Approach

The main antiphospholipid syndrome (APS) treatment goals are managing acute thrombosis, preventing thrombosis recurrence, and reducing pregnancy morbidity.[8]

Patients should be instructed on the signs and symptoms of thrombosis so that they can identify potential events early and seek emergency evaluation.

Patients should also be evaluated and treated for other risk factors of thromboembolism (previous history of thromboembolism, obesity, smoking, diabetes, immobilisation, hypertension, hyperlipidaemia, and oestrogen use). This includes smoking cessation and management of hyperlipidaemia as appropriate.

Women should be advised regarding risks associated with pregnancy (i.e., personal risk of thromboembolism during pregnancy and the immediate postnatal period, as well as the risk of pregnancy loss and pregnancy morbidity).

Management of thrombosis

Once the diagnosis is confirmed, patients are initially anticoagulated with unfractionated heparin or low molecular weight heparin (LMWH), followed by oral anticoagulation with a vitamin K antagonist (e.g., warfarin), providing there are no contraindications to therapy with these agents.[8]​​[43]​​

  • Patients with APS and an unprovoked venous thromboembolism have a high risk of recurrent thrombosis after cessation of anticoagulation, so the general recommendation is to continue anticoagulation long term.[8][43]​​[44]​​[45]​​​

  • Guidance for patients with APS with provoked thrombosis is less clear because there is lack of evidence with regard to duration of anticoagulation in patients with APS in this setting. Consideration should be given to the provoking factor associated with the thrombotic event and bleeding risks associated with long-term anticoagulation. Patients with a history of an unprovoked venous thromboembolic event should be anticoagulated with a vitamin K antagonist (e.g., warfarin) at a target international normalised ratio (INR) of 2.5 (range 2-3). Evidence suggests that high-intensity warfarin is no better than regular-intensity warfarin.[46][47]​​ However, patients with recurrent venous thromboembolic events were excluded from these studies.

  • Management of other risk factors for thromboembolism is crucial. Smoking cessation and management of hyperlipidaemia, hypertension, diabetes, and obesity, as well as addressing factors of immobility and oestrogen must be aggressively managed.

  • Optimal treatment for patients with previous arterial events remains controversial due to the lack of good prospective studies in this group. High-intensity warfarin therapy (INR range 3-4) or addition of low-dose aspirin to anticoagulation have been advocated for management of these patients. However, existing data have not been able to prove that these approaches are superior over the standard INR goal range of 2-3.

  • Management of recurrent events in patients who are already anticoagulated at a higher therapeutic INR is particularly difficult. Patients with recurrent thrombosis should have a thorough review to understand the factors involved. Patients with recurrent thrombosis despite therapeutic anticoagulation may need a target INR of 3-4 and may benefit from antiplatelet therapies.[48] Chromogenic factor X or II testing with simultaneous INR testing can be considered under these circumstances to guide INR target ranges, or these tests can be used instead of the INR in circumstances where the lupus anticoagulant also affects the prothrombin time.​[49]

Direct oral anticoagulants are not recommended for APS.[50]​ The European Medicines Agency, the UK-based Medicines and Healthcare products Regulatory Agency, and the International Society of Haemostasis and Thrombosis do not recommend these drugs in patients with APS, particularly high-risk patients (i.e., those who test positive for all 3 antiphospholipid tests, have prior arterial thrombosis, small vessel thrombosis or organ involvement, or heart valve disease according to Sydney criteria). This is due to the associated increased rates of recurrent thrombotic events compared with warfarin.[51] One randomised trial comparing rivaroxaban and warfarin (TRAPS trial) among patients with APS and at risk of thromboembolic events or with a history of thrombosis was terminated early due to a high number of thromboembolic events in the rivaroxaban arm (none were reported in the warfarin arm).[52] In a randomised controlled trial comparing apixaban with warfarin (ASTRO-APS) in patients with thrombotic APS, there was a higher rate of thrombosis (particularly stroke) in the group receiving apixaban.[53]​​​

Management of pregnancy

Management of pregnancy in women with APS encompasses both prevention of maternal thrombotic complications and prevention of pregnancy morbidity. Pregnancies of women with APS should ideally be managed by experienced multidisciplinary teams, including a haematologist, a rheumatologist, and an obstetrician.

