Page 865 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Antiphospholipid Syndrome

Thomas L. Ortel, Doruk Erkan, Michael D. Lockshin

Diagnosis of the antiphospholipid syndrome (APS) requires that may bind directly to phospholipids and are rarely associated
a patient has both a clinical event (thrombosis and/or pregnancy with thrombosis.
loss) and persistent antiphospholipid antibody (aPL), documented
by a solid phase serum assay (anticardiolipin [aCL] or anti EPIDEMIOLOGY
β 2 -glycoprotein-I [β 2 GPI] enzyme-linked immunosorbent assay)
or an inhibitor of phospholipid-dependent clotting (lupus Low-titer aCLs occur in <10% of normal blood donors, and
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anticoagulant [LA] test) or both (Table 61.1). Antiphospholipid moderate- to high-titer aCLs and/or a positive LA test occurs
syndrome occurs as an isolated diagnosis, referred to as primary in <1%. The prevalence of positive aPL tests increases with age;
APS, or is associated with other systemic rheumatic diseases because the differential diagnosis of vascular occlusion is broader
such as systemic lupus erythematosus (SLE). than it is in young adults, particular care is necessary in diagnosing
The primary antigen to which aPL binds is β 2 GPI (apoli- APS in older patients. Thirty to 40% of SLE patients and
poprotein H), a phospholipid-binding plasma protein. β 2 GPΙ approximately one-fifth of rheumatoid arthritis patients have
is normally present at a concentration of 200 µg/mL and is positive tests for aPL.
a member of the complement control protein family. An octapep- The strength of association between aPL and clinical events
tide in the fifth domain of the protein and critical cysteine bonds varies among studies. A study of healthy male physicians followed
are necessary for both phospholipid binding and antigenicity; a prospectively for 3 years showed that those with moderate to
first domain site is implicated in pathogenicity. In vivo, β 2 GPI high titers of IgG aCL have a risk for venous thrombosis or
binds, primarily as a dimer, to phosphatidylserine on activated pulmonary embolus that is eight times higher than that for men
or apoptotic cell membranes, including those of trophoblast, with negative tests. Although a number of studies have tried to
platelets, and endothelial cells, undergoing conformational estimate the annual thrombosis risk in asymptomatic aPL-positive
change and becoming antigenic. This binding may initiate cell patients, most of these studies have included predominantly
activation, clearance of apoptotic cells by macrophages, and/or patients with SLE. Despite the lack of well-controlled studies,
coagulation. 2 in aPL-positive individuals with no other systemic autoimmune
diseases or risk factors for thrombosis, the annual risk of first
thrombosis is probably very low (<1%/year). However, aPL-
KEY CONCEPTS positive patients with other systemic autoimmune diseases such
as SLE are at increased annual risk for first thrombosis (<4%/
• Antiphospholipid antibodies (aPL) exist as a family of autoantibodies year).
directed against phospholipid-binding plasma proteins, most commonly Approximately 10% of first-stroke victims have aPL, especially
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β 2 -glycoprotein-I.
• The origin of aPL is unknown but is hypothesized to be an incidental those who are young, as do up to 21% of women who have
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exposure to environmental agents inducing aPL in susceptible suffered three or more consecutive fetal losses.
individuals.
• In humans, although cross-sectional and prospective cohort studies ETIOPATHOGENESIS
demonstrate that aPL can predict future thrombosis, the pathogenic
mechanism is unknown; more than one mechanism may be involved. Antiphospholipid antibodies exist as a family of autoantibod-
• Concomitant prothrombotic risk factors may promote clotting in an ies directed against phospholipid-binding plasma proteins,
additive manner in aPL-positive patients.
most commonly β 2 GPI. Such proteins bind negatively charged
phospholipids (cardiolipin, phosphatidylglycerol, phosphati-
dylserine, phosphatidylinositol) but not zwitterionic or neutral
Autoimmune aPL binds β 2 GPI (β 2 GPI-dependent aPL), which phospholipids (phosphatidylethanolamine, phosphatidylcholine).
in turn binds negatively charged phospholipids. Drugs (such as Other phospholipid-binding plasma proteins are prothrombin,
chlorpromazine, procainamide, quinidine, and phenytoin), thrombomodulin, protein C, protein S, and annexins I and V.
malignancies (such as lymphoproliferative disorders), and infec- In vivo, the likely relevant phospholipid to which these proteins
tious agents (such as syphilitic and nonsyphilitic Treponema, bind is phosphatidylserine, which is normally sequestered on the
Borrelia burgdorferi, human immunodeficiency virus, Leptospira, inner cell membrane but is exteriorized during cell activation
or parasites) induce β 2GPI-independent transient aPL. β 2 GPI- and apoptosis. Annexins bind to exposed phosphatidylserine
independent aPLs are usually made up of low-titer aCLs, which and create a “remove me” signal on cells.

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