Coexistence of Primary Antiphospholipid
Syndrome and Protein S Deficiency in a
Hispanic Man With Ischemic Stroke

YOLANDA REYES-IGLESIAS, MD, ARTURO A. ORTIZ, MD, DARIO M. GOITIA, MD, and

RAFAEL MELENDEZ, MD, San Juan, Puerto Rico

ABSTRACT: The primary antiphospholipid syndrome and protein S deficiency are known
hypercoagulable states predisposing to ischemic strokes. The pathogenesis of those
hypercoagulable states has been independently studied and, recently, interaction between
them has been proposed. A 48-year-old Hispanic man had generalized seizures 5 months after
the acute onset of a left middle cerebral artery infarct. He had a strong family history of
strokes. After evaluation for cardiologic, rheumatologic, hematologic and metabolic etiologies
for stroke, anticardiolipin antibodies and protein S deficiency were detected. Cerebral
angiography was normal. First degree relatives were evaluated and screened for these
conditions. Lupus anticoagulant was detected in a sister who reported a transient hemisensory
deficit. None of the relatives studied had clinical or laboratory criteria for collagen vascular
diseases. Coexistence of the primary antiphospholipid syndrome and protein S deficiency, two
known prothrombotic states, has rarely been reported in Hispanic adults in association with

ischemic stroke.

ANTIPHOSPHOLIPID ANTIBODIES currently recog-
nized are the lupus anticoagulant and anticar-
diolipin antibodies.'* These are circulating
immunoglobulins associated with a prothrom-
botic state. These antibodies were initially
described in association with collagen vascular
diseases.’ The primary antiphospholipid syn-
drome (PAS) is a hypercoagulable state due to
the presence of lupus anticoagulant and/or
_ anticardiolipin antibodies without an underly-
ing collagen vascular disease or other autoim-
mune diseases. This entity has been estab-
lished as an independent risk factor for
ischemic stroke and is an important etiology
of stroke in young adults.’ Several cases of
familial occurrence of the PAS have been
reported. Despite extensive studies on these
antibodies, their exact pathogenesis has not
been established. Several mechanisms have
been proposed including interference with
the protein C-S anticoagulation system.’ An
association between free protein S deficiency
(PSD) and antiphospholipid antibodies has

From the Department of Medicine, Neurology Section,
Veterans Administration Medical Center and University of Puerto
Rico School of Medicine, San Juan.

wecprint requests to Yolanda Reyes-Iglesias, MD, Department of
icine, Neurology Section, One Veterans Plaza, San Juan,
Poets Rico 00927-5800.

been documented recently in patients with sys-
temic lupus erythematosus, human immuno-
deficiency virus (HIV-1) and early childhood.”

We describe a family with ischemic strokes,
not associated to collagen vascular diseases or
HIV-1, where the possible interaction between
the PAS and PSD may be illustrated.

CASE REPORT

A 48-year-old right-handed Hispanic man with recently
diagnosed hypertension and no toxic habits was admitted
to our service, due to the acute onset of generalized
seizures, 5 months after a left middle cerebral artery
infarct was diagnosed in a previous hospitalization. The
general physical examination was normal. The neurologic
examination revealed an alert mental status, a mild right
hemiparesis (grade 4/5), an expressive aphasia, and a
right Babinski sign. Cardiac evaluations including electro-
cardiogram and 2D-transthoracic echocardiography were
normal. Brain computed tomography (CT) scan and mag-
netic resonance imaging (MRI) revealed an old left mid-
dle cerebral artery territory ischemic infarct (Fig 1).
Cerebral arteriography was normal. Complete blood
count, routine serum chemistries, prothrombin time, and
partial thompboplastin time were within normal limits.
Sedimentation rate was at 61 mm/hr (Westergren
method). Electroencephalogram revealed focal slowing
over the left frontoparietal region, without epileptogenic
discharges. The family history revealed several members
affected by ischemic strokes, which prompted a thorough
evaluation for inherited etiologies of stroke in our patient.
Gamma G immunoglobulin (IgG) anticardiolipin antibod-
ies were detected at 20.1 g-phospholipid levels (GPL) units

296 March 1998 * SOUTHERN MEDICAL JOURNAL * Vol. 91, No. 3
FIGURE 1. Axial T1- and T2-weighted magnetic resonance images show left
middle cerebral artery territory Infarction. No significant periventricular hyper-
densities were noted.