  • Women who take warfarin should switch to anticoagulation with low-dose aspirin and heparin as soon as pregnancy is confirmed, ideally before week 6 of gestation, because of the teratogenic effects of warfarin.[43]​​

  • Pregnant women with acute thrombosis should receive therapeutic anticoagulation with LMWH or unfractionated heparin for the duration of the pregnancy. They can be switched to warfarin post-delivery.

  • Women with obstetric APS and no thrombotic history should receive prophylactic low-dose aspirin with prophylactic LMWH, during pregnancy and the postnatal period (6-8 weeks).​[43]​​[54][55] [ Cochrane Clinical Answers logo ] ​​​​

  • Women with APS and a previous history of thrombosis should receive anticoagulation throughout pregnancy and the postnatal period (6-8 weeks).[43]​​​[56]

  • Frequent antenatal examinations and serial ultrasonography are recommended, owing to the risk of adverse pregnancy outcomes (pre-eclampsia, intrauterine growth restriction, and placental abruption).

    [56][57]​​

Fetal monitoring should include uterine artery Doppler scanning at 20-24 weeks to check for evidence of increased vascular resistance, which has been shown to predict placental dysfunction in women with APS.[58] If this is abnormal, serial growth scans should be performed to monitor for intrauterine growth restriction.

In the postnatal period, women who were previously been receiving warfarin may restart warfarin and discontinue heparin. It is safe for the neonate to breastfeed while the mother is taking either heparin or warfarin.

Management of antiphospholipid antibodies (incidental aPL)

Patients who have antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibody, and anti-beta2-glycoprotein I) but no thrombotic or related obstetric complications (i.e., do not fit criteria for APS) are considered to have incidental aPL. Such patients may be at increased risk of thrombosis, but it is not possible to identify which specific patients are at risk.[59] Thus, attention should be paid to management of risk factors for cardiovascular and venous thromboembolic disease in these patients.

Evidence is conflicting regarding the use of aspirin in patients with incidental aPL. Some retrospective studies suggest a protective effect against thrombosis, while a placebo-controlled trial showed no such benefit.[60][61][62] Meta-analysis based on limited data concluded that patients with aPL who were treated with aspirin had a lower risk of thrombosis.[63] European League Against Rheumatism guidelines recommend using aspirin in patients with incidental aPL, triple positive aPL or in patients with aPL associated with systemic lupus erythematosus.[43]​ There are additional concerns regarding the use of aspirin; trials among healthy individuals have suggested that the benefit of reducing thrombosis is less than the bleeding risk, and, among individuals with diabetes, evidence suggests the use of aspirin is ineffective in reducing the risk of non-fatal myocardial infarction or cardiovascular death and may still increase the risk of major bleeding.[64]

During pregnancy, women with incidental aPL are usually given aspirin only, followed by 6 weeks postnatal thromboprophylaxis.[57][65]

Management of catastrophic APS

Catastrophic APS is a rare manifestation of APS. Patients present with multiorgan impairment due to widespread thromboses involving three or more organs/tissues.[19][66]​​​ Thrombosis is commonly microvascular thrombosis rather than large-vessel thrombosis. There is an associated high mortality (up to 50%).[67]​ Patients require aggressive management with anticoagulation and consideration of adjunctive immunosuppressive therapy.[43][68]​​​​​​ This may include corticosteroids, immunoglobulins, and/or plasma exchange.[19][43]​​​​​ In refractory cases, some case reports suggest rituximab, eculizumab, or daratumumab may be of benefit.[43][69][70]​​​​[71] ​A small, open-label trial of rituximab, a monoclonal antibody that targets the CD20 antigen, showed improvement in some manifestations, such as thrombocytopenia.[72]​ Daratumumab, a monoclonal antibody that targets the CD38 antigen, is currently being studied in the DARE-APS trial.[73]

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