From the Center for Stroke Research, Department of Neurology, Henry Ford
Hospital and Health Sciences Center, Detroit, Mich (D.T., S.R.L.) and the
Midwest Hemostasis and Thrombosis Laboratories, Ball Memorial Hospital,
Muncie, Ind (D.A.T.). Dr Tanne is currently at the Department of Neurology,
Chaim Sheba Medical Center, Tel Hashomer, Israel.
Correspondence to Steven R. Levine, MD, Director, WSU/Detroit Medical Center Stroke Program, WSU School of Medicine, University Health Center 6E, 4201 St Antoine, Detroit, MI 48201.
Within the past decade, cerebral infarction in as
many as 40% of patients was not found to have a determined cause based
on NINCDS Stroke Data Bank criteria.1 With
improved understanding of the complex pathogenic processes leading to
ischemic stroke and refined imaging and diagnostic
tests, underlying potential causes are more often recognized. Yet, the
etiology of ischemic stroke in a discouragingly large number of
patients continues to elude clinicians.
Antiphospholipid antibodies (aPL) are a heterogeneous
family of autoantibodies associated with a clinical syndrome
characterized by thrombo-occlusive events. Anticardiolipin antibodies
(aCL), detected by standard enzyme-linked immunosorbent assay (ELISA),
and the lupus anticoagulant (LA), which prolongs
phospholipid-dependent coagulation assays, are conventional assays for
aPL and the ones currently best characterized and
standardized.2 3 There is partial concordance
between the 2 assays. The preponderance of evidence indicates, however,
that LA assay is more specific for patients at risk for thromboembolic
events.4 In contrast, the aCL assay is more
sensitive but nonspecific and could be found also in various contexts
ranging from health to certain medications, malignancies, and
infectious diseases. aCL have been identified in approximately 10% of
unselected patients with first ischemic
stroke.5 The isotype mainly implicated in
thrombosis is IgG, more specifically subtype
IgG2.6 Recent data suggest
that the presence of high titers of aCL immunoreactivity, mainly IgG
isotype but possibly also IgM, correlates with an increased risk of
thrombosis.7 8 9 Generally, titers of IgG aCL
implicated are >40 GPL, although this is a somewhat arbitrary cutoff
point and is dependent on the test systems, which are not
standardized.
Data accumulating over the last few years have radically changed our
understanding of the antigenic specificities of the autoantibodies
associated with the antiphospholipid syndrome (aPS) and the pathogenic
mechanisms associated with these antibodies. The concept of a protein
target for aPL evolved from a series of independent reports in 1990
that identified ß2-glycoprotein I
(ß2-GPI; also named apolipoprotein H) as a
necessary plasma cofactor to bind cardiolipin in vitro on ELISA
plates.10 11 12 ß2-GPI is a
50-kDa plasma protein that has several anticoagulant functions.
Anti–ß2-GPI anti- bodies, now well studied, can help differentiate between
autoimmune aCL that require ß2-GPI and
"benign" alloimmune aCL that do not.13 14 In
fact, ß2-GPI is often inhibitory in
the assay system rather than a positive cofactor in these cases.
Anti–ß2-GPI antibodies were shown to be more
specific for thrombosis than conventional
aCL15 16 17 and can occasionally be the only
positive assay associated with the aPS.18 19
ELISA kits for antibodies against ß2-GPI are
currently available and FDA approved.
It soon became apparent that most autoantibodies detected in
conventional aCL and/or LA assays recognize certain
phospholipid-binding plasma proteins, not phospholipid alone. Other
proteins implicated include prothrombin, protein C, protein S,
thrombomodulin, annexin V, and kininogens. The majority of patients who
manifest the LA contain a "cocktail" of antibodies, mostly
antibodies to ß2-GPI as well as antibodies to
prothrombin and perhaps other plasma proteins. In most cases, LA
activity found in a given patient is due to predominance of antibodies
to prothrombin. Assays for antibodies against such specific plasma
proteins may enable subclassifications based on the protein component
of the protein-phospholipid complex, but currently they remain in the
realm of development and research.
