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Factor V Leiden Mutation:
An Unrecognized Cause of
Hemiplegic Cerebral Palsy,
Neonatal Stroke, and
Placental Thrombosis
Olafur 'Thorarensen, MD,' Stephen Ryan, MD,"
Jill Hunter, M D , t and Donald P. Younkin, MD*
~

Thorarensen 0, Ryan S, Hunter 1, Younkin DP.
Factor V Leiden mutation: an unrecognized cause
of hemiplegic cerebral palsy, neonatal
stroke, and placental thrombosis.
Ann Neurol 1997;42:372-375

Activated protein C (APC) resistance due to factor V
Leiden mutation is the most common cause of familial
thrombosis [I]. It has a prevalence of 2 to 7% [2-41, is
found in all ethnic groups studied to date, and is 10
times as common as protein C, protein S, and antithrombin 111 deficiencies [3]. Although APC resistance
is associated with thromboembolic disease [4] including stroke in childhood and young adults [5-71, its association with hemiplegic cerebral palsy or placental
thrombosis has not been reported. We report 3 babies
who are heterozygous for factor V Leiden mutation
and had neonatal cerebrovascular disorders, including
ischemic infarction and hemorrhagic stroke. Multiple
placental thrombi were present on the fetal side in one
of these infants. Recent studies report that 40% of cerebral palsy (CP) is related to vascular factors, including infarction and hemorrhage [S]. We suspect that
factor V Leiden mutation may be an important cause
of neonatal stroke, CP, and placental thrombosis.

Case Reports
Case 1
A male infant presented at 6 months of age with right hemiplegia, which was first observed a t 3 months. The last week

~~

Activated protein C resistance caused by an Arg506Gln
mutation in the factor V gene (factor V Leiden mutation)
is the most common cause of familial thrombosis. This

From rhe Divisions of *Neurology and tNeuroradioloLy, Children's
Hospital of Philadelphia, and Departments of *Neurology, *Pediatrics, and tRadiology, University of Pennsylvania, Philadelphia, PA.

Received Jan 2, 1397, and in revised form Mar 4.Accepted for
publication Mar 10, 1997.
Address correspondencc to Dr Younkin, Division of Neurology, 6th
Floor, Wood Bldg. Children's Hospital of Philadelphia, 34th St and
Civic Center Blvd, Philadelphia, PA 19104.

372

mutation is associated with arterial and venous thromboembolic disease in neonates, infants, and children, but is
not a significant risk factor for ischemic stroke in adults.
We report on 3 babies with different neonatal cerebrovascular disorders including ischemic infarction and hemorrhagic stroke who are heterozygous for factor V Leiden
mutation. One infant had multiple thrombi in the fetal
placental vasculature. This is the first reported association between hemiplegic cerebral palsy, placental thrombosis, and factor V Leiden mutation. We suspect that activated protein C resistance may be an important cause of
in utero cerebrovascular disease and hemiplegic cerebral
Palsy.

of the pregnancy was complicated by roxemia, which was
treated with magnesium sulfate. He was born at term by
spontaneous vaginal delivery to a 30-year-old G2P1 (two
pregnancies, one viable birth) mother. Birth weight was 7 Ib
12 oz. Apgar score was 8 and 8 after 1 and 5 minutes. O n
the firsr day of life, he had mild respiratory problems, possibly related to magnesium-induced weakness, and required
supplemental oxygen. He did not have other neurologic
problems in the nursery and was discharged on day 3 of life.
Early development was normal, but by 3 months he had a
left-hand preference. His father had a history of deep vein
thrombosis treated with warfarin. Physical examination revealed right spastic emiparesis with the arm more involved
than the leg, and mild right facial weakness. Magnetic reso-

Copyrighr 0 1997 by the American Neurological Association

falling hematocrit (40% to 33%), and hemorrhagic cerebrospinal fluid (CSF red blood cells: 2,200). She had no clinical
seizures and her neurologic examination was nonfocal. Her
paternal grandfather had a stroke at 53 years of age and the
maternal great grandfather had a myocardial infarction at 46
years of age. Computed tomographic scanning of the head
on day 3 of life disclosed a left parietal intraparenchymal and
subarachnoid hemorrhage. She was discharged on day 6 of
life and did not have subsequent neurologic problems. An
MRI of the head at 3 months revealed a large left temporalparietal hemorrhagic infarction (Fig 2). She and her mother
were heterozygous for factor V Leiden mutation, detected by
the method described by Bertina and colleagues [2]. CBC,
PT, PTT, protein C, protein S, and antithrombin 111 were
normal. She was not treated and has not had subsequent
thrombotic events.

