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A EULAR task force has reviewed the medical literature and developed evidence-based recommendations for the management of antiphospholipid syndrome (APS) in adults. They note that a high-risk antiphospholipid antibody (aPL) profile is associated with greater risk for thrombotic and obstetric APS.
The international task force included 12 specialists in rheumatology or internal medicine, 2 obstetricians, 2 vascular medicine/thrombosis specialists, 1 healthcare professional, and 2 patient representatives from 11 European countries.
A systematic literature review identified 7534 articles, of which 188 articles met inclusion criteria for review. This resulted in 3 overarching principles and 11 new recommendations after a systematic literature review and Delphi process.
The panel highlighted the need to lower risk through screening and then, managing cardiovascular and venous thrombosis risk factors, patient education about treatment adherence, and lifestyle counselling.
Low-dose aspirin (LDA) is recommended for asymptomatic aPL carriers, patients with systemic lupus erythematosus without prior thrombotic or obstetric APS, and non-pregnant women with a history of obstetric APS only, all with high-risk aPL profiles.
Patients with APS and first unprovoked venous thrombosis should receive long-term treatment with vitamin K antagonists (VKA) with a target international normalised ratio (INR) of 2–3. In patients with APS with first arterial thrombosis, treatment with VKA with INR 2–3 or INR 3–4 is recommended, considering the individual’s bleeding/thrombosis risk.
Rivaroxaban should not be used in patients with APS with triple aPL positivity. For patients with recurrent arterial or venous thrombosis despite adequate treatment, addition of LDA, increase of INR target to 3–4 or switch to low molecular weight heparin may be considered.
Women with prior obstetric APS, combination treatment with LDA and prophylactic dosage heparin during pregnancy is recommended.
In patients with recurrent pregnancy complications, increase of heparin to therapeutic dose, addition of hydroxychloroquine or addition of low-dose prednisolone in the first trimester may be considered.
- Risk stratification in aPL-positive individuals should include determination of the presence of a high-risk aPL profile (defined as any of the following: multiple aPL positivity, lupus anticoagulant or persistently high aPL titres), history of thrombotic and/or obstetric APS, coexistence of other systemic autoimmune diseases such as SLE, and the presence of traditional cardiovascular risk factors.
- A high-risk aPL profile includes any of the following:
- lupus anticoagulant (LAC; most closely related to thrombosis)
- double aPL positivity (any combination of LAC, ACL Abs or antibeta2 glycoprotein I antibodies) or triple positivity (all three subtypes)
- persistently high aPL titres (by the aPL score and Global Anti-Phospholipid Syndrome (GAPSS) Score)
- General measures for aPL-positive individuals should include screening for and strict control of cardiovascular risk factors (smoking cessation; management of hypertension, dyslipidaemia and diabetes; and regular physical activity) in all individuals and particularly those with a high-risk aPL profile, screening for and management of venous thrombosis risk factors, and use of LMWH in high-risk situations such as surgery, hospitalisation, prolonged immobilisation and the puerperium.
- Patient education and counselling on treatment adherence, INR monitoring in patients treated with VKA, use of perioperative bridging therapy with LMWH for patients on oral anticoagulants, oral contraceptive use, pregnancy and postpartum period, postmenopausal hormone therapy, and lifestyle recommendations (diet, exercise) are important in the management of APS.
