1996 to January 2000, 91 of 273 (33.3%)
consecutive white childhood stroke patients from different geographic
catchment areas of Germany were enrolled in the study. They fulfilled
the inclusion criterion of neonatal stroke defined above. The median
age at onset of the first thrombotic episode was 3 days, ranging from
newborn to <4 weeks of age (male/female ratio, 1:1.1).
Control Group
With informed parental consent, 182 age- and sex-matched healthy
neonates and infants from the same geographic areas served as
controls.
Exclusion Criteria
Preterm infants (<37 weeks of gestation)30 or
those affected by stroke associated with arterial
catheterization, surgery, metabolic
disorders, or congenital heart disease (already presented in
Reference 24 ) were excluded from participation in the
study.
Blood Samples
With informed parental consent, blood samples from patients were
collected 6 weeks to 3 months (median, 10 weeks) after the acute
thrombotic event by peripheral venipuncture
into plastic tubes containing 1/10 by volume of 3.8% trisodium citrate
or into plastic tubes without additives (Sarstedt). From healthy
control neonates, blood samples were drawn during infancy, ie, at a
median age of 3 months (range, 6 to 16 weeks). Citrated blood (3 mL)
was placed immediately on melting ice. Platelet-poor plasma and
serum were prepared by centrifugation at
3000g for 20 minutes at 4°C or at room temperature,
divided into aliquots into polystyrene tubes, stored at -70°C, and
thawed immediately before the assay procedure. For genetic
analysis, we obtained venous blood (0.5 mL) in EDTA-treated
sample tubes (Sarstedt) from which cells were separated by
centrifugation at 3000g for 15 minutes. The
buffy coat layer was then removed and stored at -70°C pending DNA
extraction by a spin-column procedure (Qiagen).
Assays for Genotyping
The FV G1691A, PT G20210A, and MTHFR C677T genotypes
were determined by polymerase chain reaction and analysis of
restriction fragments as previously reported.11 12 31
Assays for Plasma Proteins
Amidolytic protein C and antithrombin activities were measured
on an ACL 300 analyzer (Instrumentation Laboratory) with the
use of chromogenic substrates (Chromogenix). Free protein S
antigen, total protein S, and protein C antigen were measured by using
commercially available ELISA assay kits (Stago). Lp(a) and ACAs (IgM
and IgG) were also determined with ELISA techniques
(Chromogenix).13 14 23
Classification of Risk Cutoff
The type I deficiency state (protein C and antithrombin) was
diagnosed when the functional plasma activity and immunological antigen
concentration of a protein were repeatedly below the lower age-related
limit (for 3 months of age, protein C <20% and antithrombin
<30%).32 A type II deficiency was diagnosed when the
functional activity levels were repeatedly low but antigen
concentrations were normal. The diagnosis of protein S deficiency was
based on reduced free protein S antigen levels combined with a
decreased or normal total protein S antigen concentrations (for 3
months of age, <30%).33 The cutoffs used for ACAs were
<11 µg/mL (IgM) and <23 µg/mL (IgG).
Statistics
Prevalences of prothrombotic risk factors in patients and
control subjects were calculated by
2
analysis or, where relevant, by Fischers exact test. The
significance level was set at 0.05. With respect to the number of
different tests applied, Bonferronis correction was performed. In
addition, odds ratios (ORs) and 95% confidence intervals (CIs) were
calculated. All statistical analyses, including
nonparametric statistics (medians and ranges), were
performed by using the MedCalc software package (MedCalc).
| Results |
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Location of Thrombosis
At onset of acute stroke, neonates presented with left
middle cerebral artery occlusion (n=58), right middle artery occlusion
(n=29), or vascular accident of both middle arteries (n=3).One neonate
had occlusion of the anterior cerebral artery.
