Angiology

Volume 55, Number 2, 2004

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Hypereosinophilic Syndrome Associated
with Heterozygous Factor V Gene Mutation:
An Unusual Combination Resulting in
an Acute Coronary Syndrome and
Recurrent Cerebral Stroke
A Case Report
Markus G. Engelmann, MD,* Tilman Kolbe, MD,* Christian Faul, MD,*†
and Gerhard Steinbeck, MD,* Munich and Augsburg, Germany

The authors report the first case of a patient with a hypereosinophilic syndrome associated
with heterozygous factor V gene mutation, resulting in an acute coronary syndrome and
recurrent cerebral stroke despite effective anticoagulation. A 40-year-old man presented with
an acute coronary syndrome accompanied by a brachiofacial right-sided hemiparesis and
dysarthria. Diagnosis of a hypereosinophilic syndrome was established by blood testing,
myocardial biopsy, and bone marrow analysis. Eosinophilic infiltration was present in the
myocardium, accompanied by proliferation in the endomyocardium and a pneumonic infiltrate.
Although effective anticoagulation with heparin was administered, a recurrent stroke
occurred while blood eosinophils were being normalized by corticosteroid treatment. A coexisting heterozygosity of the factor V mutation was demonstrated, and it is hypothesized that
this might have contributed to the recurrent thromboembolic episodes. In patients with hypereosinophilic syndrome and recurrent thromboembolic episodes, other thrombophilic diseases,
including factor V mutations, should be considered, and long-term coagulation should be
contemplated.

Angiology 55:221–225, 2004
From the *Department of Cardiology, University Hospital
Munich, Grosshadern, Munich, and the †Medical Clinic I,
Municipal Hospital, Augsburg, Germany
No financial support was received. There is no financial involvement or interest
Correspondence: Markus G. Engelmann, MD, Department
of Cardiology, University Hospital Munich Grosshadern,
Marchioninistr. 15, 81377 Munich, Germany
E-mail: mge@lrz.uni-muenchen.de
©2004 Westminster Publications, Inc., 708 Glen Cove Avenue,
Glen Head, NY 11545, USA

Introduction
Idiopathic hypereosinophilic syndrome (HES) is
a leukoproliferative disorder of unknown origin,
characterized by sustained overproduction of
eosinophils, resulting in organ damage, usually
of the heart, skin, pulmonary, or central and peripheral nervous systems.1 Cardiac involvement
mostly presents as endomyocardial damage, and
it may lead to thrombus formation and conges-

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tive heart failure. Thromboembolic cerebral
strokes are not uncommon. We present a case
where a not previously reported association of
HES with heterozygosity of factor V mutation resulted in coronary thromboembolism and recurrent cerebral strokes despite effective intravenous
anticoagulation.

Case Report
A previously healthy 40-year-old man presented
with an unproductive cough accompanied by pain
in the right shoulder, which had been followed
by a facial paresis on the right side and an ipsilateral sensomotor hemiparesis, mainly of the
upper extremity, and slurred speech. A few weeks
before this, he had been on holiday to Portugal.
Soon after his return he noticed some epigastric
pain, fever (up to 39°C), arthralgias, night sweats,
and weight loss of 5 kg. At admission, the patient
had a fever of 40°C and the initial physical examination yielded normal findings. Neurologic examination demonstrated a brachiofacial rightsided hemiparesis and dysarthria. The white
blood count was elevated (23.6 x 109/L, normal
range 4–11) with eosinophilia (72% eosinophils).
The creatinine kinase was elevated (125 IU/L,
normal < 80), as was the cardiac-specific troponin I at 38.2 ng/mL (normal < 0.5 ng/mL).
The ECG showed ST elevation in leads III and aVF
and T-wave inversion in leads V4 –V6 Figure 1A).
A transthoracic echocardiogram detected inferolateral dyskinesia and a floating structure near
the posterior papillary muscle (Figure 1B). An urgently taken coronary angiogram appeared normal, suggesting a resolved thrombus had been the
cause of the cardiac dyskinesia. Biopsy specimens
showed eosinophilic myocarditis. A chest roentgenogram and computed tomography (CT) demonstrated infiltration of the left lower pulmonary
lobe (Figure 1C). Cranial magnetic resonance
imaging (MRI) revealed multiple left-sided subcortical white matter lesions. A bone marrow
biopsy excluded an eosinophilic leukemia and
revealed reactive eosinophilic inflammatory
changes. A parasitic infection and allergic disease
were excluded.
The patient was treated with heparin controlled to an effective activated partial thromboplastin time (aPTT). Treatment with prednisolone (1 mg/kg body weight) caused the
eosinophilia and the pulmonary infiltrate to dis-

appear over 2 days. The creatinine kinase peaked
at 153 U/L and was normal by day 2. Although
apparently efficiently anticoagulated (aPTT 98s),
the patient suffered a recurrent stroke at day 7,
manifesting as transient global aphasia and worsened right-sided brachiofacial paresis. At this
point, the eosinophil level was normal. MRI
showed new left-sided subcortical and central
white matter lesions with marked gadolinium enhancement (Figure 2A, B). Genetic thrombophilia analysis was performed. The activated protein
C (APC) sensitivity ratio was reduced to 1.7 (normal > 2.0). DNA analysis confirmed the heterozygous presence of a 1691G*A mutation in
the factor V gene (genotype +/–) by use of standard techniques (amplification of a 220-bp fragment of exon 10 of the factor V gene by polymerase chain reaction and detection of the
1691G*A mutation by Mnl I restriction fragment
length polymorphism).2 In addition, functional
protein S was minimally diminished (0.55, normal range 0.65–1.45).
The patient received long-term anticoagulation and recovered almost completely from the
neurologic deficits over the following 6 months.
With a long-term dose of 7.5 mg prednisolone per
day, peripheral blood eosinophilia was absent at
the 6-month follow-up and the steroid dose could
be tapered slowly. The echocardiogram showed
a small residual echo-dense structure near the
papillary muscle, but left ventricular function was
now completely normal.