Primary thromboprophylaxis in aPL-positive subjects
1. In asymptomatic aPL carriers (not fulfilling any vascular or obstetric APS classification criteria) with a high-risk aPL profile with or without traditional risk factors, prophylactic treatment with LDA (75–100 mg daily) is recommended
2. In patients with SLE and no history of thrombosis or pregnancy complications:
A. With high-risk aPL profile, prophylactic treatment with LDA is recommended
B. With low-risk aPL profile, prophylactic treatment with LDA may be considered
3. In non-pregnant women with a history of obstetric APS only (with or without SLE), prophylactic treatment with LDA after adequate risk/benefit evaluation is recommended
Secondary thromboprophylaxis in APS
4. In patients with definite APS and first venous thrombosis:
A. Treatment with VKA with a target INR 2–3 is recommended
B. Rivaroxaban should not be used in patients with triple aPL positivity due to the high risk of recurrent events. DOACs could be considered in patients not able to achieve a target INR despite good adherence to VKA or those with contraindications to VKA (eg, allergy or intolerance to VKA)
C. In patients with unprovoked first venous thrombosis, anticoagulation should be continued long term
D. In patients with provoked first venous thrombosis, therapy should be continued for a duration recommended for patients without APS according to international guidelines. Longer anticoagulation could be considered in patients with high-risk aPL profile in repeated measurements or other risk factors for recurrence
5. In patients with definite APS and recurrent venous thrombosis despite treatment with VKA with target INR of 2–3:
A. Investigation of, and education on, adherence to VKA treatment, along with frequent INR testing, should be considered
B. If the target INR of 2–3 had been achieved, addition of LDA, increase of INR target to 3–4 or change to LMWH may be considered
6. In patients with definite APS and first arterial thrombosis:
A. Treatment with VKA is recommended over treatment with LDA only
B. Treatment with VKA with INR 2–3 or INR 3–4 is recommended, considering the individual’s risk of bleeding and recurrent thrombosis. Treatment with VKA with INR 2–3 plus LDA may also be considered
C. Rivaroxaban should not be used in patients with triple aPL positivity and arterial events. Based on the current evidence, we do not recommend use of DOACs in patients with definite APS and arterial events due to the high risk of recurrent thrombosis
7. In patients with recurrent arterial thrombosis despite adequate treatment with VKA, after evaluating for other potential causes, an increase of INR target to 3–4, addition of LDA or switch to LMWH can be considered
8. In women with a high-risk aPL profile but no history of thrombosis or pregnancy complications (with or without SLE), treatment with LDA (75–100 mg daily) during pregnancy should be considered
9. In women with a history of obstetric APS only (no prior thrombotic events), with or without SLE:
A. With a history of ≥3 recurrent spontaneous miscarriages <10th week of gestation and in those with a history of fetal loss (≥10th week of gestation), combination treatment with LDA and heparin at prophylactic dosage during pregnancy is recommended
B. With a history of delivery <34 weeks of gestation due to eclampsia or severe pre-eclampsia or due to recognised features of placental insufficiency, treatment with LDA or LDA and heparin at prophylactic dosage is recommended considering the individual’s risk profile
C. With clinical ‘non-criteria’ obstetric APS such as a the presence of two recurrent spontaneous miscarriages <10th week of gestation, or delivery ≥34 weeks of gestation due to severe pre-eclampsia or eclampsia, treatment with LDA alone or in combination with heparin might be considered based on the individual’s risk profile
D. With obstetric APS treated with prophylactic dose heparin during pregnancy, continuation of heparin at prophylactic dose for 6 weeks after delivery should be considered to reduce the risk of maternal thrombosis )
10. In women with ‘criteria’ obstetric APS with recurrent pregnancy complications despite combination treatment with LDA and heparin at prophylactic dosage, increasing heparin dose to therapeutic dose or addition of HCQ or low-dose prednisolone in the first trimester may be considered. Use of intravenous immunoglobulin might be considered in highly selected cases
11. In women with a history of thrombotic APS, combination treatment of LDA and heparin at therapeutic dosage during pregnancy is recommended
12. A. Prompt treatment of infections by early use of anti-infective medications in all aPL-positive individuals and minimisation of interruptions in anticoagulation or low INR level in patients with thrombotic APS are recommended to prevent the development of CAPS
B. For first-line treatment of patients with CAPS, combination therapy with glucocorticoids, heparin and plasma exchange or intravenous immunoglobulins is recommended over single agents or other combinations of therapies. Additionally, any triggering factor (eg, infections, gangrene or malignancy) should be treated
In patients with refractory CAPS, B cell depletion (eg, rituximab) or complement inhibition (eg, eculizumab) therapies may be considered .