Prothrombotic Risk Factors
Sixty-two of 91 stroke patients (68.1%) were found to have
at least 1 prothrombotic risk factor compared with 44 subjects (24.2%)
in the control group (OR/95% CI, 6.70/3.84 to 11.67). An increased
Lp(a) level (>30 mg/dL) was found in 20 patients and 10 controls
(OR/95% CI, 4.84/2.16 to 10.86), FV G1691A in 17 patients and 10
controls (OR/95% CI, 3.95/1.72 to 9.0), the PT G20210A variant in 4
patients and 4 controls (OR/95% CI, 2.04/0.49 to 8.3), the MTHFR TT677
genotype in 15 patients and 20 controls (OR/95% CI, 1.59/0.77
to 3.29), and protein C deficiency in 6 neonates (P=0.0012).
Acquired IgG ACAs were measured in 3 neonates 9 weeks after the acute
stroke onset. In 3 of the 17 symptomatic patients carrying
the heterozygous FV mutation, an increased Lp(a) concentration was
diagnosed, and in 1 patient, the FV mutation was found in combination
with IgG ACAs. The overall distribution of prothrombotic risk factors
is shown in Table 1
. Antithrombin
deficiency, protein S deficiency, or IgM ACAs were not found in the
neonatal patients studied. Table 2
shows
median (range) values of Lp(a), protein C activity, free protein S
antigen, antithrombin activity, and IgG ACAs in patients and
controls.
|
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Acquired Triggering Factors
Besides spontaneous ischemic stroke (46%), additional
triggering factors, ie, asphyxia (19%), neonatal septicemia (12%),
patent foramen ovale (16%), maternal diabetes (3%), antenatal renal
venous thrombosis (3%), and fibromuscular dysplasia (1%), were found
in the patients investigated.
In 33 of the 49 subjects with additional triggering factors (67.0%), at least 1 prothrombotic risk factor was found. The FV G1691A mutation was found in 13 neonates (asphyxia n=3, septicemia n=2, patent foramen ovale n=5, maternal diabetes n=1, and renal venous thrombosis n=2). An increased Lp(a) level was additionally present in 10 cases (asphyxia n=4, septicemia n=2, patent foramen ovale n=3, and fibromuscular dysplasia n=1) and the MTHFR TT677 genotype in 7 neonates (asphyxia n=2, septicemia n=1, patent foramen ovale n=3, and maternal diabetes n=1). Furthermore, protein C deficiency was found in 2 subjects with asphyxia and in 1 baby with patent foramen ovale.
| Discussion |
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As in adults and in childhood patients >6 months of age suffering from spontaneous ischemic stroke, increased Lp(a) is the most important prothrombotic risk factor in the neonatal period.23 38 39 The heterozygous FV G1691A genotype and protein C deficiency were found in another 6 cases. The heterozygous FV gene mutation has recently been suggested to be an important risk factor for childhood antenatal porencephaly15 and is associated with a significant OR of 3.95 in neonatal stroke patients. The results reported from this subgroup analysis are in clear contrast to data published by Zenz et al20 and McColl et al.22 This discrepancy is due mainly to the small number of investigated cases and the different study designs, and it underlines the need for larger subgroup analyses in childhood patients as well.
However, confirming these reports20 22 but in contrast to children with spontaneous stroke, the carrier rates of the PT G20210A variant and the homozygous MTHFR 677TT genotype were not significantly increased compared with those in the control subjects. Furthermore, only 4.4% of infants investigated in this study had 2 prothrombotic risk factors. The FV G1691A mutation was found in combination with either increased Lp(a) or increased ACAs. Comparison of these data with results obtained from childhood patients suffering from thromboembolism beyond infancy revealed a distinctly lower proportion of combined defects in the cohort presented here.13 14 23 This finding is due mainly to the high proportion of additional acquired risk factors (54%) prospectively defined at baseline. As previously suggested in a small case series, perinatally acquired asphyxia, neonatal septicemia, and stroke associated with an open foramen ovale are the most important triggering factors for symptomatic ischemic stroke in neonates.26 27 28 29
In summary, the data presented here underline the
multifactorial etiology of symptomatic ischemic
stroke in neonates. It includes prothrombotic risk factors, acquired
underlying conditions, or a combination of acquired and genetic risks.
