Antiphospholipid syndrome (APS) is a systemic autoimmune disorder manifesting as venous and/or arterial thrombosis or obstetric complications, secondary to elevated production of antiphospholipid antibodies (aPL).
APS can occur in a primary form (primary APS, PAPS), in combination with other autoimmune diseases such as systemic lupus erythematosus (SLE) or in the rare, fulminant, form of catastrophic APS (CAPS) leading to multiorgan failure. The three types of aPL included in the most recent classification criteria for APS are the anticardiolipin (aCL) and anti-beta2 glycoprotein (anti-β2GPI) antibodies, as well as the lupus anticoagulant (LA).1
Due to the rarity of the syndrome, its wide clinical spectrum involving several thrombotic and pregnancy morbidity complications, and the lack of high-quality, randomised clinical trials, the formulation of guidelines for the management of APS has been both a dire necessity and a difficult task.
EULAR recommendations for the management of APS in adults were developed to address this issue, aiming to provide evidence-based recommendations for APS stemming from a combination of expert opinion and a systematic review of the relevant literature.
A task force comprised of specialists from 11 European countries tackled four pivotal questions regarding the prevention and treatment of different forms of APS. These were risk stratification and modification in asymptomatic individuals with positive aPL; primary and secondary prevention of thrombosis in APS; management of obstetric APS; and CAPS treatment.2
The qualitative and quantitative characterisation of aPL such as their type, single-, double- or triple-positivity, titre, and persistence of positivity in repeat measurements formulate the ‘aPL profile’. Stratification of patients into those having low- and high-risk aPL profiles is considered as one of the main pillars on which the varying recommendations are based.
High-risk aPL profile was defined as the presence of LA or double or triple aPL positivity (any combination of the three aPL or all three aPL) or of high aPL titres. Isolated aCL or anti-β2GPI antibodies at low-medium titres, particularly if transiently positive, are defined as low-risk aPL. Proposed risk attenuation measures are comprised of lifestyle modifications, emphasising the importance of treatment adherence and eliminating cardiovascular and venous thrombosis risk factors.2
As far as pharmacological treatment of APS is concerned, different substances including low-dose aspirin (LDA), vitamin K antagonists (VKA), heparin, hydroxychloroquine (HCQ) or immunosuppressive agents can be used variably in accordance to each different clinical scenario.
Administration of LDA was recommended for asymptomatic aPL carriers, patients with SLE without history of thrombotic or obstetric APS, and non-pregnant women with prior obstetric APS, if high-risk aPL profiles are present. Patients with first unprovoked venous thrombosis should receive VKA with a target international normalised ratio (INR) of 2–3, while in those with first arterial thrombosis VKA treatment of a target INR of 2–3 or 3–4 can be considered, according to each individual bleeding/thrombosis risk. In patients with recurrent thrombotic events despite an appropriate treatment, either adding LDA to the treatment regimen, increasing the target INR to 3–4 or using low molecular weight heparin are effective alternatives.2,3
Based on current evidence from the recent TRAPS randomised controlled trial that showed a higher percentage of thrombotic relapses in APS patients with triple aPL positivity treated with rivaroxaban versus those treated with warfarin,4 use of rivaroxaban is not recommended in patients with a history of vascular thrombosis and triple aPL positivity, especially in those with arterial thrombosis history. New evidence from ongoing trials on direct oral anticoagulants is anticipated that will help to better understand their efficacy and safety in thrombotic APS.
In pregnant women with a history of foetal loss after the 10th week, or delivery before the 34 weeks of gestation due to eclampsia or severe pre-eclampsia or placental insufficiency, a prophylactic dose of heparin should be considered in conjunction with LDA. In women with recurring pregnancy complications despite a combination treatment with prophylactic dose heparin and low dose aspirin, therapeutic dose of heparin plus LDA, or add-on therapy with either HCQ or low-dose prednisone during the first trimester, are appropriate treatment options.2,3 First-line treatment of CAPS includes a combination therapy with glucocorticoids, heparin and plasma exchange or intravenous immunoglobulins.
Following the formulation of the current recommendations for APS in adults, an emerging need for more high-quality studies is evident. To this end, a plan in the form of a research agenda has been drafted by the task force, underlining the main points on which future studies should be focused.
Further clarification of the pathogenetic mechanisms of APS along with studies focusing on how the different phenotypes of the syndrome may respond to various treatment types are necessary in order to facilitate the expansion and improvement of the current recommendations so as to achieve better quality of care for individuals with APS.
Author
Maria Tektonidou MD PhD
Associate professor of rheumatology, head of the Rheumatology Unit, First Department of Propaedeutic Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Greece
References
- Miyakis S, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–306.
- Tektonidou MG et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis May 2019:annrheumdis-2019-215213.
- Tektonidou MG et al. Management of thrombotic and obstetric antiphospholipid syndrome: a systematic literature review informing the EULAR recommendations for the management of antiphospholipid syndrome in adults. RMD Open 2019;5:e000924.
- Pengo V et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood 2018;132:1365–71.
