Antiphospholipid syndrome, also known as ‘Hughes Syndrome’, is an autoimmune disease characterised by a set of clinical manifestations, almost all of which are direct or indirect sequelae of a hypercoagulable state involving the venous, and to a lesser extent the arterial vasculature. The incidence and prevalence of antiphospholipid syndrome are estimated at approximately 5 de novo cases per 100 000 per year and 40–50 cases per 100 000 individuals, respectively. The clinical spectrum of antiphospholipid syndrome involves haematological (thrombocytopaenia, venous thrombosis), obstetrical (recurrent pregnancy loss), neurological (stroke, transient ischaemic attack, migraine, seizures, cognitive dysfunction, chorea, transverse myelitis, multiple sclerosis), cardiovascular (cardiac valve disease), dermatological (livedo reticularis and racemosa, skin ulceration and necrosis), renal (glomerulonephritis, renal thrombotic microangiopathy) and orthopaedic (avascular necrosis of bones, non-traumatic fractures) manifestations, among others. In addition to the classical antiphospholipid antibodies, namely anticardiolipin antibodies and lupus anticoagulant, new autoantibodies and antibody complexes of different immunoglobulin subtypes (IgA, IgG, IgM) are now recognised as significant contributors to the pathogenesis of antiphospholipid syndrome. Anticoagulation remains the cornerstone in the management of antiphospholipid syndrome; nevertheless, new drugs and therapeutic strategies are being tested, and some have been found effective for the primary and secondary thromboprophylaxis in antiphospholipid syndrome.
- antiphospholipid syndrome
- antiphospholipid antibodies
- catastrophic APS
- obstetric APS
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The literature on antiphospholipid syndrome (APS) has been undergoing an exponential growth since its first description in 19831 (initially known as anticardiolipin syndrome). Several case reports and series of patients with recurrent spontaneous miscarriages, thromboembolic events and positive serology were documented before 1983 and prepared the ground for the discovery of APS.2–5 The original description of APS included a clinical triad of recurrent miscarriages, central nervous system disease and recurrent deep venous thrombosis (DVT) in patients with systemic lupus erythematosus (SLE) with seropositive anticardiolipin antibodies (aCL) and lupus anticoagulant (LAC).1 Since then, numerous clinical manifestations and laboratory findings have been consistently added to the list of classification and non-classification criteria of the disease. International, large-scale epidemiological studies6 and clinical trials7 8 provided evidence-based knowledge about APS. Many meetings, workshops and symposia were organised, most notably the Sapporo workshop in 19989 and the Sydney workshop in 2004,10 which culminated in an international consensus on the classification criteria of APS. Recently, the enthusiasm and commitment of APS experts have led to the establishment of the APS Alliance for Clinical Trials and International Networking (APS ACTION), the primary goal of which is to further the understanding and management of the disease.11
Clinical presentation of APS
APS has an expanding range of clinical manifestations. Although up to 5% of the population might be positive for antiphospholipid antibodies (aPL),12 only a small fraction are diagnosed with APS. On the other hand, aPL prevalence rates in non-APS patients with stroke, myocardial infarction, DVT and pregnancy morbidity are much higher, reaching 13%, 11%, 9.5% and 6%, respectively.13
Thrombosis and pregnancy morbidity are the two hallmarks of APS.14 Although venous thromboembolism is the most frequent manifestation, thrombotic events in APS may also occur in virtually any vascular bed, with the cerebral circulation being the arterial territory most commonly affected, usually in the form of stroke or transient ischaemic attacks. The most common obstetrical manifestation of APS is recurrent early miscarriage, usually before 10 weeks of gestation (WG). Placental insufficiency in later gestation periods, manifested as fetal growth restriction, early (<34 WG) pre-eclampsia and fetal death, is characteristic of APS, and its occurrence should prompt the evaluation of the mother for the presence of aPL.
APS has been associated with many other clinical features,15 most of them, though not all, with a putative thrombotic pathogenetic substrate. These include, livedo reticularis, epilepsy, heart valve lesions or thrombocytopaenia, among others. The most severe and fortunately infrequent form of APS is the so-called catastrophic APS (CAPS), characterised by widespread small vessel thrombosis with multiorgan failure and high associated mortality.16 Boxes 1 and 2 depict the criteria and extra-criteria clinical manifestations of APS, respectively.
