Page 2352 - Hematology_ Basic Principles and Practice ( PDFDrive )

2094 Part XII Hemostasis and Thrombosis

women. In the APASS, 41% of patients who experienced an ischemic
stroke within 30 days were aCL antibody-positive. Immunoglobulin A Antibodies Against Cardiolipin
and β 2 -Glycoprotein I
Anti–β 2 -Glycoprotein I Antibody Assay The clinical utility of testing aPL antibodies of IgA isotype remains
controversial. The prevalence of true positivity to aCL IgA antibodies
β 2 GPI is the major protein cofactor recognized by aPL antibodies. is very low; for example one study of 795 patients reported positive
ELISAs for anti-β 2 GPI antibodies are considered to be less sensitive aCL IgA in only 2 patients, both of whom were also positive for IgG
but more specific for APS than aCL antibody assays. Although aCL. However, anti-β2GPI IgA antibodies were reported to be sig-
antibodies against β 2GPI are usually found in conjunction with aCL nificantly associated with thrombosis. A recent retrospective case-
and antiphosphatidylserine antibodies, some patients with APS only control study of 56 patients with isolated anti-β 2GPI IgA found that
have antibodies against β 2GPI. Despite the higher specificity (98%), patients with this marker had significantly more thromboembolic
β 2GPI antibodies cannot be relied upon as a stand-alone test for APS events and higher polyclonal IgA levels than controls. Anti-β 2GPI
because of its low sensitivity (40%–50%) and concurrent testing for IgA was associated with an increased risk of thromboembolic events
both antibodies, along with LA is advised. in patients with SLE.
In a systematic literature review, 34 of 60 studies, of which none aPL antibodies of IgA isotype (either aCL or anti-β2GPI) were
was prospective, showed significant associations between anti-β 2GPI not included in the international consensus statement on the criteria
antibodies and thrombosis. Of 10 studies that included multivariate for APS classification. However, testing for the IgA isotype (particu-
analysis, only 2 confirmed that IgG anti-β 2GPI antibodies were larly IgA anti-β2GPI) was recommended in cases where APS is sus-
independent risk factors for venous thrombosis. Anti-β 2 GPI antibod- pected but the IgG and IgM tests are negative.
ies were more often associated with venous than arterial events.

Annexin A5 Resistance Assay
Multipositivity for Antiphospholipid Tests and The annexin A5 resistance (A5R) assay was designed to test for a
Clinical Risk specific pathogenic mechanism: the aPL antibody-mediated disrup-
tion of annexin A5 crystallization on phospholipid surfaces. As dis-
Strong positivity for more than one of the aPL antibody criteria assays cussed earlier (section on Pathophysiologic Mechanisms), annexin A5
has been correlated with increased risk for developing clinical events forms a crystal shield on endothelial surfaces which is disrupted by
in several retrospective studies and in one prospective study. One anti-β 2 GPI/β 2 GPI complexes, thereby exposing more anionic phos-
study showed that multipositivity for aPL antibodies, but not single pholipids and accelerating coagulation reactions (see Fig. 141.2). The
positivity, was associated with antenatal and postnatal DVT. Another failure of annexin A5 to sufficiently prolong coagulation times
study of pregnant women with APS reported that patients with triple because of interference by aPL antibodies can be detected through
aPL antibody positivity and/or previous thromboembolism appeared reduction of the annexin A5 anticoagulant ratio (A5R). A study of
to have a higher probability of poor neonatal outcome than patients 96 patients demonstrated significantly lower A5R values in APS
with double or single aPL antibody positivity and no thrombosis patients with a history of thrombosis than in aPL antibody-positive
history. A retrospective analysis of 162 APS patients who were triple- patients without a history of thrombosis, aPL antibody-negative
positive for LA, aCL, and anti-β 2 GPI antibodies reported a higher patients with a thrombosis history and healthy controls. A recent
risk of recurrent thromboembolic events with a cumulative incidence study of 166 patients demonstrated a significantly lower A5R ratio
of events of 44.2% after 10 years. This finding was confirmed in a in obstetric primary APS patients and thrombotic primary APS
recent prospective analysis of 104 triple positive patients without a patients than in healthy controls (Fig. 141.3). Clinicians should be
prior history of thrombosis or pregnancy complications. When fol- aware that this assay falls into the category of laboratory developed
lowed for a mean duration of 4.5 years, the cumulative incidence of tests (LDTs) and is not commercially available in kit forms.
a first thrombotic event was 37.1% (95% confidence interval (CI),
19.9%–54.3%). Male sex and the presence of other risk factors for
venous thrombosis were associated with an increased risk of throm- Anti–Domain I of β 2 -Glycoprotein I Assay
bosis in this cohort.
A risk scale has been proposed to aid in the diagnosis and manage- This immunoassay identifies IgG antibodies against a specific amino
ment of patients with APS (Table 141.4). Both symptomatic and acid sequence, G40-R30, within domain I of β 2 GPI. A recent analysis
asymptomatic patients with triple-positive laboratory results (LA of 198 samples from patients with a variety of autoimmune conditions
positive, aCL [IgG or IgM >40 GPL] and anti-β 2 GPI [IgG or IgM revealed that the 52 patients with anti-β 2 GPI IgG antibodies could be
>99th percentile]) should be considered high-risk for future manifes- divided into two groups: one whose antibodies recognized domain I
tations of APS, whereas patients who are double positive for LA, aCL alone and another whose antibodies reacted with all domains; only the
(IgG or IgM >40 GPL) and/or anti-β 2 GPI (IgG or IgM >99th per- former had positivity for LA and an increased OR for thrombosis. A
centile) or single positive for LA should be considered at medium recent multicenter study of 442 patients who tested positive for anti-
risk for APS. Finally, single positivity for aCL (IgG or IgM >40 GPL) β 2 GPI antibodies reported that specific anti-domain I IgG antibodies
or anti-β 2 GPI (IgG or IgM >99th percentile) should be considered were more strongly associated with thrombosis and obstetric complica-
low risk for APS, but treatment may be warranted if such patients tions than anti-β 2 GPI antibodies detected using the standard anti-
develop thrombosis or pregnancy complications or have other high β 2 GPI antibody assays. Anti–domain I IgG antibodies were present in
risk factors. the plasma of 55% of patients, of which 83% had a history of throm-
bosis (OR, 3.5) and 57% had pregnancy complications (OR, 2.4).

“Noncriteria” Antiphospholipid Assays
Antiprothrombin Antibody Assay
Occasionally clinicians may consider testing selected patients with
one of the assays that are not included within the formal diagnostic Prothrombin is considered the second major cofactor for aPL
criteria. An example of such a situation would be a patient with SLE antibodies after β 2GPI. In a systematic literature review, 17 of 46
or another autoimmune disorder who has clinical manifestations that studies showed significant associations between antiprothrombin
suggest APS but who has negative assays for aCL and β 2GPI IgG and antibodies and thrombosis. Of the eight studies that included mul-
IgM along with negative LA tests. tivariate analyses, 2 confirmed that antiprothrombin antibodies were