Medical Care
Patients with antiphospholipid syndrome (APS) may be evaluated in an outpatient setting. Inpatient evaluation is required if the patient presents with a significant clinical event. Patients with catastrophic APS (CAPS) require intense observation and treatment, often in an intensive care unit.
In general, treatment regimens for APS must be individualized according to the patient's current clinical status and history of thrombotic events. Asymptomatic individuals in whom blood test findings are positive do not require specific treatment.
Prophylactic therapy
Eliminate other risk factors, such as oral contraceptives, smoking, hypertension, or hyperlipidemia. Prophylaxis is needed during surgery or hospitalization, as well as management of any associated autoimmune disease.
Low-dose aspirin is used widely in this setting; however, the effectiveness of low-dose aspirin as primary prevention for APS remains unproven. [16] Clopidogrel has anecdotally been reported to be helpful in persons with APS and may be useful in patients allergic to aspirin.
In patients with systemic lupus erythematosus (SLE), consider hydroxychloroquine, which may have intrinsic antithrombotic properties.
Consider the use of statins, especially in patients with hyperlipidemia. European League against Rheumatism (EULAR) guidelines, citing a lack of studies of cardiovascular risk management in patients with APS, recommend managing hyperlipidemia and hypertension in these patients according to recommendations for the general population. [27]
Treatment of thrombosis
Perform full anticoagulation with intravenous or subcutaneous heparin followed by warfarin therapy. Based on the most recent evidence, a reasonable target for the international normalized ratio (INR) is 2.0-3.0 for venous thrombosis and 3.0 for arterial thrombosis. Patients with recurrent thrombotic events may require an INR of 3.0-4.0. For severe or refractory cases, a combination of warfarin and aspirin may be used. Treatment for significant thrombotic events in patients with APS is generally lifelong.
Direct oral anticoagulants (ie, direct thrombin inhibitors and factor Xa inhibitors such as rivaroxaban) have been used in patients who are warfarin intolerant/allergic or have poor anticoagulant control. [16, 28] However, studies of these agents in APS patients have largely proved disappointing.
In the Rivaroxaban for Antiphospholipid Syndrome (RAPS) trial—a controlled, open-label, phase II/III non-inferiority trial in 116 APS patients—the percentage change in endogenous thrombin potential at 42 days for rivaroxaban was inferior to that of warfarin. However, because no thromboembolic events occurred over the 210‐day follow‐up in either group, the investigators concluded that rivaroxaban might be an effective and safe alternative in patients with APS and previous venous thromboembolism (VTE). [29]
A cohort study in 176 APS patients followed for a median of 51 months reported an increased risk of recurrent thromboembolic events and recurrent VTE alone in patients receiving direct oral anticoagulants compared with those receiving warfarin. No differences were found between rivaroxaban and apixaban or among single-positive, double-positive, and triple-positive APS. [30]
The phase III Rivaroxaban in Thrombotic Antiphospholipid Syndrome (TRAPS) trial, which was conducted in high-risk APS patients triple-positive for lupus anticoagulant, anti-cardiolipin, and anti-β2-glycoprotein I antibodies of the same isotype, was terminated prematurely after the enrollment of 120 patients because of an excess rate of arterial thromboembolic events in patients on rivaroxaban: 12% (4 ischemic strokes and 3 myocardial infarctions) versus 0% in patients on warfarin, after 569 days’ follow‐up. [31]
In May 2019, the European Medicines Agency (EMA) issued a guidance statement recommending against the use of direct-acting oral anticoagulants (including rivaroxaban, apixaban, edoxaban, and dabigatran etexilate) for patients with a history of thrombosis who are diagnosed with APS, in particular those that are triple positive. This poses a challenge for clinicians, however, because current guidelines recommend direct oral anticoagulants for treatment of VTE. A proportion of patients with a first unprovoked VTE will have antiphospholipid antibodies, and some of those will have APS. However, when a patient presents with unprovoked VTE it is impossible to know whether APS is present, as the diagnosis of APS requires testing on two or more occasions at least 12 weeks apart. [32]
Rituximab can be considered for recurrent thrombosis despite adequate anticoagulation. A nonrandomized prospective study showed rituximab to be effective for noncriteria aPL manifestations (ie, thrombocytopenia and skin ulcers). [8]
Obstetric considerations
Guidelines from the American College of Obstetricians and Gynecologists (based primarily on consensus and expert opinion [level C]) recommend that women with APS who have a history of thrombosis in previous pregnancies receive prophylactic anticoagulation during pregnancy and for 6 weeks postpartum. For women with APS who have no history of thrombosis, the guidelines suggest that clinical surveillance or prophylactic heparin use antepartum, along with 6 weeks of postpartum anticoagulation, may be warranted. [33]
Prophylaxis during pregnancy is provided with subcutaneous heparin (preferably low–molecular-weight heparin [LMWH]) and low-dose aspirin. Therapy is withheld at the time of delivery and is restarted after delivery, continuing for 6-12 weeks, or long-term in patients with a history of thrombosis.
The European League Against Rheumatism (EULAR) has published recommendations for women's health and the management of family planning, assisted reproduction, pregnancy, and menopause in patients with SLE and/or APS. EULAR also recommends prophylactic heparin and low-dose aspirin during pregnancy for patients with APS. [34]
Warfarin is contraindicated in pregnancy. Breastfeeding women may use heparin and warfarin.
Corticosteroids have not been proven effective for persons with primary APS, and they have been shown to increase maternal morbidity and fetal prematurity rates.
Unfortunately, current treatment fails to prevent complications in 20 to 30% of APS pregnancies. [35, 36] Retrospective clinical studies suggest that treatment with hydroxychloroquine may help prevent pregnancy complications in women with aPL and APS, and this strategy is currently being studied in a randomized controlled multicenter trial. [36]
See also Antiphospholipid Syndrome and Pregnancy.
Catastrophic antiphospholipid syndrome
Patients with CAPS are generally very ill, often with active SLE. [37] The condition is too rare to support clinical trials, but improved mortality has been reported with triple therapy consisting of anticoagulation, corticosteroids, and plasma exchange and/or intravenous immunoglobulin. [18] In addition, attention should be paid to associated disorders (eg, infection, SLE). Cyclophosphamide has been used in cases associated with SLE, although its use in first-trimester pregnancy increases risk of fetal loss. [34, 37] In refractory or relapsing cases, rituximab and eculizumab have been used. [37]
Surgical Care
Placement of an inferior vena cava (IVC) filter may be considered in patients with APS who require cessation of anticoagulation or who continue to experience thrombotic complications despite maximal anticoagulation. Experts recommend avoiding IVC filters in the setting of acute APS, due to reports of adverse events including IVC thrombosis and pulmonary embolus. Baig et al evaluated the use of retrievable IVC filters in five patients with APS and concluded that retrievable IVC filters can be safely placed and removed in such patients, even during anticoagulation. [38]
Consultations
Consultations may include the following:
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Rheumatologist
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Hematologist
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Neurologist, cardiologist, pulmonologist, hepatologist, ophthalmologist (depending on clinical presentation)
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Obstetrician with experience in high-risk pregnancies
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Antiphospholipid syndrome. Livedo reticularis.
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Antiphospholipid syndrome. Arterial thrombosis resulting in ischemia and necrosis of the foot.