A comprehensive list of organ system-based, criteria clinical manifestations of antiphospholipid syndrome
Criteria clinical manifestations of the antiphospholipid syndrome.
Cerebral venous thrombosis
Transient ischaemic attack
Retinal artery/vein thrombosis
Nasal septum ischaemia/perforation
≥1 unexplained fetal* death ≥10 WG
≥1 premature birth* at or <34 WG due to:
Severe placental insufficiency
≥3 unexplained consecutive spontaneous abortions† at or <10 WG
Pulmonary artery thrombosis
Hepatic vein thrombosis
Renal artery/vein thrombosis
Arterial/Venous thrombosis (upper extremity)
Arterial thrombosis (lower extremity)
Deep vein thrombosis
Jugular vein thrombosis
Subclavian vein thrombosis
Superficial venous thrombosis/thrombophlebitis
*Confirmed normal morphology.
†Absence of maternal anatomical/hormonal and maternal/paternal chromosomal abnormalities.
‡Any other vessel is at risk of developing thrombotic disease.
ENT, ear, nose and throat; WG, weeks of gestation.
A comprehensive list of organ system-based, extra-criteria clinical manifestations of antiphospholipid syndrome
Extra-criteria clinical manifestations of the antiphospholipid syndrome.
Cognitive dysfunction (in the absence of cerebral thrombosis)
Epilepsy and seizures
Multiple sclerosis-like lesions
Sensorineural hearing loss
Cardiac valve disease
Late premature birth
3 non-consecutive miscarriages
2 unexplained miscarriages
≥2 unexplained in vitro fertilisation failures
Alveolitis with alveolar haemorrhage
Skin ulceration and necrosis
Arterial stenosis (renal, coeliac, cerebral and so on)
Avascular necrosis of bone
Bone marrow necrosis
Laboratory presentation of APS
The documentation of aPL positivity has been an essential component in the APS diagnostic—not only classification—approach for patients who are suspected to have the disease. aCL, LAC and anti-β2 glycoprotein-I antibody (anti-β2GPI) should test repeatedly positive at medium-to-high titres. During the last decade, a huge body of basic and clinical research on this topic unveiled several novel autoantibodies,17 of which the exact role in APS pathogenesis and significance in clinical risk assessment are not clearly elucidated yet. Many new antibodies have been proposed so far; antidomain I β2GPI (anti-β2GPI DI) and anticomplex phosphatidylserine-prothrombin (anti-PS/PT) are the two most promising to become clinically relevant aPL.18 Moreover, while aPL positivity has always been critical to diagnose APS, a new entity—seronegative APS (SNAPS)—was introduced in 2003.19 Patient candidates for the diagnosis of SNAPS show several clinical manifestations suggestive of APS, with persistently negative aCL, anti-β2GPI and LAC, but not for the extra-criteria aPL. It has been shown in a recent study that around one-third of such patients are seropositive to at least one alternative aPL, including anti-PS/PT in 12% of patients but not anti-β2GPI DI, which was however positive in 27% of ‘seropositive’ patients.20 Another small series tested 40 patients with APS meeting the clinical and serological criteria (group 1) for five extra-criteria aPL, namely IgG, IgM and IgA anti-β2GPI DI, IgA aCL and IgA anti-β2GPI, and compared the results with another group of patients meeting the clinical but not the serological criteria for APS (group 2). Interestingly, 62.5% of patients in group 1 were positive for at least one extra-criteria aPL, whereas 10% of group 2 were positive for one of the extra-criteria aPL. Specifically, three patients (7.5%) were positive for IgG anti-β2GPI DI and one patient (2.5%) was positive for IgA anti-β2GPI.21 The authors in this study defined the normal cut-off value of IgG anti-β2GPI DI as 10 absorbance units (AU); however, the positive values were actually borderline (16 AU, 15.3 AU and 22.2 AU) and may not be taken for granted as positive values since these new assays, including IgA anti-β2GPI, are still used as research kits and normal cut-off values are yet to be defined.22 Noteworthy, a much higher prevalence of anti-β2GPI DI is reported in patients with seropositive APS (45.4%),23 and domain I seems to be much more prevalent (66%) compared with other domains (IV/V) of anti-β2GPI (22%).24 Intriguingly, it seems that the anti-β2GPI epitope specificity profile (domain I vs domain IV/V) may predict future APS complications. Higher risk of recurrence of vascular and obstetrical APS was found to be associated with anti-β2GPI DI23 25 26 but not as much with domain IV/V,24 26 and a ratio of antidomain I to antidomain IV/V of more than or equal to 1.5 was found to be predictive of systemic autoimmunity.24
