Page 2351 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 141 The Antiphospholipid Syndrome 2093

antibodies, but not for aCL antibodies alone, predicted a higher risk coagulation factor inhibitors, may coexist and yield a confusing labo-
of recurrent thromboocclusive events in patients with first ischemic ratory picture. LAs may also cause artifactual decreases in contact
stroke. In the Risk of Arterial Thrombosis In relation to Oral contra- activation pathway coagulation factor levels because those assays are
ceptives (RATIO) study, the presence of LA was found to be a major based on the aPTT; these patients are sometimes misdiagnosed as
risk factor for arterial thrombotic events in young women with an having multiple coagulation factor deficiencies. This problem can be
OR of 5.3 for myocardial infarction and 43.1 for ischemic stroke. In handled by repeating the coagulation factor assays after dilution of
LA-positive women on oral contraceptives, the OR for myocardial the plasma or by using an aPTT reagent that is insensitive to LA for
infarction increased to 21.6 and the OR for ischemic stroke increased the coagulation factor assays.
to 201.0. For LA-positive women who were also cigarette smokers,
the ORs for myocardial infarction and ischemic stroke increased to
33.7 and 87.0, respectively. Finally, the PROMISSE study demon- Dilute Russell Viper Venom Time
strated that of the available aPL markers, a positive LA was the single
strongest predictor of adverse pregnancy outcomes in patients with The dRVVT is considered to be one of the most sensitive LA tests.
APS. The assay uses Russell viper venom (RVV) in a system containing
limiting quantities of diluted rabbit brain phospholipid. RVV directly
activates factor X, leading to clotting. aPL antibodies can prolong
Patient Selection the dRVVT by interfering with assembly of the prothrombinase
complex; this prolongation is reversed by adding excess phospholipid
LA testing should not be routinely performed in patients without a to the reaction (sometimes referred to as a “confirmatory test”).
history of thrombosis and/or pregnancy complications that may be To ensure that prolongation of the clotting time is not a result
attributable to APS or a history of SLE. The Antiphospholipid of a factor deficiency, the procedure includes mixing of patient
Antibodies Subcommittee of the International Society of Thrombosis plasma with control plasma. Anticoagulant therapy with heparin,
and Hemostasis (ISTH) has prioritized the appropriateness of testing warfarin, or direct thrombin inhibitors can yield falsely abnormal test
for LA into low, moderate, and high groups. Patients in the low- results.
appropriateness group include elderly patients with venous or arterial
thromboembolism. The moderate group includes asymptomatic
patients who are incidentally found to have a prolonged aPTT (often Antiphospholipid Immunoassays
during routine testing) and young patients with recurrent spontane-
ous early pregnancy loss or provoked VTE. Patients in the high- Antiphospholipid Antibody and Cofactor Assays
appropriateness group include those with unprovoked VTE, arterial
thrombosis in young patients (<50 years of age), thrombosis in The quantities of aCL IgG and aCL IgM bound are expressed in GPL
unusual sites, late pregnancy loss, and thrombosis or pregnancy and MPL units, respectively; one unit representing the cardiolipin
morbidity in patients with autoimmune diseases (SLE, rheumatoid binding activity of 1 µg/mL of affinity-purified aPL antibodies from
arthritis, autoimmune thrombocytopenia, autoimmune hemolytic reference sera. Binding reflects both the titer and affinity/avidity of
anemia). In our opinion these same guidelines should also be applied the antibody. The levels of aCL antibodies detected in reference sera
to aPL testing. can vary among laboratories, particularly when the tests are done with
different commercial ELISA kits.
It is important for the clinician to recognize that the majority of
Choosing the Appropriate Lupus Anticoagulant Assays patients with elevated aCL antibodies detected on routine screening
do not have APS. The prevalence of positive immunoassays in the
The Subcommittee on Antiphospholipid Antibodies of ISTH has asymptomatic “normal” population ranges from 3% to nearly 20%.
proposed specific criteria for standardizing the diagnosis of LA. They In a prospective study of 2132 consecutive Spanish patients with
recommend performing two different LA tests that are based on VTE, 4.1% had elevated levels of aCL antibodies (i.e., about the same
different assay principles. The dRVVT is widely used in clinical labo- prevalence as in the asymptomatic healthy population). In one group
ratories and is believed to be specific for detecting LA in patients at of healthy young women, 18.2% had elevated levels of aCL antibod-
high risk for thrombosis. aPTT tests performed with silica as an ies and 12.8% were LA positive. Many individuals have elevated
activator and low phospholipid content were recommended as the antibody levels in response to infections; these antibodies are not
second test of choice because of their sensitivity for LA. associated with thrombotic complications. Patients with syphilis,
Lyme disease, and other infections may be misdiagnosed with APS
based on elevated aCL antibody levels when concurrent stroke or
Activated Partial Thromboplastin Time arterial thrombosis is present.
High levels of aCL antibodies are associated with an increased risk
A prolonged aPTT in an otherwise healthy individual without a of thrombosis. During a 10-year follow-up of patients with elevated
history of bleeding is most frequently caused by an LA. Commercial levels of aCL antibodies, approximately 50% of those without clinical
aPTT reagents vary in their sensitivities to LA, so it is important to manifestations of APS at baseline went on to develop APS. The
know the characteristics of the particular reagent that is being utilized. presence of elevated titers of aCL antibodies 6 months after an episode
The LA needs to be differentiated from inhibitors of specific coagula- of VTE is a predictor of an increased risk of recurrence and of death.
tion factors and from anticoagulant medications such as heparin. In In a systematic review, 15 of 28 studies showed significant associations
addition to specific assays to evaluate these possibilities, the clinician between aCL antibodies and thrombosis. In all cases, higher antibody
can check whether the aPTT normalizes when an LA-insensitive titers were associated with an increased risk of thrombosis. Elevated
aPTT reagent is used or when the assay is performed using frozen levels of aCL antibodies, whether of high or low titer, were signifi-
washed platelets as the source of phospholipid, a procedure referred cantly associated with both myocardial infarction and ischemic stroke.
to as the platelet neutralization procedure. Mixing and incubating the Only high-titer aCL antibodies significantly increased the risk of deep
test plasma with normal plasma may be helpful in differentiating LAs vein thrombosis (DVT). With respect to pregnancy losses, a meta-
from coagulation factor inhibitors. aPTTs performed on mixtures of analysis that reviewed 25 studies evaluating the impact of aPL anti-
normal plasma and plasma containing a factor VIII inhibitor usually bodies on recurrent fetal loss showed a significant correlation with
require incubation for 1 to 2 hours at 37°C to show prolongation, increased levels of aCL IgG, but the highest correlation was with LA.
whereas LA-containing plasmas typically prolong the aPTT immedi- Elevated levels of aCL antibodies of the IgG or IgM isotype are
ately without requiring incubation. The clinician should be aware reported to be a significant risk factor for stroke. aPL antibodies are
that in rare patients both types of anticoagulants, i.e., LA and specific also reported to be an independent risk factor for stroke in young