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Antiphospholipid antibodies.

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BRIEF REVIEW
Antiphospholipid Antibodies
Steven R. Levine, MD, and K. M. A. Welch, MD
Lupus anticoagulants and anticardiolipinantibodies, known collectively as antiphospholipid antibodies, are becoming
established as markers for increased risk of thrombosis, including ischemic cerebrovascular disease. In this brief
review, we highlight evidence for and against a pathogenetic role of these antibodies in ischemic brain disease and
comment on currently available laboratory studies to detect them. Future research on the association of antiphospholipid antibodies with neurological disease should focus on establishing the pathogenicity of these antibodies,
identifying groups at high risk for recurrent ischemic cerebrovascular events, and initiating prospective multicenter
natural history and treatment protocols.
Levine SR, Welch KMA. Antiphospholipid antibodies. Ann Neurol 1989;26:386-389
Recently, a clinical association between specific neurological syndromes and the presence of antiphospholipid antibodies (APLAb) has been observed. Two
recent articles in Annals 11, 21 and a recent clinicopathological discussion in the New England Journal of
Medicine [31 suggest that neurologists should be aware
of this association.
Recognized causes for transient ischemic attack
(TIA), cerebral infarction, encephalopathy, migrainous
cephalgia, and transient or permanent visual loss are
often lacking, especially in younger patients. A growing number of reports suggest that some otherwise
unexplained cerebrovascular episodes are due to a
group of immunocoagulopathic disorders encompassing the antiphospholipid antibody syndrome.
APLAb, although recognized for many years as an
innocuous laboratory phenomenon, are thought to be
implicated in immune-mediated thrombotic disorders
141: ischemic stroke, TIA, visual disturbances (including ischemic optic neuropathy and amaurosis fugax),
migraine-like syndromes, and ischemic encephalopathy 11-3, 5-91. Chorea, epilepsy, and the GuillainBarre syndrome are less frequently associated with
APLAb 17, 101.
What Are the Lupus Anticoagulant and
Anticardiolipin Antibodies?
The lupus anticoagulant (LA) and anticardiolipin antibodies (ACLA), known as APLAb, are the two best
characterized groups of acquired or familial serum immunoglobuhns that recognize and bind negatively charged
or neutral phospholipid moieties 111-131. LA and
ACLA are related though not necessarily identical 114,
151. LA and ACLA have an overlap of structure but
From the Center for Stroke Research, Department of Neurology,
Henry Ford Hospital, Deu-oit, MI.
Received Oct 31,1988, and in revised form Feb 14,1989. Accepted
for publication Feb 14, 1989.
with distinct epitopes (antigenic determinants or portions of a molecule that the antibody recognizes). Different protein fractions responsible for LA and ACLA
activities have recently been isolated 1151. The specific
epitopes with which APLAb react have not been fully
defined, but are probably the phosphodiester-linked
phosphate groups. Phospholipids are a major constituent of cellular membranes and many coagulation
factors. speclfically, phosphatidylcholine, phosphatidic
acid, phosphatidylinositol, phosphatidylethanolamine,
phosphotidylserine, and cardiolipin can be bound by
antibody. Why is this important and relevant to the
nervous system? APLAb may bind phospholipids in
vascular endothelium, on platelet membranes, and on
neuronal membranes (myelin sheaths) and alter cellular structure and, hence, cellular function.
Laboratory Testing for Antiphospholipid
Antibodies
Although there are several tests to check for the presence of antibodies to phospholipids, it is uncertain
which tests are most valuable in predicting clinical phenomena including neurological disease. Currently, the
most readily available methods to detect APLAb
include the Venereal Disease Research Laboratory
(VDRL,) serological test for syphilis (cardiolipin is in
the assay), phospholipid-dependentcoagulation studies
such as the activated partial thromboplastin time
(PTT) and prothrombin time (PT), and the ACLA test
using either the enzyme-linked immunosorbent assay
(ELISA) or a radioimmunoassay (RIA). Other less
commonly employed investigations include determining the presence of antibodies speclfically against anionic or neutral phospholipids other than cardiolipin
Address correspondence to Dr Levine, Center for Stroke Research,
Henry Ford Hospital, Department of Neurology, K-11, 2799 W.
Grand Blvd, Detroit, MI 48202.
386 Copyright 0 1989 by the American Neurological Association
114). A major factor leading to controversies over the
prevalence and associations of APLAb is the variety of
assay systems used in different laboratories 1163. Recent data suggest that VDRL results are only positive
in approximately 25% of patients with APLAb { 3 } .
The VDRL test is thus too insensitive to be used as a
screening study. The yield on detecting an LA may be
increased by more sensitive coagulation assays (employing less phospholipid) such as the Russell vipor
venom time, the kaolin clotting time, and the diluteactivated PTT. Confirmational studies, demonstrating
the nonspecific nature of the LA (as opposed to an
antibody directed at a single coagulation factor) and its
phospholipid dependency, are required to prove the
presence of the LA. When occult heparin is excluded,
the most common cause of an unexplained prolonged
PTT is the LA.