aPL: from disease markers to risk assessment
In an attempt to assess the risk of developing the clinical manifestations related to vascular thrombosis and pregnancy morbidity in patients with APS, the first Risk Scale for the diagnosis of APS was proposed in 2011.27 The study was successful in pointing out that triple aPL positivity substantially increases the risk of APS, and LAC is more strongly associated with APS diagnosis compared with other aPL.27 This pilot model was followed by the Antiphospholipid Score model, which is calculated by a formula based on the relative risk or OR of having clinical manifestations of APS for different aPL testing methods.28 While these two models were solely based on aPL as disease markers, a quantitative model, the Global APS Score, was developed to account for other independent, yet significant conventional cardiovascular risk factors that are related to thrombosis and pregnancy morbidity, namely hyperlipidaemia and arterial hypertension.29 As for long-term survival and quality of life of patients with APS, a new disease-specific cumulative damage index in patients with thrombotic APS has been proposed to evaluate principal APS manifestations that are associated with a worse prognosis and organ damage.30
The management of APS has been in continuous evolution over the last 30 years. Over this time, we have learnt that a number of different variables, such as the aPL profile (number of different positive antibodies, serum levels of aPL and persistence of positivity over time), the site of thrombosis (arterial vs venous vs small vessel disease) and the concurrence of additional cardiovascular risk factors, may substantially modify the clinical profile and thus the occurrence of both first and recurrent thrombosis. The last consensus guidelines were published back in 2011, after the 13th International Congress on aPL, held in Galveston in 2010.31 Updated consensus recommendations by the European League Against Rheumatism Task Force are now under way. The current trend is to design tailored treatment strategies taking into account individual risk assessments.32 Figure 1 depicts a management plan for persistently aPL-positive patients.
Despite the lack of appropriate studies addressing its efficacy, cardiovascular risk control is considered the necessary background to any pharmacological—primary or secondary—thromboprophylaxis.31 Low-dose aspirin (LDA) at 75–100 mg/day is recommended in high-risk, aPL-positive patients31 and was proven to have similar efficacy, although safer, compared with a combination primary thromboprophylactic regimen of LDA and low-intensity warfarin.33 The results of a recent meta-analysis including 11 observational studies reinforce the role of LDA as a preventive therapy in asymptomatic aPL-positive individuals (HR: 0.50; 95% CI 0.27 to 0.93); the effect was significant for arterial thrombosis (HR: 0.48; 95% CI 0.28 to 0.82) and borderline for venous thrombosis (HR: 0.58; 95% CI 0.32 to 1.06). Significant risk reductions were seen among asymptomatic aPL carriers, patients with SLE and women with obstetrical APS.34 A second meta-analysis using individual patient-level data, including 5 of the above 11 cohorts, confirmed the global protective role of LDA against thrombosis (HR: 0.43; 95% CI 0.25 to 0.75). Similar effects were seen after adjustment for gender, age, centre, presence of cardiovascular risk factors, type of aPL and treatment with hydroxychloroquine (HCQ). Furthermore, the risk reduction was the same (0.43) for patients with and without SLE.35 The role of HCQ in preventing thrombosis has been shown in several studies involving patients with lupus with and without aPL.36 37
Therefore, primary thromboprophylaxis with LDA is recommended for asymptomatic individuals and women with purely obstetrical APS with high-risk aPL profile, particularly in the presence of cardiovascular risk factors. HCQ is the primary prophylactic agent in patients with SLE, in whom the addition of LDA should be considered in patients with persistently positive aPL, more so in those triple-positive and with cardiovascular risk factors. Also, preventive measures including thromboprophylaxis with low molecular weight heparin (LMWH) should be taken in high-risk individuals such as postsurgical, postpartum and immobilised patients.
