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PEDIATRICS Vol. 107 No. 6 June 2001, pp. 1400-1404
,,
From the * Departments of Paediatrics and Background and Purpose. The aim of
this study was to evaluate the occurrence of prothrombotic disorders in
a well-characterized cohort of infants with neonatal stroke and to
document any association of prothrombotic disorders with the type of
infarct seen on magnetic resonance imaging (MRI) and clinical
outcome.
Methods. Twenty-four infants with perinatal cerebral
infarction confirmed by neonatal MRI were enrolled in the study. All
the infants and, when possible, both parents were tested to identify
inherited and acquired prothrombotic disorders.
Results. None of the infants had a significant bleeding
diathesis, but 10 (42%) had at least 1 prothrombotic risk factor. Five
children showed heterozygosity for factor V Leiden, and 6 had high
factor VIIIc concentrations. There was a striking association between the occurrence of these abnormalities and both the presence of cerebral
hemorrhage on MRI and poor neurologic outcome. Eight of the 11 patients
(73%) with hemiplegia or global developmental delay had factor V
Leiden and/or raised factor VIIIc, whereas only 1 of the 13 patients
(8%) with normal outcome had any prothrombotic risk factors. In
particular, all 5 infants with factor V Leiden had hemiplegia, compared
with only 4 of the 19 infants without factor V Leiden (21%).
Conclusions. These data suggest that the presence of
prothrombotic risk factors and, in particular, of the factor V Leiden
mutation, is significantly associated with poor outcome after perinatal
cerebral infarction.
Haematology and the
§ Medical Research Council Clinical Sciences Centre, Imperial College,
Hammersmith Campus, London, United Kingdom.
ABSTRACT
Top
Abstract
Methods
Results
Discussion
References
As a consequence of the wider availability of brain imaging
in the newborn, neonatal cerebral infarction has become an increasingly recognized entity, and recent population-based data report an incidence
of 1 in 4000 term infants.1,2 In the past, these lesions
were mainly diagnosed on postmortem examination and were always
associated with severe conditions, such as sepsis, congenital heart
disease, disseminated intravascular coagulation, or severe asphyxia. In
the last decade, however, several studies using early and serial
imaging have demonstrated that infarcts can also be observed in the
absence of severe antenatal and/or perinatal events.3,4
Although neonatal imaging has dramatically improved the detection of
infarcts and may also provide information on the timing of the
insult,5 the cause of these lesions is usually unknown. By
contrast, there is increasing evidence that inherited or acquired
prothrombotic disorders may play a significant role in patients who
have suffered a stroke. In particular, the incidence of factor V Leiden
mutation and/or increased factor VIII have been found to be
significantly associated with increased risk for
thrombosis.6-13 The majority of these studies, however,
reported strokes occurring in childhood or adulthood6-10
and only a small number of newborns with infarction have been
studied.11-14
The aim of this study was to assess the thrombophilic status in a
cohort of infants who showed cerebral infarction on neonatal magnetic
resonance imaging (MRI) and to establish: 1) the prevalence of factor V
Leiden mutation and of increased factor VIII in these infants, and 2)
whether the presence of these risk factors is related to the type and
extent of lesions on MRI scans or to outcome.
The study has been approved by the Hammersmith Hospital Trust
Research Ethics Committee. Twenty-four infants who showed evidence of
cerebral infarction on neonatal MRI were enrolled in this prospective study. In 23 of the 24 infants, the infarct was detected after convulsions in the first days after birth; in 1 infant, the lesion was
an incidental finding when the infant was scanned on day 2 as part of a
normal control group. All infants had normal Apgar scores at 5 minutes
( MRI
The infants were imaged on a 1.0 Tesla Picker HPQ system using
conventional T1-weighted spin echo (860/20 ms), inversion recovery (3800/30/950), and T2-weighted spin echo (3000/120 ms) sequences. Although infants have been serially studied, in this study, we only
assessed the scans performed between 1 and 4 weeks after birth, when
perinatally acquired lesions are at their most obvious. The scans were
assessed by an independent observer (M.R.) who was blind to the
hematologic data.