Case 3
A female infant presented on the first day of life with neonatal seizures. She was born at term after an uneventful
gestation to a 20-year-old GlPO mother. During labor,
meconium-stained amniotic fluid was noted and several late
fetal heart decelerations occurred. She was born by vaginal
delivery with low forceps assistance, suctioned, and intubated. A small amount of thin meconium was obtained on
the first intubation. Birth weight was 7 Ib. Apgar score was 8
and 9 after 1 and 5 minutes. At 6 hours of age repetitive,

F& 1. T2-wekhted image showing atrophy with ex vacuo
dilatation of the body of the lateral ventricle and gliosis in the
left frontotemporal region without evidence of blood products.
Imaging in other planes conjrmed the absence of any communication with the body of the l e j lateral ventricle. A magnetic
resonance angiogram pe$ormed concurrently revealed a small
l e j middle cerebral artery.

Fig 2. Axial T2-weighted image demonstrating loss of brain
tissue with a rim of hemosiderin (T2 bypointensity) in the lefi
posterior temporal region in association with altered blood
products (T2 bright signal).

nance imaging (MRI) of the head performed at 2 years of
age disclosed a large left middle cerebral artery distribution
area of encephalomalacia involving the frontotemporal region
with evidence of gliosis (Fig I). The patient and his father
were heterozygous for the factor V Leiden mutation. The
mutation was detected with polymerase chain reaction and
the restriction enzyme MnlI as described by Bertina and colleagues [ 2 ] . Determinations of complete blood count (CBC),
prothrombin time (PT), partial thromboplastin time (PTT),
protein C, protein S, antithrombin 111, and bleeding time
were normal. H e was not anticoagulated and has not had
subsequent thrombotic events. At 30 months, he has persistent hemiparesis, mild global developmental delay, and intractable seizures.

Case 2
A female infant was referred at 1 month of age for evaluation
of neonatal hemorrhagic cerebral infarction. She was born by
spontaneous vaginal delivery after an uncomplicated 36-week
pregnancy to a 26-year-old GlPO mother. Birth weight was
5 Ib 11 oz. Apgar score was 6 and 8 after 1 and 5 minutes.
O n day 1 of life, she had mild respiratory difficulty, rapidly

Brief Communication: Thorarensen et al: Factor V Leiden Mutation

373

Fig 3. Axial 72-weighted slice ncquired near the vertex, returning T2 dark signal consistent with hevnosiderin deposition
in the rentra sriniovnle overlying the bodies of the lnteral ventricles, secondnry to prior hemorrhage i n the periventricular
white rudtter.
brief focal seizures were noted. With the exception of lethargy and hypotonia, neurologic examination disclosed no abnormalities. Family history was nonrevealing. MRI showed
hemorrhagic periventricular leukomalacia (Fig 3). DNA analysis, described by Bertina and colleagues [2],showed that she
was heterozygous for the factor V Leiden mutation. Protein
S determination was normal. Protein C functional assay was
46% of control (normal adult range, 72-142% of control).
The placenta was grossly normal, bur histological examination revealed intravascular thrombosis associated with fragmentarion of erythrocytes in multiple fetal vessels. The infant
was discharged from the hospital at 6 days of age, appearing
well. She was treated with coumadin and has not had subsequent thrombotic events.

Discussion
Rapid but controlled thrombosis results from a complex balance between coagulant and anticoagulant
factors. APC is an important anticoagulant factor.
Thrombin formed at sites of vascular injury leads to
coagulation by converting factors V and VIII to activated forms (Va and VIIIa), but it also activates protein C by binding with the endothelial membrane protein thrombomodulin. APC, with its cofactor protein
S, acts as an anticoagulant by inactivating both Va and
VIIIa “)I. Deficiencies of protein C, protein S, and antithrombin 111 are recognized causes for familial thrombosis, but they only comprise a small percentage of pa-

