Page 2358 - Hematology_ Basic Principles and Practice ( PDFDrive )

2100 Part XII Hemostasis and Thrombosis

recommendation may be modified if DOACs are proven to be useful thrombosis in patients with APS and SLE. The potential effectiveness
in this setting. Interestingly, the current standard of care for pregnant of this treatment has been supported by an animal model for aPL
patients with APS is based on only two randomized controlled trials antibody thrombosis and by a recent reports that HCQ directly
conducted prior to 2000 and included only 150 patients. More recent disrupts aPL IgG–β 2GPI complexes, and also reverses the aPL
trials have shown conflicting results with some showing no difference antibody–mediated disruption of annexin A5 binding on phospho-
in prevention of pregnancy loss in APS patients receiving aspirin lipid bilayers and on human placental syncitiotrophoblasts. In a
alone versus aspirin and LMWH and others showing a small benefit. longitudinal cohort study that included 272 patients with APS and
However, the likelihood of a good pregnancy outcome in treated 152 taking HCQ (17 of 272 patients on warfarin, 203 were on
women with APS has been estimated to be about 75%–80%. prednisolone, 112 on azathioprine, 38 on aspirin) there were fewer
The presence of elevated aPL antibodies in pregnant women thrombotic complications in those taking HCQ (OR, 0.17; 95% CI,
without any history of spontaneous pregnancy losses, other attribut- 0.07–0.44; p < .0001). In asymptomatic aPL antibody-positive
able pregnancy complications, thrombosis or embolism is currently patients with SLE, primary prophylaxis with aspirin and HCQ
not sufficient justification for treatment. A recent systematic review appeared to reduce the frequency of thrombotic events. A recently
found no benefit of prophylactic treatment with aspirin to prevent published prospective, nonrandomized study compared oral antico-
pregnancy complications in aPL antibody carriers in the absence of agulant plus HCQ versus oral anticoagulant alone. In this study, 30%
other risk factors. Because 2%–3% of the general obstetric population (6/20) of patients had a thrombotic event if they were on oral anti-
has low titers of aPL antibodies, with a live birth rate of 60% among coagulant alone, despite therapeutic range INR, versus no thrombotic
these patients, it is not recommended that physicians screen for aPL events in the oral anticoagulant plus HCQ group (0/20). However
antibodies or LA in their routine prenatal screening panel. this study was limited by the small sample size and short follow-up.
A prospective randomized controlled trial comparing HCQ to
placebo in aPL-positive patients without a prior history for throm-
Catastrophic Antiphospholipid Syndrome bosis (clinicaltrials.gov NCT01784523) was recently terminated
because of insufficient recruitment.
Patients with CAPS require aggressive treatment because of the high
mortality. Treatment for CAPS is directed toward the thrombotic
events and suppression of the cytokine cascade. Conventional anti- Rituximab
coagulant therapy is usually insufficient and treatment modalities
may include anticoagulation with heparin, immunosuppressive Rituximab is an anti-CD20 chimeric monoclonal antibody effective
therapy in the form of high-dose steroids, IVIG, cyclophosphamide, against non-Hodgkin lymphomas and approved for the treatment of
azathioprine, or rituximab. Plasmapheresis may be a helpful adjunct rheumatoid arthritis. Limited case reports have shown rituximab as
in some patients. A triple therapy strategy of anticoagulation, steroids, effective in treating thrombocytopenia and hemolytic anemia in aPL
and either intravenous immunoglobulin or plasma exchange or both antibody–positive patients; however, it is unknown if rituximab is
has improved outcomes. The higher rate of this triple therapy strategy effective against aPL antibody–mediated thrombosis. An open-label,
has resulted in a significant reduction in mortality rate to 30% in phase II pilot study demonstrated safety and effectiveness of ritux-
CAPS. Cyclophosphamide is recommended for CAPS patients with imab in aPL antibody–positive patients with anticoagulant resistant
inflammatory features of SLE or high-titer aPL antibodies. Rituximab manifestations but did not show any effect on aPL laboratory
may be useful for refractory or relapsing cases of CAPS. parameters.

Asymptomatic Antiphospholipid
Antibody–Positive Patients Main Points and Clinical Pearls

A recent task force at the 13th International Congress on Antiphos- • The antiphospholipid (aPL) syndrome (APS) is an acquired
pholipid Antibodies has recommended that asymptomatic patients thrombophilic disorder in which patients have vascular
with no previous thrombosis but a high risk aPL antibody profile (LA thrombosis and/or pregnancy complications attributable to
positive, triple positive (LA+, aCL antibody+, anti-β 2 GPI antibody+), placental insufficiency, accompanied by laboratory evidence for
the presence of antiphospholipid antibodies in blood.
or persistently positive medium-high titers of aCL antibodies be given • Rare patients have a catastrophic form of APS (CAPS) in which
long-term prophylaxis with low-dose aspirin, especially if there are there is disseminated thrombosis in large- and small-vessel
other thrombotic risk factors. Furthermore, aPL-antibody carriers thrombi, often after a triggering event such as infection or
should receive thromboprophylaxis with usual doses of LMWH in surgery, and often with multiorgan ischemia and infarction.
high-risk situations, such as surgery, prolonged immobilization and • Laboratory testing for aPL antibodies should generally be limited
the puerperium. In addition to low-dose aspirin, aPL-antibody car- to patients who present with the thrombotic and/or the pregnancy
riers with SLE should receive hydroxychloroquine (HCQ) as primary manifestations of the disorder or asymptomatic patients with
prophylaxis. A recent meta-analysis of five international studies that autoimmune disease such as systemic lupus erythematosus
included 495 patients confirmed the benefit of low-dose aspirin in because they are at increased risk for having aPL antibodies and
for experiencing thrombosis.
asymptomatic aPL antibody carriers with and without SLE. The risk • The syndrome is identified by persistent positivity of criteria
of a first thrombotic event is significantly decreased in SLE patients laboratory tests including high titers for aCL and anti-β 2 GPI IgG
and asymptomatic aPL antibody carriers treated with low-dose or IgM antibodies detected by immunoassays and by positive LA
aspirin. Specifically, low-dose aspirin showed a protective effect using two different coagulation tests.
against arterial but not venous thrombosis. The meta-analysis failed • Weak positive test results for aPL immunoassays are unlikely
to show an independent protective effect of HCQ. to have any clinical significance. Transient aPL antibodies can
develop as a result of infection, HIV, liver disease, cancer,
and certain medications such as phenothiazines, quinine,
NONANTICOAGULANT TREATMENTS UNDER STUDY FOR procainamide, oral contraceptives, and anti-TNF agents.
ANTIPHOSPHOLIPID SYNDROME • In clinical practice selected patients may be suspected to have
APS without necessarily meeting the strict investigational criteria.
Hydroxychloroquine • When a patient has the clinical appearance of APS but
negative standard aPL assay results, think about the possibility
of seronegative APS. Noncriteria tests such as anticardiolipin
HCQ, a synthetic antimalarial drug with many antiinflammatory and (aCL) and anti–β 2 -glycoprotein I (anti-β 2 GPI) immunoglobulin A
antithrombotic effects has been associated with a reduced risk of