hal. J. Neurol. Sci. 13.'607-610, 1992

Cerebral ischemia and livedo
reticularis in a patient with
impairment of coagulation factor VII
and free protein S
Martini A., Orlandi G., Cosentino E., Pagnani L.E., Giraldi C., Muratorio A.
lstituto Clinica Neurologica Universit~ di Pisa

The association of ischemic cerebrovascular lesions with livedo reticularis is
known as Sneddon syndrome. It affects young subjects, primarily women, and
its neurological manifestations are TIAs, ischemic stroke, progressive dementia and epileptic seizures. Its etiopathogenesis has still to be clarified. Some
authors have associated it with an antiphospholipid antibody syndrome. Recently it has been assumed that a defect in blood coagulation may be involved
in its pathogenesis. Here we report a case in which both an increase in coagulation factor VII activity and a deficiency in free protein S were documented.

Key Words: Cerebral ischemia - - livedo reticularis - - Sneddon syndrome - - coagulation defect.

Introduction

Case report

Several cases of livedo reticularis have in the past
been associated with ischemic cerebral lesions. In
1965 this association acquired the status of an anatomoclinical and nosological entity, receiving the
name of Sneddon syndrome [11]. It affects young
persons, primarily women, and its neurological
manifestations consist of TIAs [7, 9, 11, 12], ischemic strokes [9, 11, 12], progressive dementia
[9, 12] and epileptic seizures [9, 11, 12]. Frequently mild arterial hypertension, R a y n a u d ' s
phenomenon or acrocyanosis are present [7, 9].
The etiopathogenesis of Sneddon syndrome has
still to be clarified. Levine et al. [7] related it to
an antiphospholipid antibody syndrome. Burton
[2], on the other hand, suggested that a defect in
coagulation might be involved in the pathogenesis. We report a case of Sneddon syndrome in
which both an increase in factor VII coagulation
activity and a deficiency in the free form of protein S were documented.

A 38 year old righthanded woman had been suffering from diplopia and episodes of dizziness for
3 days. She does not smoke, drink or take oral
contraceptives. Livedo reticularis, of which no family history was reported, has been present since
adolescence; she had a miscarriage at age 29 due
to gestosis and since then has had mild arterial
hypertension, kept under control with Captopril 50
m g • 1/die. From the age of 30 progressive loss of
memory has been present. General physical examination revealed livedo reticularis (racemosa)
involving both upper and lower limbs and acrocyanosis of the hands. Neurological examination
revealed a deficit of the medial rectus muscle of
the right eye with concomitant divergent strabismus and very brisk reflexes in all four limbs,
symmetrically. The neuropsychological tests performed show speech impairments resulting from
a transcortico-sensory aphasia; the tests for memory visuo-perceptive gnosis and praxis revealed

Received 1 March 1991 - Accepted 30 March 1992

607

The Italian Journal of Neurological Sciences

Fig. I A-B. CT s c a n wiHu~ttt contra.~l (IA) and
with c(mtrast f / B ) showing a large hypodense
area in the left frontoparietal region.

Fig. 2A-B- 7~ aml I , weighted NMR images
showing ischemic areas both in the supratentoriaI
(2A) and infratentorial (2B) region.

impairments. Laboratory tests were within the
normal range, and tests for LE cells, RA, cryoglobulins, syphilis and antiphospholipid antibodies were negative. Platelet and coagulation functions were within normal limits, except the activity of factor VII: 143.5% (normal 60-120%) and
free Protein S: 25.5% (normal 70-120%). These
values remained abnormal in a test 3 months later. Factor VII activity (VII:C) was determined by
one-stage clotting assay using an artificial factor
VII-deficient plasma as reagent; free protein S was
assayed after precipitation of the C4b-bp-protein
S complex, by Laurell electrophoretic analysis of
supematant from plasma samples treated with polyethylene glycol 6000. Chest x-ray, ECG, dynamic ECG (Holter), echocardiography, Doppler
of lower limbs, vertebral and carotid Doppler were
all within normal limits. An EEG showed slight
anomalies in the left temporo-central region. Cutaneous and subcutaneous biopsies gave normal
results.
The cranial CT scan revealed an ischemic type
hypodense area in the left frontoparietal region.
Other smaller hypodense areas were observed in
the central temporal region, right posterior parietal region, and at the left occipital subcortical-basal
level.
Cortical atrophy was evident (Fig. 1A and 1B).