Antibodies against phospholipids other than cardiolipin have been less
well studied and characterized than aCL. One reason is that there is
extensive cross-reactivity of aCL with other negatively charged
phospholipids. Whereas cardiolipin occurs primarily intracellularly,
such as in the mitochondrial membrane, other phospholipids are
important constituents of the cell membrane. Patients with clinical
(and other laboratory) manifestations of the aPS may occasionally have
persistently negative conventional assays for LA and aCL but
positive for antibodies directed against other phospholipids.
These include mainly anionic moeities such as
phosphatidylserine and phosphatidylinositol and
occasionally neutral phospholipids such as
phosphatidylethanolamine.20 21 22 23 24 25 Preliminary data
also suggest that antibodies directed against
phosphatidylserine may react directly with central
nervous system tissue26 and may be more
specifically associated with ischemic
stroke.27
Thus, antiphospholipid-protein antibodies (aPL-P), rather than being a
single or even a homogenous group of autoantibodies, constitute a
heterogeneous family of autoantibodies with different
isotypes, different specificities, different requirements of cofactor
proteins, and different immunochemical characteristics. aPL-P may
interfere with the kinetics of coagulation reactions or stimulate the
prothrombotic activities of endothelial cells and
monocytes and promote coagulation by complex molecular
interactions.28 The specificity of different
aPL-P to thrombosis in the venous and/or the arterial
circulation remains a matter of investigation. aPL-P are likely
associated with venous thromboembolism in approximately two thirds of
cases, and in the other third of cases arterial events
predominate. The interesting observation of the fidelity with which one
sees recurrent events (ie, arterial
event
Preliminary data suggest that immunological factors may contribute not
only to thrombosis but also to atherosclerosis,
mediated by aPL-P. Patients with aPS have increased levels of
antibodies to oxidized LDL, associated with progression of
atherosclerosis and risk of thrombo-occlusive
events.30 31 32 33 Antibody responses to
phospholipids, oxidized LDL, ß2-GPI,
prothrombin, and endothelial cells partially overlap
and may reflect a broadening spectrum of autoantibody-associated
atherothrombotic disease.
After a decade of research on the association between aPL and stroke,
it is still unclear whether aPL are an intriguing but rare cause of
stroke in young patients, play a pathogenic role in a large proportion
of unselected ischemic stroke patients, or
both.5 34 35 36 37 38 Patients with ischemic
stroke are often elderly, with multiple vascular risk factors, diffuse
atherosclerosis, and cardiac impairment, and thus have
potentially multiple underlying mechanisms for thromboembolism.
Cardiovascular risk factors are associated with
substantially higher rates of IgG isotype aCL and with higher
immunoreactivity, and these may complicate interpretation of a positive
assay in such a population.39 Thus,
cerebrovascular disease associated with aCL is probably not the same as
the aPS with cerebrovascular manifestations.
Recent reports demonstrating that the presence of antibodies against
phospholipids, oxidized LDL, and prothrombin is a predictor of
myocardial infarction support an important role of aPL-P in the
pathogenesis of thrombo-occlusive
events.32 40 41 42 It is possible that the presence
of certain aPL alters the threshold for thrombosis and thus creates a
"permissive thrombotic environment."
In an interesting study reported in this issue of
Stroke,43 a high prevalence of
antiphosphatidylinositol antibodies was identified in a young
population of cryptogenic stroke or transient ischemic attack
patients. Antibodies directed to 7 different phospholipids were
systematically assessed, and an especially high prevalence (44%) of
antibodies directed to 1 or more of these phospholipids (dependent on
ß2-GPI) was found in this population.
Furthermore, nearly one quarter of patients with negative
immunoreactivity to aCL demonstrated positive immunoreactivity specific
to noncardiolipin phospholipids. Among the aPL-P studied, those with
specificity for phosphatidylinositol had the highest prevalence. This
preliminary study suggests that by assessing only aCL and LA in young
stroke patients, we may be underestimating the potential prevalence of
aPL-P.