The infarcts were classified according to the arterial distribution of
the lesions. This was based on the location, extent, and shape of the
lesions.4 Infarcts were characterized as being in the
territory of the main arteries or in a border zone distribution. The
infarcts in the territory of the main arteries were further subdivided
according to whether they occurred in the main branch or in 1 of the
cortical branches of the artery.
The lesions were also classified according to whether the ischemic
lesion was associated with hemorrhage, either within the ischemic
lesion or in other sites.
Outcome
Follow-up assessments were performed at 6, 12, 18, and 24 months
of age, and then at least yearly after that. All the infants were
assessed with a structured neurologic examination15 and on
the developmental scales of Griffiths.16
Coagulation and Thrombophilia Profile
The coagulation profile included prothrombin time, activated
partial thromboplastin time, thrombin time, platelet count, fibrinogen, and von Willebrand factor antigen. The prothrombotic screen included measurement of factor VIIIc, protein C, protein S, and antithrombin. In
addition, the presence of the factor V Leiden mutation and the G Blood samples from children and parents were drawn into 0.105 M
trisodium citrate bottles for coagulation tests and
ethylenediaminetetraacetic acid bottles for full blood counts, blood
film, and blood grouping. Blood samples were immediately centrifuged at
4°C for 10 minutes at 3000 rpm; platelet-poor plasma was separated
and either tested immediately or stored in aliquots at Hematologic results were classified as normal or abnormal according to
age-specific normative data.17,18
Statistics
Data were analyzed using MRI
Twenty-two of the 24 children had arterial infarction in the
distribution of the middle cerebral artery and 2 had border zone lesions. Of the 22 children with infarction of the middle cerebral artery, 5 had an infarction in the main branch and 17 in 1 of the
cortical branches. Eleven of the 24 children also showed signal changes
on T1 and transverse relaxation time images consistent with hemorrhage,
which was always in other sites (Figs 1 and 2). Details of the site and size of
the lesions are shown in Table 1.
TABLE 1
METHODS
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Abstract
Methods
Results
Discussion
References
8) and normal cord pH (>7.2). Twenty-one of the 24 were white and 3 were Asian.
A
transition at position 20210 of the prothrombin gene were screened
using polymerase chain reaction-based mutation analysis. Blood groups
were determined as factor VIII levels are related to the blood group
systems of A, AB, B, and O.
80°C for
testing. Ethylenediaminetetraacetic acid samples were frozen at
40°C for DNA analysis. Coagulation screens were performed on fresh
platelet poor plasma on the ACL 300 R (Instrumentation
Laboratory, Lexington, MA) and KC10 (Brownes Ltd,
Reading, UK) instruments before January 1997 and on Sysmex CA 6000 (Sysmex UK Ltd, Milton Keynes, UK) after January 1997. All the children
born after May 1996 were tested within the first 2 weeks after birth
(n = 13). The children born before that date (n = 11) were tested at 1 of their follow-ups.
2 tests with
Fisher's exact test, where appropriate. Testing the level of
significance was set at 0.01 because of multiple significances.
RESULTS
Top
Abstract
Methods
Results
Discussion
References
View larger version (64K):
[in a new window]
Fig. 1.
Female infant imaged at 15 days. Inversion recovery (3800/30/900)
sequence in the transverse plan. At low ventricular level (A), there is
large infarct involving most of the left hemisphere. There is abnormal
low and high signal intensity in the left basal ganglia and asymmetry
of myelin in the posterior limb of the internal capsula. At a lower
level (B), there is atrophy of the left part of the brainstem (arrow)
consistent with Wallerian degeneration.
View larger version (62K):
[in a new window]
Fig. 2.
Male infant image at 7 days of age. T1-weighted spin echo (860/20) in
the transverse plan. At low ventricular level (A), there are widespread
areas of cortical highlighting with low signal intensity in the white
matter. These changes are consistent with an infarction of the left
middle cerebral artery. There is also bilateral subdural hemorrhage
(arrow). At a lower level (B), there is a hemorrhagic lesion
within the right brainstem (arrow).