Discussion
The idiopathic hypereosinophilic syndrome is a
leukoproliferative disorder of unknown origin
characterized by sustained overproduction of
eosinophils (usually > 1,500/µL present for
longer than 6 months). Other apparent etiologies
for eosinophilia, including parasitic and allergic
diseases, must be absent.1 Clonal expansion of
Th2 lymphocytes secreting interleukin-5 and interleukin-4 may be involved in the pathogenesis
of the disease.3 Patients affected are mostly males
in their fourth decade. The clinical manifestations
result from cytotoxic eosinophilic infiltration with
subsequent organ damage, and are heterogeneous. The most common presenting clinical
manifestations are cardiac (54–73%), cutaneous
(50–73%), pulmonary (40–64%), and neurologic
(35–73%). Cardiac disease is a major cause of

Engelmann

Hypereosinophilic Syndrome and Factor V Gene Mutation

Figure 1. A. Electrocardiogram at
admission. The initial ECG demonstrates
significant ST elevation in leads III, aVF
and T inversions in V4 –V6 , indicating
inferolateral myocardial damage.
B. Echocardiograms at day 1. Transthoracic
echocardiography shows a floating
structure (bottom, arrow) near the
posterior papillary muscle; endomyocardial
thickening can be visualized by
transesophageal echocardiography (top,
double arrow). LV: left ventricle. C. Chest
radiograph (top) and spiral computed
tomograph (bottom) at day 1. A pulmonary
infiltrate of the left lower lobe (arrow) is
visible, which disappeared after initiation
of oral corticosteroid treatment.

A

B

morbidity and is characterized by damage to the
heart ranging from an early necrotic stage to
more severe thrombosis and fibrosis (Loeffler’s
endocarditis parietalis fibroplastica4 ). In the final
fibrotic stage, the affected heart develops a restrictive cardiomyopathy with congestive heart
failure. Neurologic manifestations are largely
caused by thromboemboli subsequent to intra-

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C

cardiac thrombus formation.1 Pulmonary involvement is reported in about 40% of HES patients;
most commonly a persistent, nonproductive
cough secondary to congestive heart failure or
eosinophilic infiltration of the lungs is seen, as reported in the case presented here. Standard therapy for HES consists of the use of corticosteroids
and hydroxyurea.5

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Figure 2. Magnetic resonance imaging at day 7. A. T2-weighted image
demonstrates multiple lesions (maximum 2 cm in diameter), predominantly in the left
white matter and in the central region (TR 3580, TE 96 ms). B. Marked gadolinium
enhancement is detected (TR 550, TE 17 ms).

Resistance to activated protein C is a recognized major cause of venous thromboembolism.
It has not previously been associated with a hypereosinophilic syndrome. APC resistance is
caused by an autosomal dominant inherited mutation in the gene of factor V (G-A in position
1691) that results in the mutation Arg506Gln factor V (factor V Leiden) resistant to inactivation by
APC.2 The prevalence of heterozygosity for APC
resistance in Caucasians is 5% (with a relative
risk for venous thrombosis of 5- to 10-fold compared with subjects with normal factor V).6 It is
disputed whether APC resistance may be a risk
factor for arterial thrombosis, including myocardial infarction.7,8 The association of inherited APC
resistance with ischemic stroke in young patients
has been reported.9
The patient described here presented with
an embolic stroke resulting in right-sided hemiparesis accompanied by an acute coronary syndrome indicated by ST elevation and increase in
creatinine kinase and troponin. While the spread
of thromboemboli into remote organs resulting
in cerebral infarction is a feature of HES, acute
coronary syndromes or myocardial infarction are
very uncommon, with only 2 reported cases,10,11
possibly relating to thrombi from the endocardial border. In this patient, the rarity of coronary syndromes in HES led to further investiga-

tions to identify any coexisting condition that
might increase the risk of thrombosis. The association of HES and heterozygosity of factor V
Leiden reported here is to our knowledge the
first published.

Conclusion
We report the first case of an association between
HES and heterozygosity of factor V mutation, resulting in recurrent cerebral and coronary thromboembolic episodes. Patients suffering from HES
with recurrent thromboembolic events should be
screened for coexisting APC resistance, as heterozygosity of this genetic disorder is common. In
patients who are identified to be at risk, longterm anticoagulation should be considered.

Acknowledgment
We are indebted to Dr. Tanya Y. Huehns, DM,
MRCP, for her support in preparing the manuscript.

Engelmann

Hypereosinophilic Syndrome and Factor V Gene Mutation

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