A comparison of a cranial NMR with the CT
scan revealed additional ischemic lesions in the
anterior-superior regions of the left cerebellar
hemisphere. Other small areas of a similar nature
were seen in the white matter of the semioval
center in the right frontal lobe (Fig. 2A and 2B).

608

Discussion

The foregoing description fits Sneddon syndrome.
The patient came to observation, complaining of
d i p l o p i a and dizziness after a vertebrobasilar
stroke and was suffering from livedo reticularis,
multiple ischemic cerebrovascular lesions, dementia, mild arterial hypertension and acrocyanosis.
Although the dopplersonographic assessment did
not exclude intracranial lesions, the presence of
other pathologies responsible for cerebral ischemia was excluded both by negative laboratory and
instrumental tests by the absence in the history of
the most common thrombotic risk factors. Additionally, the absence of antiphospholipid antibodies in our patient ruled out the possibility of a relation with an antiphospholipid antibody syndrome [7]. In agreement with all the published
cases [1, 7, 9, 12], the neuroradiological investi-

Martini A.: Coagulation factor VII and free protein S in Sneddon syndrome

gations in our case showed multiple ischemic lesions and cortical atrophy. Further, the cutaneous
and subcutaneous biopsies were normal [7, 9].
Some authors [3] have documented hemostatic alterations with an increase in coagulation factor VII
activity following invasive diagnostic procedures,
and it is for this reason that in our case, in which
the factor VII activity was already elevated, we did
not consider it wise to carry out cerebral angiography. We did, on the other hand, examine our patient's platelet and coagulation functions and found
both an increase in factor VII activity and a deficiency of the free form of protein S. Factor VII is
a vitamin K-dependent glycoprotein capable of
triggering the coagulative mechanism because, in
the presence of the tissue factor, it activates both
factor IX by means of its intermediate active form
(~x-VIIa) and factor X by means of its definitive
active form ([3-VIIa), thereby playing an important
role in thrombogenesis [8].
Protein S is another vitamin K=dependent glycoprotein traceable in plasma in its free form or
linked to inhibitory protein fractions of the complement pathway (C4b). In particular, free protein
S is a cofactor which forms a complex with the
activated protein C; this complex then acts as a
physiological anticoagulant and inactivates factors Va and VIIIa [6].
It is now accepted that ~during the acute phase of
a stroke, whether ischemic or hemorrhagic, he-

mostasis is activated, resulting in a state of hypercoagulability. This is not the case, however,
when hemostatic changes already exist at the time of the stroke and may therefore contribute to
its pathogenesis, or when they are only a consequence of the tissue lesions of the acute phase [5].
Considering that the increase in factor VII activity was revealed 30 days after the stroke as well
as in the second test 3 months later, we think it
very unlikely that the increase was related to coagulative phenomena of the acute phase of the
stroke [3, 5].
It has been observed that a deficiency of protein
S may be hereditary (autosomal dominant) or may
develop during liver disease, pregnancy or treatment with estrogens and progestrogens [4]. In this
case it was impossible to find out whether the impairment of coagulation factors, especially the free
protein S deficiency, was hereditary or not because of the difficulty in tracing blood relations of
the patient. Schafer and Von Felten [10] observed
that a deficiency of protein S can be found in a
large number of young people who have had an
ischemic stroke of unknown etiology.
We, in agreement with Burton's hypothesis [2],
have documented a case of Sneddon syndrome in
conjunction with a defect in coagulation, and we
submit that an increase in factor VII activity and
a deficiency of the free form of protein S could
be involved in the pathogenesis of this syndrome.

Sommario
L'associazione di lesioni cerebrovascolari ischemiche e livedo reticularis k conosciuta come sindrome
di Sneddon. La sua eziopatogenesi non b ancora stata chiarita. Noi descriviamo un caso in cui sono
stati documentati un aumento dell'attivitgt del f a t t o r e VII della coagulazione ed una carenza della f o r ma libera della proteina S.

Address reprint requests to:
Dr. Antonio Martini
Istituto di Clinica Neurologica
Via Roma, 67 - 56100 Pisa

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The Italian Journal of Neurological Sciences

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