Coagulation Factors, MRI findings, and Outcome
Outcome
All children were at least 24 months old at the time of their final assessment (range: 2-7 years). Thirteen children had a normal outcome, 9 had a hemiplegia, and 2 had global developmental delay but no signs of hemiplegia. In all 9 children with hemiplegia, the clinical signs suggestive of hemiplegia were already present before the age of 2 years.
Coagulation and Thrombophilia Profile
None of the 24 children studied had thrombocytopenia or any significant abnormality in the coagulation profile, and there was no evidence of disseminated intravascular coagulation.
Thrombophilia screening was normal in 14/24 patients (58%). In the 10 patients with abnormal results, the abnormalities were increased factor VIIIc (n = 6) and heterozygous factor V Leiden (n = 5). One patient had both increased factor VIIIc and heterozygous factor V Leiden. Table 1 shows the details of the individual findings. Parental samples were available for 4 of the 5 children with factor V Leiden heterozygosity. In all 4, 1 of the parents (the father in 2 and the mother in the remaining 2), was also heterozygous for factor V Leiden. Of the 6 children with increased factor VIIIc, parental samples were available for 11 parents and were normal in 10 (1 mother had a raised factor VIII when tested 11 months postnatally). In 4 of the 6 children, the increased factor VIIIC was detected at follow-up. Antithrombin, protein C, and protein S were normal in all of the infants tested and in their parents. There was no evidence of the G20210A mutation of the prothrombin gene in any of the children tested.
Correlation Between Hematologic Factors and MRI Findings
Hematologic Factors and Extent and Site of Lesion There was no association between the extent of the lesions and abnormal hematologic factors. Both normal and abnormal factor VIIIc and factor V Leiden heterozygosities were found in lesions in the territory of cortical and main branch arteries. Both children with border zone lesions had increased factor VIIIc.
Hematologic Factors and Hemorrhage
Factor VIIIc was increased both in children with purely ischemic
lesions and in those with additional hemorrhage (4/13 and 2/11). Factor
V Leiden heterozygosity was found in 5/11 children with a hemorrhage
and in none of the infants with purely ischemic lesions
(2, P = .006; Fisher's exact
test, P = .01).
Outcome and Hematologic Factors
Eight of the 11 children (73%) with hemiplegia or developmental
delay had at least 1 abnormality of their thrombophilic profile, whereas only 2 of the 13 (8%) with normal outcome had abnormal thrombophilic profile (2, P = .005). Factor V Leiden heterozygosity was significantly associated with
the presence of a hemiplegia (Fisher's exact test, P = .003). All 5 children with factor V Leiden developed a hemiplegia, compared with only 4 of the 20 children without this mutation.
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DISCUSSION |
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Top
Abstract
Methods
Results
Discussion
References
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The results of this study showed that ~40% of infants with neonatal cerebral infarction had prothrombotic risk factors. Specifically, 5 infants were heterozygous for factor V Leiden, 1 of whom also had a raised factor VIIIc, and 5 infants had raised factor VIIIc as an isolated finding.
The prevalence of factor V Leiden mutation in our cohort (24%) was substantially higher than that reported in the normal population, which has been estimated between 2.7% and 10% in Europe and North America. In the United Kingdom, the frequency of factor V Leiden mutation is 3.4%.19 Factor V Leiden has previously been reported in childhood and adult stroke9 and is well-known as a risk factor for venous thrombosis.20-22 Recently, it has also been found in neonatal porencephalopathy and in other newborn infants with arterial thrombosis.11,23
This study is the first to demonstrate a relationship between the presence of factor V Leiden and both the nature and outcome of a major vascular occlusive event. All 5 infants in this study with factor V Leiden had residual hemiplegia (100%), whereas only 4 of the 19 infants without factor V Leiden (21%) had hemiplegia.
