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2242 Part XII: Hemostasis and Thrombosis Chapter 131: The Antiphospholipid Syndrome 2243

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the “definite” autoimmune APS (see Table 131–3). Because no single thrombosis. None of the studies were prospective. Of the 10 studies
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test is sufficient for diagnosing the disorder, a panel of tests, including that included multivariate analysis, only two confirmed that anti-β GPI
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antibodies against cardiolipin, and β GPI, and coagulation tests for LA IgG antibodies were independent risk factors for venous thrombosis.
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should be performed when APS is suspected. The investigational cri- Anti-β GPI antibodies were more often associated with venous than
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teria require that positive results have to be obtained on two or more arterial thrombosis. Anti-β GPI IgA antibodies were significantly asso-
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occasions at least 12 weeks apart to qualify for diagnosis. ciated with thrombosis.
Although these antibodies usually are present in conjunction with
abnormal aCL and antiphosphatidyl serine antibodies, some patients
IMMUNOASSAYS with APS present solely with antibodies to β GPI. 272,273 Despite their
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Anticardiolipin Antibody Assays higher specificity for APS (98 percent), β GPI antibodies alone cannot
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Most patients with APS are identified by elevated levels of aCL anti- be relied upon for the diagnosis because of their low sensitivity (40 to 50
bodies, a test with high sensitivity but poor specificity. The prevalence percent). 274,275 Also, interlaboratory variability is a significant problem
of positive tests in the asymptomatic healthy population has generally with anti-β GPI antibody assays. 276
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ranged from approximately 3 to 10 percent. In a prospective study of Epitope-specific anti-β GPI antibodies, not yet in general use,
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2132 consecutive Spanish patients with venous thromboembolism, 4.1 may offer a better predictive value for diagnosis and prognosis of APS.
percent had elevated levels of aCL antibodies (i.e., about the same prev- A recent analysis of 198 samples from patients with a variety of auto-
alence as in the asymptomatic healthy population), but in a group immune conditions revealed that the 52 patients with anti-β GPI IgG
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of healthy young women in another study, the prevalence of elevated antibodies could be divided into those that recognize domain I alone
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levels of aCL was 18.2 percent. Many individuals have antibody lev- and those with reactivity for all domains ; the former were positive for
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els that are elevated in response to infections that are not associated LA and were associated with an increased risk for thrombosis. As men-
with thrombotic complications. Patients with syphilis, Lyme disease, tioned earlier, positivity for this assay has been correlated with positivity
and other infections may be misdiagnosed with APS based on elevated for a functional coagulation assay that measures resistance to annexin
aCL antibody levels when concurrent stroke or arterial thrombosis is A5 anticoagulant activity. 52
present, so these conditions must always be ruled out in susceptible
patients. In a systematic literature review, 15 of 28 studies showed sig- Assays for Antibodies Against Prothrombin and Phosphatidyl
nificant associations between aCL antibodies and thrombosis. In all Serine
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cases, a correlation existed between high antibody titers and a high risk Prothrombin is considered the second major cofactor for aPL antibod-
of thrombosis. Elevated levels of aCL antibodies, whether high or low ies. In a systematic literature review, 17 of 46 studies showed significant
titer, were significantly associated with both myocardial infarction and associations between antiprothrombin antibodies and thrombosis. Of
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cerebral stroke. Only high-titer aCL antibodies significantly increased the eight studies that included multivariate analysis, two confirmed that
the risk of deep vein thrombosis. During a 10-year followup of patients antiprothrombin antibodies were independent risk factors for throm-
with elevated levels of aCL antibodies, approximately 50 percent of bosis, and three other studies showed that antiprothrombin antibod-
patients who presented with the antibodies but without clinical man- ies added to the risk borne by LA or aCL antibodies. A recent study
ifestations of the syndrome subsequently developed the APS. The indicated that the sensitivity of antiprothrombin immunoassays in the
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presence of elevated titers of aCL antibodies 6 months after an episode primary aPL syndrome is too low to warrant inclusion in recommenda-
of venous thromboembolism is a predictor for increased risk of recur- tions for APS testing. 277
rence and of death. Women with aCL IgM antibodies, or with an aCL Tests for antibodies against phosphatidyl serine have been hypoth-
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IgG antibody titer less than 20 IgG-binding units, and without a posi- esized to be more relevant than antibodies against cardiolipin, because
tive LA do not appear to be at risk for APS. In contrast, women with the latter are present in intracellular membranes, whereas phosphatidyl
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an aCL IgG titer greater than 20 binding units or a positive LA were serine is exposed on syncytialized cells, on apoptotic cells, and on acti-
more likely to develop complications. With respect to pregnancy vated platelets. Antibodies against phosphatidyl serine were reported to
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losses, a meta-analysis of 25 studies on aPL antibodies in women with correlate more specifically with APS than aCL antibodies, particularly
recurrent fetal losses showed a significant correlation with increased in arterial thrombosis. 278,279 However, antiphosphatidyl serine antibody
aCL IgG, and particularly with the LA. 262 tests are not included as an international consensus criterion. 257
With respect to stroke, elevated levels of aCL antibodies of IgG or Newer studies indicate that assays for detecting autoantibodies
IgM isotype were reported to be significant risk factors. aPL antibodies that recognize prothrombin complexed to the anionic phospholipid,
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also are an independent risk factor for stroke in young women. 266 phosphatidyl serine, may have improved utility for diagnosing APS by
Approximately 20 percent of patients taking procainamide have identifying patients suspected for the disorder but with negative results
moderate to high levels of aCL antibodies. In these patients, the anti- in the conventional assays; in one series of 728 patients who were sus-
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bodies are associated with anti-β GPI specificity. There have been case pected of having APS but tested negative by conventional assays, 41
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reports of associated thrombosis. Treatment with chlorpromazine has were found to be positive for anti–prothrombin/phosphatidyl serine.
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been associated with the development of aCL antibodies, although It has also been suggested that positivity for these assays may correlate
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more recent data indicate that aPL antibodies are frequently elevated with positivity for LA assays. 281
in patients with severe psychiatric disorders whether or not they are
treated with antipsychotic medications. 270 Assays for Antibodies Against Other Phospholipids
Some investigators have advocated testing for antibodies against a
Anti-β Glycoprotein I Antibody Assays panel of phospholipids other than cardiolipin, 282–285 but others have
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β GPI is believed to be the major protein cofactor for aPL antibodies. disagreed. Although one review has indicated that measurement for
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Enzyme-linked immunosorbent assays (ELISAs) for anti-β GPI anti- antiphosphatidyl ethanolamine antibodies may identify some patients
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bodies are considered to be more specific but less sensitive to APS whose conventional tests are negative for aPL antibodies, the current
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than to aCL assays. In a systematic literature review, 34 of 60 studies consensus holds that no benefit has been demonstrated for tests for anti-
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showed significant associations between anti-β GPI antibodies and bodies against panels of different phospholipids. 257
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