The initial management of thrombotic events in patients with APS is frequently similar to the general population until persistent aPL has been demonstrated. According to current recommendations, patients with venous thromboembolism are best treated with standard-intensity oral anticoagulation at a target international normalised ratio (INR) of 2.0–3.0.31 The duration of anticoagulation, however, has been a subject of debate; some authors have suggested 3–6 months of anticoagulation in patients with a first venous thromboembolic event who are known to have a transient/reversible precipitating factor and in whom aPL becomes negative over time.38 However, recent data in 241 patients with a first unprovoked venous thromboembolism have shown a borderline significantly increased risk for recurrent events after stopping anticoagulant therapy in those with aPL (HR: 1.8; 95% CI 0.9 to 3.6).39 Compared with aPL-negative patients, the rates of recurrence further increased in patients with the same type of positive aPL on the two occasions tested (HR: 2.7; 95% CI 1.1 to 6.7) and in patients with two or three types of aPL on the same or different occasions (HR: 4.5; 95% CI 1.5 to 13.0). The increased risk of recurrence was independent of the results of the D-dimer test. Thus, these results support long-term anticoagulation after a first episode of venous thromboembolism in patients with persistently positive aPL.
For patients with APS and arterial thrombosis, the Galveston guidelines recommended either high-intensity anticoagulation at a target INR of 3.0–4.0 or combined therapy with LDA plus anticoagulation at a target INR of 2.0–3.0.31 However, the degree of agreement on this specific point was low. New data on this topic come from a recent retrospective study by Jackson et al 40 on 139 patients with APS from the cohorts of the New York Presbyterian Hospital and APS ACTION presenting with arterial thrombosis. The authors found that dual therapy with LDA plus anticoagulation (most of them at an INR of 2.0–3.0) decreased the rate of recurrent events: 6.9% compared with 23.7% and 37.2% on anticoagulant and antiplatelet therapy alone, respectively; and increased the time to recurrence of thrombosis: 16.3 years compared with 7.3 and 3.4 years on anticoagulant and antiplatelet therapy alone, respectively.40 These data support the use of dual anticoagulant and antiplatelet therapy in this controversial setting.
Therefore, patients with APS presenting with venous thromboembolism and persistent aPL should receive long-term oral anticoagulation at a target INR of 2.0–3.0; for those presenting with arterial events, oral anticoagulation at a target INR of 3.0–4.0 or combined therapy with LDA plus oral anticoagulation at a target INR of 2.0–3.0 are our preferred treatment options.
Direct oral anticoagulants and other drugs
Long-term anticoagulation with direct oral anticoagulants (DOACs) such as direct factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) and direct thrombin inhibitors (dabigatran) offers some advantages compared with anticoagulation with vitamin K antagonists in terms of a better drug–drug interaction profile, a fixed dosing protocol without the need for blood level monitoring and a narrow therapeutic range. The US Food and Drug Administration and the European Medicines Agency have approved DOACs for thromboprophylaxis and treatment of several venous thromboembolic diseases including DVT and pulmonary embolism.41–44 The recently published Rivaroxaban in APS study showed that thrombin generation markers are not increased with rivaroxaban compared with warfarin in patients with APS who had previous venous thromboembolism. Taking also into account the absence of clinically significant bleeding, the study concluded that rivaroxaban could be efficacious and safe in this subgroup of patients with APS.7 Nevertheless, the study results cannot be extrapolated to patients with APS with arterial or venous thrombosis who require higher intensity anticoagulation, according to the authors. The Rivaroxaban in Thrombotic APS is a multicentre, randomised, controlled, open-label study, non-inferiority trial comparing rivaroxaban (20 mg/day) with warfarin (INR 