Thus, although an underlying disease is diagnosed in
54% of cases,
comprehensive screening for prothrombotic risk factors is recommended
in children suffering vascular accidents during the neonatal
period.
| Acknowledgments |
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| Footnotes |
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1 Participants in the Childhood Stroke Study Group are listed in the Appendix. ![]()
| Appendix 1 |
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Received June 1, 2000; revision received July 20, 2000; accepted July 25, 2000.
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M. Tzoufi, S. Giotopoulou, P. Papadimitriou, E. Dokou, N. I. Kolaitis, A. Siamopoulou, and G. Vartholomatos Genetic Risk Factors Associated With Thrombosis in Children With Congenital Neurologic Disorders J Child Neurol, June 1, 2005; 20(6): 509 - 512. [Abstract] [PDF] |
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M. Tzoufi, S. Giotopoulou, P. Papadimitriou, E. Dokou, N. I. Kolaitis, A. Siamopoulou, and G. Vartholomatos Genetic Risk Factors Associated With Thrombosis in Children With Congenital Neurologic Disorders J Child Neurol, June 1, 2005; 20(6): 509 - 512. [Abstract] [PDF] |
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D Tousoulis, C Antoniades, E Bosinakou, M Kotsopoulou, C Tsioufis, C Tentolouris, A Trikas, C Pitsavos, and C Stefanadis Effects of atorvastatin on reactive hyperaemia and the thrombosis-fibrinolysis system in patients with heart failure Heart, January 1, 2005; 91(1): 27 - 31. [Abstract] [Full Text] [PDF] |
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D. M. Ferriero Neonatal Brain Injury N. Engl. J. Med., November 4, 2004; 351(19): 1985 - 1995. [Full Text] [PDF] |
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Y. W. Wu, W. M. March, L. A. Croen, J. K. Grether, G. J. Escobar, and T. B. Newman Perinatal Stroke in Children With Motor Impairment: A Population-Based Study Pediatrics, September 1, 2004; 114(3): 612 - 619. [Abstract] [Full Text] [PDF] |
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A. Kosch, E. Kuwertz-Broking, C. Heller, K. Kurnik, R. Schobess, and U. Nowak-Gottl Renal venous thrombosis in neonates: prothrombotic risk factors and long-term follow-up Blood, September 1, 2004; 104(5): 1356 - 1360. [Abstract] [Full Text] [PDF] |
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M. R. Golomb, P. T. Dick, D. L. MacGregor, R. Curtis, M. Sofronas, and G. A. deVeber Neonatal Arterial Ischemic Stroke and Cerebral Sinovenous Thrombosis Are More Commonly Diagnosed in Boys J Child Neurol, July 1, 2004; 19(7): 493 - 497. [Abstract] [PDF] |
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K.-H. Jung, K. Chu, S.-W. Jeong, S.-Y. Han, S.-T. Lee, J.-Y. Kim, M. Kim, and J.-K. Roh HMG-CoA Reductase Inhibitor, Atorvastatin, Promotes Sensorimotor Recovery, Suppressing Acute Inflammatory Reaction After Experimental Intracerebral Hemorrhage Stroke, July 1, 2004; 35(7): 1744 - 1749. [Abstract] [Full Text] [PDF] |
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S. Ashwal, B. S. Russman, P. A. Blasco, G. Miller, A. Sandler, M. Shevell, and R. Stevenson Practice Parameter: Diagnostic assessment of the child with cerebral palsy: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society Neurology, March 23, 2004; 62(6): 851 - 863. [Abstract] [Full Text] [PDF] |