The reasons for this observation are not clear. In our cohort, factor V Leiden was not specifically associated with the size of the infarct because it was found in both main branch and cortical branch distributions. All of the infants with factor V Leiden, however, showed additional hemorrhagic lesions, which were found in only 30% of infants without factor V Leiden. We have previously reported that the presence of MRI abnormalities within the basal ganglia, the cerebral hemisphere, and in the posterior limb of the internal capsule predicted the development of hemiplegia.4 All the infants with factor V Leiden in the present study had MRI abnormalities in these 3 areas. It is, therefore, possible that although the presence of prothrombotic risk factors is not associated with the absolute size of an infarct, they may influence both its nature and the combination of sites involved, thereby leading to a high risk of hemiplegia. Factor V Leiden might equally modulate the chance of reperfusion after ischemia or the ability of neural tissue to repair after the insult.
The association between factor V Leiden and hemiplegia support recent findings by Debus et al23 and Nelson et al.24 Both studies looked retrospectively at children with cerebral palsy and/or neurodevelopmental delay and found a high incidence of prothrombotic factors. Debus et al23 also found that >25% of the infants in their cohort had deficiencies of proteins C and S. These were normal in our cohort. This may reflect both sampling error and different gene pools among the study populations.
The other primary finding in the present study was the presence of a raised factor VIIIc level in 6 of the 22 infants in whom this was measured (27%). This is similar to the prevalence of raised factor VIIIc (>1.5 IU/mL) among adults with venous thrombosis in the Leiden Thrombophilia Study (25%)25 and in patients with ischemic cerebrovascular disease and compares with an expected prevalence of raised factor VIIIc in the normal healthy population of 11%. Unlike these studies, we did not demonstrate an increased level of von Willebrand factor, which has also been associated with an increased risk of cerebral infarction.25
Family studies were available for 11 of the parents of the 6 infants with a raised factor VIIIc but only 1 mother had a moderately raised factor VIIIc, which could possibly suggest a genetic basis for the raised factor VIIIc. Factor VIII is well known to behave as an acute phase reactant and so it is possible that increased factor VIII may, in some cases, be a result of rather than a cause of the stroke. However, of the 6 children with raised factor VIIIc, 4 maintained raised factor VIIIc levels beyond the neonatal period, 1 returned to normal at 5 months of age, and 1 was not retested. Normal levels of antithrombin, protein C, and protein S in all the parents tested make it seem unlikely that an anticoagulant deficiency has been missed as a result of the difficulty in applying normal ranges to young children.
These data indicate that the role of elevated factor VIIIc in neonatal stroke is worthy of additional investigation. Three of the 6 infants who had abnormal outcome but did not have the factor V Leiden mutation had increased factor VIIIc (>1.5 IU/mL). Taken together, our results show that infants with a neonatal stroke but a normal factor VIIIc and factor V Leiden seem more likely to have a favorable long-term outcome; only 3/14 (21%) having hemiplegia or developmental delay. In contrast, the presence of factor V Leiden and/or a raised Factor VIIIc in infants with neonatal stroke is associated with a high risk (80%) of poor neurologic outcome.
The high prevalence of factor V Leiden in our cohort also suggests that genetically determined abnormalities of thrombophilia play a role in the cause of cerebral infarction. These lesions are probably attributable to a multifactorial cause rather than to a single factor. Although by using early and serial imaging we were able to time the insult to the perinatal period, none of our children had severe acute perinatal events that could be clearly implicated as responsible for the lesion. It is, therefore, likely that genetic factors increase the risk for thrombosis, which can then be triggered even by otherwise minor adverse perinatal events.
This study highlights the need to assess all infants with focal hypoxic-ischemic and/or hemorrhagic brain injury for prothrombotic risk factors. The results have implications for prognosis and likely development of cerebral palsy, as well as for the possibility of future thrombotic events. Preventive measures and counseling of families may be indicated.
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FOOTNOTES |
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Received for publication Jun 26, 2000; accepted Dec 4, 2000.
Reprint requests to (E.M.) Department of Paediatrics, Hammersmith Hospital, Du Cane Road, London, W12 OHN, United Kingdom. E-mail:emercuri{at}ic.ac.uk
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ABBREVIATIONS |
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MRI, magnetic resonance imaging; T1, longitudinal relaxation time.
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REFERENCES |
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