2.5) with respect to cumulative incident, arterial or venous, thrombosis in patients with triple aPL positivity. After randomising 59 patients to the rivaroxaban arm and 61 patients to the warfarin arm, the study was terminated due to occurrence of more events in the rivaroxaban group; thromboembolic events and major bleeding occurred in 12% and 7% in the rivaroxaban arm compared with 0% and 3% in the warfarin arm, respectively. Noteworthy, seven arterial events were documented in the rivaroxaban group versus none in the warfarin group.45 Another study, the Rivaroxaban in APS Pilot Feasibility Study (ClinicalTrials.gov: NCT02116036), prospectively follows patients with definite APS with known history of venous thromboembolism, with or without arterial thrombosis, on rivaroxaban (20 mg/day) for thrombosis (minor, major or fatal bleeding) as a secondary endpoint. Seventy-nine patients were identified and will be followed for 1 year, and no thrombotic events have occurred until now, although an unexplained hepatitis occurred in one patient. The Apixaban for Secondary Thrombosis Prevention in APS study is a phase IV pilot, prospective, open-label, randomised, blinded trial studying the efficacy and safety of apixaban (2.5 mg twice a day; then increased to 5 mg twice a day based on a recommendation by the data safety monitoring board (DSMB)) compared with warfarin (INR 2.0–3.0) in secondary thromboprophylaxis in patients with history of APS. After the enrolment of 30 patients, the DSMB re-evaluated the data and recommended to exclude patients with prior arterial thrombosis and to perform brain MRI for all candidates to exclude prior silent stroke.46 A recent study by Malec and colleagues47 revealed a 6% risk of recurrent venous thromboembolism in patients with APS treated with DOACs, the data of which were dissected by Yazici et al,48 who interpreted the results in the opposite way and argued for following the recommendations of the APS Treatment Trends Task Force.49 50 The role of DOACs in the management of thrombotic APS manifestations is still not clear, and there are concerns regarding their role in arterial thrombosis. The recent 15th International Congress on aPL Task Force on Treatment Trends states that there is insufficient evidence to make recommendations at this time regarding the use of DOACs in APS.49
Preliminary studies on statins (fluvastatin; 20 mg and 40 mg per day for 1 and 3 months, respectively) showed benefit in preventing thrombus formation in patients with APS,51 52 but their current use in the treatment of APS is limited to patients with hyperlipidaemia. The 15th International Congress on aPL Task Force on Treatment Trends suggested that statins may be used in patients with APS with high risk for cardiovascular events and in those with recurrent thrombosis despite adequate anticoagulation.49
Patients with immune-mediated thrombocytopaenia (platelet count less than 20 ×10^9/L) and haemolytic anaemia may benefit from glucocorticoids with or without intravenous immunoglobulins as first-line treatment, whereas azathioprine, cyclophosphamide and mycophenolate mofetil may be used as second-line therapies.53
Several other drugs such as B-cell inhibitors (rituximab and belimumab) and other immunosuppressants, intravenous immunoglobulins, corticosteroids, complement inhibitors (eculizumab), integrin inhibitors, adenosine 2A receptor agonists (defibrotide), cilostazol, protease activator receptor (Par) antagonists, Toll-like receptor antagonists and tissue factor inhibitors are still under investigation for their potential benefit in the APS therapeutic plan.8 22 49 50 54–57 In particular, aPL/β2GPI receptor blockers may have a future role in the management of refractory obstetrical APS. 1N11 monoclonal antibodies can inhibit the binding of β2GPI to its receptors on the trophoblast surface.58 In the same context, non-complement fixing antibodies (CH-2 deleted antibody)59 and synthetic peptides (TIFI)60 can also target β2GPI domains I and V, respectively, thus preventing the binding of aPL and β2GPI.
More preclinical studies and controlled trials are needed to elucidate the true role of these novel therapies in the management of APS.