Caution should, however, be exercised in overinterpreting these
provocative preliminary findings. The issue of phospholipid
specificity for aPL is one that has not been appropriately addressed in
the past. On the basis of the majority of available information, one
would assume that ß2-GPI represents the
antigenic target in most cases in which we are dealing with negatively
charged phospholipids applied to a microtiter plate. However, there is
a distinct possibility that other plasma proteins may serve as
"cofactors" for the phosphatidylinositol studies. Recent work on
phosphatidylethanolamine would support this hypothesis. In the case of
phosphatidylethanolamine, both high- and low-molecular-weight
kininogens have been implicated as cofactors.44
Thus, antibodies to antiphosphatidylethanolamine would be missed in a
test system that did not provide a source of kininogens. Do antibodies
to phosphatidylinositol indeed have a specific protein cofactor? Does
the participation of a specific phospholipid in a phospholipid-protein
complex confer greater pathogenicity to the complex antigen?
It is imperative that studies on aPL-P include specific descriptions of
the assays used because interpretation of any finding highly depends on
the microtiter plates used (assays using oxidized or irradiated
microtiter plates are made to be highly sensitive, presumably by
reconfiguration of protein to expose a neotype), as well as other
aspects of the procedure including buffers, blocking agents, and the
presence of animal ß2-GPI (eg, bovine). One of
the major difficulties in the area of aPL-P is laboratory variability.
Efforts to standardize assays are required to allow reliable comparison
of results between studies and to enable any future useful
implementation in clinical practice. Assaying in parallel for
antibodies against specific plasma proteins may help to clarify the
specificity of such findings. Only carefully designed case-control and
complementary prospective studies (or case-control studies nested in a
prospective study) of sufficient statistical power, coupled with
assessment of unselected ischemic stroke patients, will enable
us to critically assess the role of these non–aCL aPL-P in
ischemic stroke.45 46 Similarly, we look
forward to results from the nested case-control analysis from
the Honolulu Heart Study assessing
ß2-GPI–dependent aCL and antibodies to
ß2-GPI in stroke and myocardial infarction
patients from this cohort (Steven J. Kittner, personal communication,
April 1998).
Currently, aCL testing (using irradiated or highly sensitive microtiter
plates) and evaluation for the LA following accepted
criteria3 are the recommended screening tests.
These tests may be useful only in appropriate clinical settings, as
outlined in the Figure
It is important for the clinician to appreciate the test systems used
by their local or reference laboratories and by their quality control
systems. These promising immunoassays, however, must be
standardized, their variability among different laboratories assessed,
and their clinical utility in ischemic stroke established
before they can be recommended for general use.
Acknowledgments
This work was supported in part by National Institutes of Health
grant RO1-NS-30896.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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Abstract.
© 1998 American Heart Association, Inc.
Editorial
Antiphospholipid-Protein Antibodies and Ischemic Stroke
Not Just Cardiolipin Any More
Key Words: antibodies, anticardiolipin • antibodies, antiphospholipid • cerebral ischemia
arterial event, venous eventvenous event) was
first proposed by Rosove and Brewer.29 
. Retesting for
persistence of the antibody after at least 8 weeks is of great
importance. Data based on patients with the aPS suggest that there
remain approximately 10% to 15% of patients who, despite
presenting the clinical picture of the aPS, have negative tests for
aCL and LA. Thus, in patients with high clinical suspicion, further
testing is indicated, such as antibodies to
ß2-GPI, possibly to prothrombin (however, this
is somewhat controversial because there is no clear correlation between
the presence of antibodies to prothrombin and thrombotic events), or to
noncardiolipin phospholipids. Antibodies against
ß2-GPI or other specific proteins may be used
as more specific confirmatory tests in patients with positive aCL and
potentially related thrombo-occlusive events.
View larger version (32K):
[in a new window]
Figure 1. An algorithm for testing for antiphospholipid antibodies.
1Suggested setting based on available data and authors'
clinical experience. 2Such as recurrent miscarriages, deep
vein thrombosis, livedo reticularis, left-sided cardiac valve lesions
or thickening, or systemic lupus erythematosus
(SLE)/lupus-like disease. 3Such as thrombocytopenia,
false-positive VDRL, elevated activated partial thromboplastin
time, or antinuclear antibody. 4High sensitivity,
low specificity. Likely autoimmune if IgG isotype, titer >40 GPL,
persistent after at least 8 weeks (thus requires retesting to assess
for persistence). 5Highest specificity but low sensitivity.
6Under investigation; based mainly on data from patients
with SLE or the aPS. Antibodies to ß2-GPI are more
specific for thrombosis when compared with aCL.
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