(normal, 0 to 11.9, Roche Laboratories, NC) and free pro-
tein S level was decreased at 53% (normal, >78%, Roche).
Total protein S was >100% (normal, >79%, Roche). Lupus
anticoagulant was negative (Roche), Serum venereal dis-
ease research laboratories (VDRL) and antinuclear anti-
bodies (ANA) titers were negative. Protein C antigen and
antithrombin IIT levels were normal. Hemoglobin elec-
trophoresis, lactate levels, lipid profile, and a 24-hour uri-
nary cysteine collection were within normal limits. Liver
function tests, renal function, and human immunodefi-
ciency virus (HIV) testing were negative. Serum e-galac-
tosidase levels were normal. Routine cerebrospinal fluid
values were within normal limits and no oligoclonal bands
were detected. The patient was treated with enalapril, ticlo-
pidine and phenytoin, IgG anticardiolipin antibodies and
free protein S deficiency were still present 6 months after
the initial testing at 58.4 GPL units and 56%, respectively.
At this time, total protein S level was at 90%.

After diagnosis of the PAS and PSD in our index case,
we screened several first-degree relatives for these condi-
tions (Fig 2). Other tests included complete blood count,
serum chemistries, lipid profile, ANA and VDRL titers, sed-
imentation rate, sickle cell preparation, and antithrombin
III levels. Neurologic examinations were done and no neu-
rologic deficits were found in any of the members exam-
ined. One sister reported a transient right-sided numbness
lasting a few minutes, several months before our evalua-
tion, She was found with a positive lupus anticoagulant test
(Nichols Institute, Calif), She had no history of miscar-
riages or thromboses. All members tested had a brain CT
scan to evaluate for subclinical cerebrovascular disease and
all scans were unremarkable, None of the members tested
was found with clinical or laboratory features of collagen
vascular diseases.

FAMILY MEMBERS WITH STROKE/TIA
* FAMILY MEMBERS AVAILABLE FOR TESTING

FIGURE 2. Pedigree of family.

DISCUSSION

Antiphospholipid antibodies are known to
induce a prothrombotic state through a still
undefined mechanism. Several possibilities
have been proposed. Interference with activa-
tion of coagulation factors X, XI, and XII at
phospholipid dependent steps has been sug-
gested. Inhibition of prothrombinase com-
plex", inhibition of endothelial prostaglandin
L,” and binding of the lupus anticoagulant to
Beglycoprotein 1 (apoprotein H) are other
proposed mechanisms. Finally, an association
between the protein C-S pathway and the pres-
ence of antiphospholipid antibodies in
patients with systemic lupus erythematosus has
been reported.‘ In our case, it would be
unlikely that the anticardiolipin antibodies
were an epiphenomenon of stroke since they
were first detected 5 months after the initial
ischemic infarct and before the patient was
started on phenytoin.

The protein C-S pathway is a vitamin K-
dependent anticoagulant system.'*" Intra-
vascular thrombosis is prevented through this
system, together with antithrombin III and the
fibrinolytic system. The active protein C inacti-
vates coagulation factors Va and VIIa, in the
presence of the cofactor protein S and phos-
pholipid membranes. Protein S exists in an
active free fraction, and in an inactive fraction
bound to complement C4b binding protein."
Familial and acquired forms of protein S defi-
ciency have been described. Acquired forms
have been described in patients receiving war-
farin therapy, and in those with the nephrotic
syndrome, severe liver disease, disseminated
intravascular coagulation, and HIV infec-
tion,®"" among others. Several studies have
reported reduced free protein S levels in

Reyes-Iglesias et al » HISPANIC MAN WITH ISCHEMIC STROKE 297
patients with collagen vascular diseases and
antiphospholipid antibodies.**”* In our
patient, the decrement in free protein S level
was consistent and persisted up to 11 months
after the stroke. Family screening favored an
acquired pattern of protein S deficiency in our
patient, although an autosomal recessive
inheritance cannot be totally excluded.

Our patient was an adult Hispanic man with
an ischemic stroke and coexistence of the pri-
mary antiphospholipid syndrome and protein
§ deficiency. Protein S deficiency has been
described in a woman with human T-cell lym-
photropic virus type I (HTLV-I) without
antiphospholipid antibodies.'’® The possibility
of interaction between these two prothrom-
botic states in the setting of systemic lupus ery-
thematosus (SLE) and HIV-infected patients
as a mechanism of thrombosis has already
been suggested. In patients with SLE, a blood
component binding to protein S and inactivat-
ing it has been proposed.‘ In HIV-1 infected
patients, there is an increased incidence of
anti-protein S autoantibodies.'” Our patient
did not have any autoimmune process making
the coexistence of antiphospholipid antibod-
ies and protein S deficiency more relevant.
The binding of antiphospholipid antibodies to
protein S interfering with its function is a pos-
sibility that requires further testing. In an ear-
lier study, the presence of anticardiolipin anti-
bodies seemed to be related to acquired
deficiencies of total protein S, free protein S,
and C4b binding protein.” Further studies on
these coexistent prothrombotic states are
needed to establish whether the free protein S
deficiency is independent, acts synergistically,
or occurs due to the presence of antiphospho-
lipid antibodies.

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