Brain & Development 28 (2006) 604–606
www.elsevier.com/locate/braindev

Case report

Factor V Leiden mutation, deficiency of antithrombin III and
elevation of factor VIII in a child with
ischemic stroke: A case report
Rıdvan Duran a,*, Betül Biner a, Muzaffer Demir b, Cosßkun Çeltik a,
Serap Karasalihoğlu a, Betül Acunasß a
b

a
Department of Pediatrics, Trakya University School of Medicine, Edirne, Turkey
Department of Hematology/Internal Medicine, Trakya University School of Medicine, Edirne, Turkey

Received 9 October 2005; received in revised form 20 February 2006; accepted 18 March 2006

Abstract
A 4-year-old boy was admitted with left hemiplegia. Thrombophilia marker examination resulted with factor V Leiden mutation
heterozygosity, a deficiency of antithrombin III and a high level of factor VIII. Cranial computed tomography scan revealed an
ischemic infarct in the region of right anterior cerebral artery. In the literature, combinations of multiple thrombophilia risk factors
that trigger cerebral ischemic stroke in children have been emphasized. To our knowledge, this is the first child with these combinations of thrombophilia risk factors and ischemic stroke to be reported in the literature.
Ó 2006 Elsevier B.V. All rights reserved.
Keywords: Ischemic stroke; Child; Factor V Leiden; Factor VIII; Antithrombin deficiency

1. Introduction
Childhood ischemic stroke is increasingly recognized.
The incidence of childhood ischemic stroke has been
estimated to be between 3.3 and 8 per 100.000 children
per year. Several prothrombotic disorders such as prothrombin 20210G-A (PT20210), the factor V Leiden
(FVL) mutation, and hereditary deficiencies of protein
C (PC), protein S (PS), antithrombin III (ATIII) are also
associated with stroke in children [1]. Recently, another
thrombophilic factor has been described, that is an
increased plasma concentration of factor VIII (FVIII).
The combination of thrombophilia markers increased
the risk of stroke and the ‘‘thrombophilia burden’’ is
definitely increased in children with ischemic stroke
*

Corresponding author. Tel.: +90 284235 23 38; fax: +90 0284 235
23 38.
E-mail address: ridvan_duran@yahoo.com (R. Duran).
0387-7604/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.braindev.2006.03.008

[1–3]. We report a 4-year-old boy who presented with
ischemic stroke associated with a combination of heterozygous FVL mutation, a deficiency of ATIII, and a high
plasma level of FVIII. To our knowledge, this is the first
pediatric patient with these combinations of ischemic
stroke to be reported in the literature.

2. Case report
A 4-year-old boy was admitted with mild left spastic
hemiplegia. He was born after a normal pregnancy and
uneventful delivery, weighing 3200 g. He was the first
child of his parents who were healthy and nonconsanguineous. At the age of 3 years, his left extremities experienced sudden numbness and weakness. The case had
no infection and head trauma history before the onset
of the left hemiplegia. On examination, mental status,
cranial nerves, strength, reflexes and sensation of the

R. Duran et al. / Brain & Development 28 (2006) 604–606

right upper and lower extremities were normal. Reflexes
were also normal on the right side of the body. Left
upper and lower extremities were flaccid, paralyzed
and areflexic and a plantar response could not be
obtained. The pain perception and tactile sensation were
normal on the left side. The child was diagnosed with
left hemiparesis. Laboratory examinations, including
complete blood count, urinalysis and biochemical tests
were normal. Bleeding time, prothrombin time, thrombin time and activated partial thromboplastin time were
within normal limits. Cranial computed tomography
scan that was performed 6 months after the stroke
revealed two separate infarct areas in the right anterior
peripheral border zone localized to cortical–subcortical
areas and deep white matter without edema or atrophy
(Fig. 1).
A thrombophilia marker screening done 1 year
afterwards revealed an activated protein C sensitivity
ratio (APC-SR) value of 1.76 (normal value of APCSR is >1.81). APC-SR was measured by using FV
depleted plasma, aPTT based coagulometric assay.
Therefore the patient was diagnosed with APC resistance and FVL mutation heterozygosity. A deficiency
of antithrombin (antithrombin value: 5.3 mg/dL, normal value: >5.87 mg/dL) and a high level of FVIII
(FVIII level: 300 IU/dL, normal value: <150 IU/dL)
were also diagnosed. The activities of protein C
and S, and antiphospholipid antibody results were
found to be normal. All markers were studied two
times, 1 month apart. Other thrombophilia markers
such as prothrombin 20210 mutation and MTHFR
mutation studies were not available. Also, the investigation of the family for thrombophilia markers was
also not available because of technical problems. The
patient is now suffering from mild left spastic hemiplegia and is attending to special physiotherapy
program.

Fig. 1. Ischemic infarct in the region of right anterior cerebral artery
visualized in cranial CT.

605

3. Discussion
Among the various causes for ischemic stroke in children, inherited gene defects of coagulation system are
being increasingly recognized. The combination of
thrombophilia markers increased the risk of stroke
and the ‘‘thrombophilia burden’’ is definitely increased
in children with ischemic stroke [3,4].
The FVL mutation is a prothrombotic polymorphism
resulting from the substitution of arginine with glutamine
at amino acid residue 506 in factor V causing resistance to
activated protein C [5]. FVL mutation occurs in 5% of the
white population. Heterozygosity for this mutation
increases the risk of ischemic stroke in children by almost
5-fold [3,6]. The presence of this mutation might have
played a role in the pathogenesis of stroke in our patient,
especially when combined with other risk factors.
Recently, new laboratory phenotypes such as high
FVIII, FIX and FXI associated with an increased risk
of venous thrombosis have been reported [2]. Among
these, only elevated FVIII is a strong risk factor for
recurrence. In the general population, the prevalence
of elevated FVIII levels (P150 IU/dL) is 11%, whereas
it has been found in 25% of patients with a first episode
of venous thrombosis. In a pediatric thrombosis study
of both venous and arterial, high levels of FVIII have
been calculated to increase the risk of thrombosis
approximately 11-fold [7]. The plasma FVIII level in
the presented case was determined to be 300 IU/dL.
In children with stroke, the association of the rare
defect of deficiency of ATIII is currently inconclusive.
Some reports established a relation [8]. However, in others such an association was not found [3].
Our patient had an ATIII deficiency, FVL mutation,
and a high plasma FVIII level. Recent reports have also
described an enhanced risk for the development of thrombosis in individuals with a combined defect compared with
a single defect. Akar et al. [4] reported that two patients
with ischemic stroke had a combination of a FVL and a
PT20210 mutation. Lewandowski et al. [9] noted combined hemostatic defects with symptomatic carriers of
Leiden mutation of factor V (e.g., FVL with PT20210
mutation, and PS and ATIII deficiency). Deda et al. [10]
reported a 10-year-old boy who presented with ischemic
stroke associated with combination of FVL mutation,
PS deficiency, and high plasma level of FVIII. This report
and the other data indicate a higher risk for development
of thrombosis in individuals with combined defect.
The presented patient had a combination of multiple
risk factors, which enhanced the occurrence of ischemic
stroke. It is possible that an interaction occurred
between these hypercoagulable states. In conclusion,
all children with combined ischemic stroke should be
evaluated for the presence of a thrombotic state which
may warrant prophylactic anticoagulation therapy for
the prevention of recurrence risk.

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