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C H A P T E R 141

THE ANTIPHOSPHOLIPID SYNDROME

Jacob H. Rand and Lucia R. Wolgast

The antiphospholipid (aPL) syndrome (APS) is an autoimmune CCP domains, each consisting of about 60 amino acids, with a fifth
thrombophilic condition that is defined by a combination of clinical domain that includes a phospholipid binding site near the carboxy-
and laboratory criteria. This chapter reviews the current understand- terminus of the protein. Binding of β 2GPI to membranes that express
ing of aPL-mediated pathogenic mechanisms, diagnostic tests for anionic phospholipids occurs via the affinity of cationic residues near
the condition, its clinical manifestations, and current treatment the carboxy-terminus for anionic polar heads of phospholipids that
approaches. adjoin a hydrophobic loop that inserts into the lipid bilayer. Although
patients with APS have been described to have antibodies that rec-
ognize all of the five domains of β 2 GPI, IgG antibodies against an
DEFINITION OF ANTIPHOSPHOLIPID SYNDROME epitope on domain I comprising Gly40-Arg43 has been particularly
correlated with an increased risk for thrombosis; this domain I
APS is an autoimmune thrombophilic condition in which patients epitope is cryptic in the circulating protein and becomes exposed after
have circulating antibodies against plasma proteins that bind to β 2 GPI binds to phospholipid bilayers. The specific conformation of
phospholipids. The precise mechanism(s) by which these autoanti- the unbound form of β 2 GPI is not entirely clear; transmission elec-
bodies cause disease has (have) not yet been precisely established. tron microscopy of negatively stained β 2 GPI molecules indicates that
Investigational diagnostic criteria (referred to as the Sydney Criteria), the unbound protein has a circular conformation that was attributed
detailed in Table 141.1, have been formulated to provide consistency to the affinity of its carboxy-terminus domain (domain V) for the
for clinical trials. These require that patients have documented evi- protein’s amino-terminus domain, whereas β 2 GPI bound to phospho-
dence of vascular thrombosis and/or obstetric complications attribut- lipid has a “J-shaped” conformation with the binding site for phos-
able to placental vascular insufficiency; the latter include otherwise pholipid near the carboxy-terminus of the J. On the other hand, small
unexplained recurrent miscarriages, intrauterine growth restriction, angle x-ray scattering studies indicate an “S” shape configuration for
intrauterine fetal demise, preeclampsia/toxemia, placental abruption, the free form (Fig. 141.1).
and preterm labor. The laboratory criteria require persistent abnor-
mality (defined as at least two abnormal measurements at least 12
weeks apart) of one or more of the aPL assays, which include elevated Other Antigenic Targets of Antiphospholipid Antibodies
anticardiolipin (aCL) immunoglobulin (Ig) G or IgM, antibodies,
anti–β 2 -glycoprotein I (anti-β 2 GPI) IgG or IgM antibodies or an Besides β 2 GPI, prothrombin (factor II), factor V, protein C, protein
abnormal lupus anticoagulant (LA). S, annexin A2, annexin A5, high- and low-molecular-weight kinino-
Because these criteria were intended to provide a uniformly gen, heparin, factor VII/VIIa, plasmin, vimentin, and other proteins
rigorous definition of APS for standardizing clinical research and have been identified as targets for autoantibodies in APS patients.
not for the diagnosis of APS in “real world” clinical practice set- Antibodies have also been found to bind to sulfatides, acidic glyco-
tings, some patients may be diagnosed clinically with presumptive sphingolipids that can interact with sulfatide-binding proteins such
APS without meeting the strict investigational criteria. For example, as von Willebrand factor, thrombospondin, and P-selectin.
some patients with APS have positive results on “noncriteria” clinical
laboratory tests (described later) that have not been included by
consensus panels as diagnostic criteria for the disorder. Also, some PATHOGENIC EFFECTS OF ANTIPHOSPHOLIPID
patients present with manifestations that have been associated with ANTIBODIES
aPL antibodies that were not included in the investigational criteria.
These “noncriteria manifestations” include thrombocytopenia, livedo As described later, numerous mechanisms have been proposed to
reticularis, skin ulcers, nephropathy, migraine, cognitive defects, explain the thrombotic manifestations of APS (Table 141.3).
diffuse alveolar hemorrhage, and valvular heart disease (Libman-Sachs Although all of these are based on in vitro findings or on animal
endocarditis). models, their in vivo significance in the human disease process remain
At the present time, APS may be divided into the following to be established.
subcategories: (1) Primary APS is the “stand alone” disorder, in the
absence of systemic lupus erythematosus (SLE), (2) secondary APS
occurs in the presence of SLE, (3) catastrophic APS (CAPS), mani- Antiphospholipid-Mediated Promotion of Tissue
fests as disseminated thrombosis in large and small vessels with Factor Expression
resulting multiorgan failure (Table 141.2), and (4) SNAPS includes
patients whose diagnostic tests are entirely negative but who, on aPL antibodies can bind to, injure, and/or activate cultured vascular
clinical grounds, are still suspected to have the disorder. endothelial cells. Antibody binding to β 2 GPI on the endothelial
surface may trigger signaling cascades that promote the expression of
ANTIGENIC SPECIFICITIES OF ANTIPHOSPHOLIPID tissue factor and adhesion molecules. There is evidence that annexin
A2, which forms tetramers with S100 and is an endothelial surface
ANTIBODIES receptor for tissue plasminogen activator and plasminogen, serves as
a receptor for β 2GPI on vascular endothelium. Annexin A2 and the
β 2-Glycoprotein I signaling coreceptors, Toll-like receptor-4 (TLR4) and Toll-like
receptor-2 (TLR2) have been implicated as triggers of the signaling
β 2 -Glycoprotein I (β 2GPI), a 50-kDa glycoprotein member of the cascade. Downstream signaling appears to involves TRAF6 (tumor
complement control protein (CCP) superfamily, is a major antigenic necrosis factor receptor–associated factor 6) and MyD88 (myeloid
target for aPL antibodies. The protein consists of five homologous differentiation factor 88). Tissue factor expression is mediated by p38

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