374

Annals of Neurology

Vol 42

No 3

September 1997

tients with thrombophilia; the overwhelming majority
are due to APC resistance [9].
In 1993 Dahlback and collaborators [3, 101 reported
a family with autosomal dominantly inherited venous
thrombosis secondary to APC resistance. Subsequently,
APC resistance was localized to a point mutation in the
factor V gene that replaces arginine with glutamine at
the cleavage site for APC on factor Va [ 1, 21. Mutated
factor Va has procoagulant activity but is resistant to
APC [8]. Factor V Leiden mutation occurs in 2 to 6%
of the population and causes most cases of APC resistance [2, 41.
The relationship between factor V Leiden mutation
and venous thromboembolic disease has been established in children [I11 and adults [4]. Three recent
studies show that this mutation is not a significant risk
factor for ischemic stroke [4, 121 or transient ischemic
attack [13]in adults. However, the prevalence of APC
resistance and factor V Leiden mutation appears to be
higher in pediatric and juvenile stroke populations
[5-7, 141. Simioni and co-workers [5],in their report
on three Italian families with hereditary APC resistance, found 1 heterozygous 8-month-old child with
ischemic stroke without any other known prothrombotic conditions. Ganesan and associates [6] found that
16% of their British pediatric stroke population was
heterozygous for factor V Leiden mutation. The prevalence of factor V Leiden mutation was 38% in a German population of neonates, infants, and children with
arterial thromboembolic disease [7].This study found
arterial stroke predominantly in the neonatal age group
but did not specify how many neonates had factor V
Leiden mutation. Young patients with this mutation,
in addition to other risk factors for thrombosis, may
not survive to adulthood. To o u r knowledge, this is the
first report linking factor V Leiden mutation and
hemiplegic cerebral palsy.
Familial thrombosis is rarely associated with neonatal
stroke. Babies who are homozygous for protein C or
protein S deficiency can develop cerebral infarction in
association with purpura fulminans, a fatal thromboembolic condition [ 151. Both heterozygous and homozygous cases of factor V Leiden mutation have increased risk for thrombosis throughout life but usually
are asymptomatic in youth unless associated with other
acquired or genetic prothrombotic conditions, including central venous catheters, trauma, surgery, cancer,
pregnancy, oral contraceptives, deficient protein C or
protein S, and homocystinuria [7, 16-19].
Several factors unique to the fetus may predispose
these babies to in utero infarction. The thrombotic system in the normal fetus is tilted slightly in favor of
thrombosis; factor V Leiden mutation could further alter the balance toward pathologic thrombosis. The fetus has a high hematocrit and relatively slow blood
flow, factors known to lead to thrombosis in older chil-

dren. Finally, the fetus has a patent foramen ovale,
which allows venous emboli to enter the arterial system. More than 60% of fetal cardiac output goes to
the brain, which would predispose it to embolic infarction. In comparison with the right common carotid artery, the left has a relatively straight path, which would
lead to preferential streaming and explain the higher
incidence of left hemispheric infarction in neonates.
We suspect that, as in adults, venous thrombosis and
ernbolic stroke may be the predominant mechanism of
infarction in neonates with factor V Leiden mutation.
Long-term anticoagulation prevents recurrent thrombosis in patients with factor V Leiden mutation [9, 1 I]
but has considerable risk in infants and toddlers. The
incidence of recurrent infarction in babies with neonatal stroke is extremely low; therefore, we did not anticoagulate Case I and Case 2. Given the coexistence of
low protein C functional assay and factor V Leiden
mutation, predisposing to thromboembolism, anticoagulation with coumadin was initiated in Case 3. With
follow-up as long as 2 years, none has had subsequent
venous or arterial thrombosis.
Placental thrombosis in the fetal and maternal circulation has been associated with maternal coagulopathies
[lo]. Recurrenr abortions and placental infarctions
were reported in 3 women both heterozygous for homocystinuria and factor V Leiden mutation [19]. This
is the first report linking placental thrombosis and factor V Leiden mutation without other prothrombotic
conditions.
CP is one of the most common neurologic disorders
of childhood. It occurs in 0.25% of live births and affects more than 100,000 American children. Known
perinatal complications comprise fewer than 20% of
the cases of CP; the vast majority are attributed to unknown prenatal factors. A recent MRI-based study attributed 40% of the cases to usually unknown vascular
factors [8]. We speculate that some of these were secondary to factor V Leiden-induced cerebral infarction.
Infantile hemiplegia is frequently attributed to preor perinatal cerebral infarction, but the etiology is usually unknown. As demonstrated by these 3 babies, factor V Leiden mutation may cause hemiplegic CP and
hemorrhagic stroke. We recommend testing for this
mutation in all babies with unexplained prenatal or
neonatal cerebral infarction or CP related to vascular
events, especially if there is a family history of venous
thrombosis, early stroke, or heart disease.

We thank Dr Robert Clancy for referring a patient included in this
report, and D r Katherine A. High for testing for factor V Leiden
mutation and helpful discussion.

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Brief Communication: Thorarensen e t al: Factor V Leiden M u t a t i o n

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