Antiphospholipid Antibodies as a Marker for
Increased Thrombotic Risk
The presence of LA, whether in patients with systemic
lupus erythematosus or not, appears to confer an
increased risk of intravascular thrombotic events,
including ischemic cerebrovascular disease. Druginduced (e.g., phenothiazines, penicillin, phenytoin)
APLAb have been believed to be a “benign” subset of
these immunoglobulins, although recent data suggest
that they too can be associated with a thrombotic tendency 1171. However, caution is warranted because an
association does not mean a cause-and-effect relationship. Therefore, we must examine the weight of the
evidence favoring the implication of ACLA and LA in
ischemic brain disease as well as the evidence suggesting that these antibodies are guilty by association only
{16} and are otherwise relatively common in the general and elderly population { 1s}. We have summarized
some of this evidence for and against a pathogenetic
role for these antibodies in ischemic brain disease
(Table 1).
The two recent articles on APLAb in Annals {l, 2)
are pertinent because they educate neurologists concerning the association of these antibodies with neurological disease and they raise questions for further research in this area. Briley and co-workers 111 make
several important points based on reviewing the medical records of 80 patients with significantly elevated
ACLA levels. Twenty-five patients (31%)had associated neurological symptoms ot disorders fitting into
four main categories linked presumably by cerebroocular ischemia: encephalopathy, recurrent cerebral
infarctions, migraine-like headaches, and amaurosis
fugax or ischemic optic neuropathy. The highest
ACLA levels were in the encephalopathic patients,
who may respond to immunosuppressive therapy and
plasmapheresis. Natural fluctuations in APLAb levels
make uncontrolled observations of therapeutic re-
Table I . Evidence For and Against the Role of
Antiophospholipid Antibodies in Ischemic Brain Disease
For
Against
Increased risk of thrombotic
events in patients with
LA.
Nearly all patients with
strokes associated with
LA have had other definite or probable/possible
coexisting risk factors for
stroke.
High prevalence of recurrent stroke in patients
with APLAb.
Patients who have SLE with
APLAb have greater incidence of CNS involvement and stroke than patients who have SLE
without APLAb.
APLAb may enhance
thrombosis via prostacyclin inhibition, decreased
fibrinolysis, or platelet activation.
Bizarre, yet stereotypic and
recurrent, transient CNS
events not easily categorized are seen frequently
in patients with APLAb
and CNS symptoms.
Other strong associations
with APLAb include miscarriages (placental infarction) and thrombocytopenia.
APLAb are frequently
found in patients with
AIDS who, at autopsy,
have a higher than expected incidence of ischemic cerebrovascular disease.
No consistent correlation
with level of APLAb,
isotype, or specificity and
onset of CNS event.
Lack of a consistent mechanism to explain enhanced
thrombosis. Some patients with LA have increased prostacyclin levels.
The vast majority of
APLAb are detected on
routine screening by a
prolonged PTT or a falsepositive VDRL result in
patients without a history
of CNS disease or thrombosis.
APLAb are frequently
found in patients with
AIDS or primary immunodeficiency diseases who
have no clinical evidence
of thrombosis.
Approximately 50% of normal individuals older than
SO years may have
ACLA.
Two percent of patients
screened in a coagulation
laboratory with PTT had
Almost 50% of patients of
LA.
Briley and co-workers 111
had no other risk factors
for neurovascular disease. Lack of a consistent therapeutic response to an
autoimmune disease.
APLAb from patients with
SLE bind vascular endoAPLAb primarily occur in
thelium.
patients with SLE who
have multiple causes for
In patients with coronary
CNS events.
artery disease, those with
ACLA composed a s u b
group at higher risk of
subsequent major thrombotic events.
LA = lupus anticoagulant, APLAb = antiphospholipid antibodies,
SLE = systemic lupus erythematosus, CNS = central nervous system, PTT = partial thromboplastin time, VDRL = Venereal Disease Research Laboratory test, AIDS = acquired immunodeficiency
syndrome, ACLA = anticardiolipin antibodies.
Brief Review: Levine and Welch: Antiphospholipid Antibodies
387
sponse tenuous. Treatment of APLAb syndrome is
empirical because the natural history is not well
defined and there are no controlled therapeutic trials.
Despite the lack of definitive treatment, the positive
therapeutic response found by Briley and associates is
encouraging for this subset of acutely ill patients with
APLAb. Highly specific therapy, using anti-idiotypic
antibodies directed against APLAb, has been preliminarily successful [191.
Migraine-like disturbances, vertigo, and diplopia occur frequently in patients with neurological disease and
APLAb. The basis for this is obscure. However, migraine, migraine-like cephalgia, and migraine equivlents are relatively common in the general population. Patients with isolated, recurrent, and stereotypic
events in the central nervous system, especially involving transient monocular visual obscuration (including
but not necessarily limited to amaurosis fugax) may,
in fact, have migraine coincidental with or related to
APLAb. This distinction is important but difficult
to establish, and it will require large numbers of
well-studied patients before this distinction can be
discerned. The spectrum of LA-associated visual disturbances including amaurosis fugax [7, 81 and migrainous disturbances [91 suggests it may be difficult
in a given patient with APLAb to separate primary
ischemic events from primary migrainous events.