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K. Kurnik, A. Kosch, R. Strater, R. Schobess, C. Heller, and U. Nowak-Gottl Recurrent Thromboembolism in Infants and Children Suffering From Symptomatic Neonatal Arterial Stroke: A Prospective Follow-Up Study Stroke, December 1, 2003; 34(12): 2887 - 2892. [Abstract] [Full Text] [PDF] |
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P.O Bonetti, L.O Lerman, C Napoli, and A Lerman Statin effects beyond lipid lowering--are they clinically relevant? Eur. Heart J., February 1, 2003; 24(3): 225 - 248. [Full Text] [PDF] |
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L. Sironi, M. Cimino, U. Guerrini, A. M. Calvio, B. Lodetti, M. Asdente, W. Balduini, R. Paoletti, and E. Tremoli Treatment With Statins After Induction of Focal Ischemia in Rats Reduces the Extent of Brain Damage Arterioscler Thromb Vasc Biol, February 1, 2003; 23(2): 322 - 327. [Abstract] [Full Text] [PDF] |
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K. Gertz, U. Laufs, U. Lindauer, G. Nickenig, M. Bohm, U. Dirnagl, and M. Endres Withdrawal of Statin Treatment Abrogates Stroke Protection in Mice Stroke, February 1, 2003; 34(2): 551 - 557. [Abstract] [Full Text] [PDF] |
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H. Austin, M. I. Chimowitz, H. A. Hill, S. Chaturvedi, L. R. Wechsler, R. J. Wityk, E. Walz, J. L. Wilterdink, B. Coull, C. A. Sila, et al. Cryptogenic Stroke in Relation to Genetic Variation in Clotting Factors and Other Genetic Polymorphisms Among Young Men and Women * Editorial Comment Stroke, December 1, 2002; 33(12): 2762 - 2768. [Abstract] [Full Text] [PDF] |
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D. D. Waters, G. G. Schwartz, A. G. Olsson, A. Zeiher, M. F. Oliver, P. Ganz, M. Ezekowitz, B. R. Chaitman, S. J. Leslie, T. Stern, et al. Effects of Atorvastatin on Stroke in Patients With Unstable Angina or Non-Q-Wave Myocardial Infarction: A Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Substudy Circulation, September 24, 2002; 106(13): 1690 - 1695. [Abstract] [Full Text] [PDF] |
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L. T. McGrath, L. Dixon, D. R. Morgan, and G. E. McVeigh Production of 8-epi prostaglandin F2{alpha} in human platelets during administration of organic nitrates J. Am. Coll. Cardiol., August 21, 2002; 40(4): 820 - 825. [Abstract] [Full Text] [PDF] |
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K. Juul, A. Tybjarg-Hansen, R. Steffensen, S. Kofoed, G. Jensen, and B. G. Nordestgaard Factor V Leiden: The Copenhagen City Heart Study and 2 meta-analyses Blood, June 17, 2002; 100(1): 3 - 10. [Abstract] [Full Text] [PDF] |
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I. Mader, M. Schoning, U. Klose, and W. Kuker Neonatal Cerebral Infarction Diagnosed by Diffusion-Weighted MRI: Pseudonormalization Occurs Early Stroke, April 1, 2002; 33(4): 1142 - 1145. [Abstract] [Full Text] [PDF] |
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R. Strater, K. Kurnik, C. Heller, R. Schobess, P. Luigs, and U. Nowak-Gottl Aspirin Versus Low-Dose Low-Molecular-Weight Heparin: Antithrombotic Therapy in Pediatric Ischemic Stroke Patients: A Prospective Follow-Up Study Stroke, November 1, 2001; 32(11): 2554 - 2558. [Abstract] [Full Text] [PDF] |
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M. E. Andrew, P. Monagle, G. deVeber, and A. K.C. Chan Thromboembolic Disease and Antithrombotic Therapy in Newborns Hematology, January 1, 2001; 2001(1): 358 - 374. [Abstract] [Full Text] [PDF] |
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