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2244 Part XII: Hemostasis and Thrombosis Chapter 131: The Antiphospholipid Syndrome 2245

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(VTE). Therapeutic CFX values range from 20 to 40 percent; thus, of the high mortality. Treatment for CAPS is directed toward the
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a CFX of 40 percent would approximate an INR of 2.0, and a CFX of thrombotic events and suppression of the cytokine cascade. This
20 percent would approximate an INR of 3.0. includes anticoagulation with heparin and immunosuppressive therapy
New oral anticoagulants (NOACs), either direct factor Xa or in the form of high-dose glucocorticoids. A triple therapy strategy of
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thrombin inhibitors, are effective for treatment of VTE. However, anticoagulation, glucocorticoids, and either intravenous immunoglob-
their use specifically in APS patients has not been thoroughly evaluated. ulin or plasma exchange or both has improved outcomes. Cyclophos-
In two recent case studies, NOACs have failed to prevent thrombosis in phamide is recommended for patients with CAPS and inflammatory
APS patients. Of six APS patients studied, five suffered recurrent VTE features of SLE or high-titer aPL antibodies. Rituximab may be useful in
and one suffered a recurrent TIA after transitioning to NOACs. 312,313 At refractory or relapsing cases of CAPS. 178
the time of writing, a prospective randomized controlled trial of war-
farin versus rivaroxaban named “RAPS” (Rivaroxaban in Antiphos-
pholipid Syndrome) is ongoing in patients with thrombotic APS (study PREGNANCY COMPLICATIONS
ISRCTN68222801). Until the trial is concluded (expected completion The current approach to treating pregnant women with APS and recur-
in 2015), caution should be applied in using NOACs for APS patients. rent pregnancy losses or the other aPL antibody–associated complica-
Fibrinolytic treatment has been reported for patients with primary tions of pregnancy includes daily low-dose aspirin (75 to 81 mg/day)
APS and extensive thrombosis of the common femoral and iliac veins and either UFH or LMWH. 300,337,338 Although clinical studies have
315
extending to the lower vena cava, acute ischemic stroke, and acute shown efficacy with UFH, most clinicians treat with LMWH because
314
myocardial infarction. 316 it has a better pharmacokinetic profile and a lower risk of heparin-
The antimalarial drug hydroxychloroquine (HCQ) is associ- induced thrombocytopenia and osteopenia. Heparin is then withheld
ated with reduced risk of thrombosis in patients with APS 271–273,317–319 when labor begins or 24 hours prior to a cesarean section. Anticoagu-
and SLE. 319–321 The potential effectiveness of this treatment has been lation is resumed 6 weeks postpartum because of the increased risk of
supported by an animal model for aPL thrombosis and by a recent VTE in this time period. Interestingly, the current standard of care
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301
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report that HCQ directly disrupts aPL IgG–β GPI complexes, and for pregnant APS patients is based on two randomized controlled trials
2
also reverses the aPL antibody-mediated disruption of annexin A5 conducted prior to 2000 that included only 150 patients. Newer trials
binding on phospholipid bilayers and on human placental syncitio- show conflicting results, with some showing no difference in prevention
324
trophoblasts. In a longitudinal cohort study consisting of 272 patients of pregnancy loss in APS patients receiving aspirin alone versus aspirin
325
with the APS and 152 taking HCQ (17 of 272 patients on warfarin, 203 and LMWH, and others showing a small benefit. With this manage-
339
302
were on prednisolone, 112 on azathioprine, 38 on aspirin) investigators ment, the likelihood of a good pregnancy outcome in women with APS
found fewer thrombotic complications for patients on HCQ (odds ratio has been estimated to be approximately 75 to 80 percent.
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[OR] 0.17, 95% confidence interval [CI] 0.07 to 0.44; p <0.0001). In Other treatment modalities such as glucocorticoids or intravenous
asymptomatic aPL antibody-positive patients with SLE, primary pro- IgG (IVIG) should be considered only for patients who are refractory to
phylaxis with aspirin and HCQ appeared to reduce the frequency of anticoagulant therapy, who have a severe immune thrombocytopenia,
327
thrombotic events. A published prospective, nonrandomized study or who have a significant contraindication to heparin therapy. The addi-
compared oral anticoagulant plus HCQ versus oral anticoagulant alone. tion of glucocorticoids has shown no clear benefits and has been associ-
In this study, 30 percent (6/20) of patients had a thrombotic event if they ated with premature rupture of membranes or preeclampsia; however, a
were on oral anticoagulant alone, despite therapeutic range INR, versus newer study showed that for patients with refractory APS, the addition
no thrombotic events in the oral anticoagulant plus HCQ group (0/20). of low-dose prednisolone (10 mg) from time of a positive pregnancy
This study, however, was limited given the small number of patients test up to 14 weeks’ gestation may help to increase livebirth rates.
340
328
studied and short followup. Recently, the natural 4-aminoquinolone, Although the addition of IVIG has not been shown to be superior to
quinine, was shown in vitro to disrupt the immune complexes bound heparin and aspirin in large multicenter clinical trials, it has shown
341
329
to phospholipid layers. However, both HCQ and quinine will require some efficacy in patients with refractory APS in small case studies. 342,343
clinical testing in appropriately designed clinical trials. A prospective
randomized controlled trial comparing HCQ to placebo in aPL-positive REFERENCES
patients without a prior history for thrombosis is currently in progress.
Other proposed treatments for APS include statins, rituximab 1. Hughes GR: The anticardiolipin syndrome. Clin Exp Rheumatol 3:285–286, 1985.
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J Rheumatol Suppl 13:210, 1987.
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studies, APS patients treated with statins demonstrated downregulation lant. A case-control study. Thromb Haemost 76:187–189, 1996.
of tissue factor and reduced proinflammatory/prothrombotic markers 4. Ginsberg JS, Wells PS, Brill-Edwards P, et al: Antiphospholipid antibodies and venous
such as interleukin-1β, vascular endothelial growth factor, tumor necro- thromboembolism. Blood 86:3685–3691, 1995.
sis factor α, interferon-inducible protein 10, and soluble CD40L. 330,331 It 5. Out HJ, Bruinse HW, Christiaens GC, et al: Prevalence of antiphospholipid antibodies
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has been suggested that a B-cell inhibitor such rituximab may be useful 6. Shapiro SS, Thiagarajan P: Lupus anticoagulants. Prog Hemost Thromb 6:263–285, 1982.
in reducing aPL antibody titers in APS patients. The Rituximab in Anti- 7. Shapiro SS: Lupus anticoagulants and anticardiolipin antibodies: Personal reminis-
cences, a little history, and some random thoughts. J Thromb Haemost 3:831–833, 2005.
phospholipid Syndrome (RITAPS) trial did not show reduction in aPL 8. Asherson RA: The primary, secondary, catastrophic, and seronegative variants of the
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controlling noncriteria manifestations of APS. Because low vitamin D Hemost 34:227–235, 2008.
levels correlate with arterial and venous thrombosis as well as noncri- 9. Moore JE, Mohr CF: Biologically false positive serological tests for syphilis: Type, inci-
dence, and cause. JAMA 150:467–473, 1952.
teria APS manifestations, 333–335 it is recommended that vitamin D defi- 10. Moore JE, Lutz WB: Natural history of systemic lupus erythematosus: Approach to its
ciency (<10 to 20 ng/mL) and insufficiency (<30 ng/mL) be corrected in study through chronic biologic false positive reactors. J Chronic Dis 1:297–316, 1955.
aPL antibody-positive patients. 336 11. Bell WN, Alton HG: A brain extract as a substitute for platelet suspensions in the
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