This is evident in several of the patients described by
Digre and colleagues [2]. Further, presence of other
risk factors for stroke in many patients with
APLAbassociated visual and cerebrovascular disease
[6] warrants further detailed study using case-controlled methods. However, we 181 agree with Digre
and colleagues [2] that otherwise unexplained visual
loss, either transient or permanent, deserves a search
for APLAb.
Cardiac Valvulopathy and Antiphospholipid
Antibodies
A subset of patients with APLAb have had cardiac
valvular disease, including several of those reported by
Digre and co-workers [2] (probably explaining their
patients’ subungual splinter hemorrhages), predominantly miVal or aortic, characterized by v a l d a r prolapse or insufficiency, myxomatous degeneration,
associated thrombus, or changes akin to verrucous
endocarditis (Libman-Sacks) and valvulitis 120-22).
The valve surface and subjacent endocardial tissue may
be another site of action of the APLAb and thus may
provide an alternative mechanism for ischemic brain
and eye syndromes-namely cardioembolic. This has
both potential diagnostic and therapeutic implications
for those patients with stroke and TIA associated with
APLAb [23]. Echocardiography and, more recently,
magnetic resonance imaging of the heart may be useful
in idenufying those patients with cardiac valvdopathy
and may indicate a subset of patients who could benefit
from anticoagulation therapy. Caution dictates that the
presence of cardiac valve disease in a patient with an
ischemic cerebrovascular syndrome does not imply
cause and effect; in situ thrombosis may not be readily
distinguished from cardiac-initiated embolus in a given
patient with APLAb.
Test Selection
Comparative studies of the LA and ACLA have
yielded varying results in defining and predicting subsets of patients with thrombosis [14,24,25f. Although
ACLA tests (ELISA) are more sensitive than LA assays
for the presence of APLAb, PTT assays may be more
specific [24}; however, this is not established [25}.
Vascular Pathology
Pathological studies of cerebral arteries thrombosed in
association with APLAb are quite rare [l}. When
these arteries or similarly occluded systemic arteries
are examined, vasculitis is not seen. Rather, the vessel
wall is normal or shows vascular endothelial swelling;
no cellular infiltrates are seen within the vessel wall in
the region near the platelet-fibrin thrombus. What is
not known and clearly deserves further study is why
these antibodies associated with vascular occlusive disease do not consistently cause vasculitis as do several
other autoimmune vasculopathies. One possibility is
that the immune reaction is at the level of the coagulation cascade causing thrombosis rather than at the vessel wall. These antibodies have also been shown (by
indirect immunofluorescence) to bind vascular endothelium, but do not generally fix complement or induce detectable injury morphologically or by the techique of chromium-5 1 release.
Findings from more basic studies of these antibodies
suggest that the structural conformation of the phospholipid in the membrane (hexagonal or lamellar) may
determine recognition and binding by the APLAb
1261. Research in this area may answer why a given
phospholipid is bound by APLAb only in certain circumstances and only in specific membranes.
Unanswered Questions
Several issues and questions are currently unanswered:
Should we treat the antibody titer? Should asymptomatic patients found to have LA, ACLA, or both,
be treated? Should symptomatic patients with LA,
ACLA, or both, be treated and if so, with which class
of therapeutic agents? How long should therapy be
maintained-indefinitely or until the antibody titers
normalize? What are the exact mechanisms by which
these antibodies promote thrombosis? What is the natural history of neurological disease associated with
388 Annals of Neurology Vol 26 No 3 September 1989
Table 2. Future Directions in Research of the Association of
Antipbospbolipid Antibodies with Newologt'cal Disease
Standardize the assay for anticardiolipin antibodies and
agree o n criteria for the lupus anticoagulant.
Determine why some groups of patients with APLAb
appear to be at h g h e r risk for thrombotic CNS events.
Determine the actual levels and variations of the APLAb
with time and CNS events.
Determine the immunological epitopes recognized by the
APLAb.
Determine if APLAb are markers for another immunemediated pathogenetic mechanism.
Carry out prospective multicenter studies of patients with
APLAb for natural history and treatment data.
APLAb = antiphospholipid antibodies, CNS = central nervous
system.
these antibodies (e.g., percent recurrence of thrombotic events)? Future directions for research are listed
in Table 2.
In summary, APLAb are heterogeneous in several
respects: immunoglobulin class, specific phospholipids
that they will or will not bind to, clinical syndromes
and diseases they are associated with, effects on the
coagulation system and vascular endothelial cells that
might explain enhanced thrombotic tendency, and
their differential responses to treatment. Further study
of APLAb may elucidate new mechanisms of neurological disease, including stroke.
Supported in part by National Institutes of Health grant NS23393
and a grant-in-aid from the American Heart Association of Michigan.
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Brief Review: Levine and Welch: Antiphospholipid Antibodies
389
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