The 15th International Congress on aPL Task Force on Treatment Trends suggested that the mammalian target of rapamycin inhibitors may have a role in the treatment of aPL-positive patients with microthrombosis, and clopidogrel (or other adenosine diphosphate (ADP) P2Y12 receptor antagonists) can be considered as an adjunctive therapy in some patients with APS with arterial thrombosis refractory to conventional treatment.49
CAPS is an acute to subacute, severe life-threatening variant of APS, characterised by rapid onset of systemic, multiple organs small vessel thromboses, which may lead to dysfunction, and often failure, of the involved organs if not diagnosed early and managed promptly. Three criteria must be met for a definite diagnosis, based on the preliminary CAPS criteria initially proposed by Asherson et al 61 in 2003: (1) aPL positivity, (2) multisystem organ dysfunction/failure during a 1-week period and (3) histopathological confirmation of small vessel occlusion. The pathophysiology of CAPS is not clearly defined yet; however, some authors hypothesise that a precipitating factor, including but not limited to surgery and infections, may cause an acute endothelial injury, which initiates a cycle of cytokine overproduction and systemic inflammatory responses, ultimately leading to large-scale microangiopathy and small vessel thromboses.16 62 Although CAPS is very rare occurring in less than 1% of patients with APS,6 the treatment must be initiated as soon as possible to overcome the high mortality (up to 48%16) associated with CAPS.
The 14th International Congress on aPL Task Force report on CAPS recommended the use of triple therapy, a combination of full-dose anticoagulation, high-dose glucocorticoids and plasma exchange; intravenous immunoglobulins and cyclophosphamide may be added to the regimen in the presence of an infection and concomitant autoimmune disease such as SLE, respectively.63 Rituximab may be used as an initial adjuvant therapy if microangiopathic haemolytic anaemia is present, as an alternative adjuvant therapy when anticoagulation is contraindicated, or as a second-line therapy in refractory cases.8 63 The recent 15th International Congress on aPL Task Force on CAPS highlighted the effectiveness of adding eculizumab to standard triple therapy with or without thrombotic microangiopathy. The Task Force group also stressed on the importance of choosing the best steroid dose and tapering schedule, the best replacement fluid during plasma exchange, and the best therapeutic dose and time to administer intravenous immunoglobulins, and discussed the role of rituximab and new anticoagulants in the management of CAPS.64
Preconception planning in women with APS should include complete profiling of aPL using standardised tests, and these patients may benefit from long-term, preconceptional aspirin, which may increase the likelihood of pregnancy and embryo implantation, favourable fetal outcomes, as well as achieving successful live births in >70% of pregnancies.65 66 Dual antiplatelet and anticoagulation therapy is generally recommended in pregnant patients with APS, although some patients with recurrent early miscarriages (<10 WG) may benefit from LDA alone. Due to their teratogenicity, oral anticoagulants must be stopped as early as possible on confirmation of pregnancy (within the first 6 WG) and replaced with LDA plus LMWH at prophylactic or therapeutic doses in women without and with history of thrombotic events, respectively50 67 (figure 1). During the postpartum period, women who do not have risk factors for thrombosis and who did not receive antenatal thromboprophylaxis may benefit from LMWH for 7-10 days only; if additional risk factors for thrombosis are present or if women were treated with LMWH during pregnancy, thromboprophylaxis should be extended to 6 weeks.65
For women with refractory obstetrical APS, several alternatives have been proposed based on observational case series: HCQ,68 69 prednisone 10 mg/day up to week 14,70 pravastatin 20 mg/day in cases of severe placental insufficiency with pre-eclampsia as soon as the complication is detected,71 and intravenous immunoglobulins (2 g/kg per month) and/or plasma exchange.69 72 In our opinion, the latter is only recommended in patients with severe thrombotic APS and very selected cases of obstetrical APS.
Over the last 35 years, APS has been recognised as a major, treatable condition in obstetrical medicine, neurology, cardiology, rheumatology and in most other branches of medicine. The recognition of the many non-thrombotic manifestations of APS has added to the importance of separating APS diagnosis from classification. Patients with strong clinical features suggestive of APS but with negative standard tests—the so-called ‘Seronegative’ APS—are now being identified using non-criteria laboratory tests, and the role of extra-criteria aPL is being investigated. The current treatment of APS is still largely confined to aspirin, clopidogrel, heparin and warfarin. The introduction of DOACs in the treatment of APS has been predictably cautious, and it is too early to generalise.
Handling editor Josef S Smolen
Contributors IU, MHAN, GR-I, MK: planning, write-up and critical revision.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
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