Mark Goodfield1 and Shyamal Wahie2
1Department of Dermatology, Chapel Allerton Hospital, Leeds, UK
2University Hospital of North Durham, Durham, UK
The antiphospholipid syndrome (APLS) is an autoimmune disease with clinical features of thrombosis (venous, arterial and microvascular) and pregnancy complications, which include recurrent fetal loss, preterm delivery and placental insufficiency [1]. The condition is associated with a spectrum of autoantibodies directed against the cellular phospholipid component (hence the term ‘antiphospholipid antibodies’ or APA); most commonly: lupus anticoagulant, anticardiolipin and anti-β2-glycoprotein I (anti-B2GPI).
APLS is diagnosed in a patient with thrombosis and/or defined pregnancy morbidity in the presence of persistent APA. The term ‘primary APLS’ is used when the condition occurs in the absence of any other related disease. The term ‘secondary APLS’ is used when the condition occurs in the context of other autoimmune diseases, such as systemic lupus erythematosus (SLE).
The true prevalence of the syndrome is unclear [2]. In the general population, APA can be detected in about one in five patients who have had a stroke at less than 50 years of age [3]. About 40% of patients with SLE have APA [4] but less than 40% of them will eventually have thrombotic events [5, 6]. Approximately one in four patients with a venous thromboembolism, tested for thrombophilia, exhibit APA [7]. Approximately one in 10 women with recurrent miscarriage are diagnosed with APLS [8].
APLS is commonest in young to middle-aged adults; however, it also manifests in children and elderly people.
As with many autoimmune diseases, APLS is commoner in women than in men [9]. The apparent female preponderance may be related to the issue that recurrent pregnancy loss is a prominent feature of the disease and that early reported series of patients with APLS were often confined to those with SLE.
A number of racial populations have been reported with APLS including white people, Hispanics, Asians, Afro-Caribbeans and Native Americans [10].
Secondary APLS is associated with SLE and other autoimmune diseases such as rheumatoid arthritis, Sjögren syndrome and systemic sclerosis. The development of APA can occur with syphilis and hepatitis C.
Many mechanisms for thrombosis in APLS have been suggested, such as increased expression of tissue factor on monocytes and endothelial cells [11, 12], interference in the protein C anticoagulant pathway [13, 14], inhibition of fibrinolysis and inhibition of annexin V binding to phospholipids [15]. B2GPI (apolipoprotein H) is a cofactor required for APA to bind to cardiolipin [16]. These findings suggested that APA are directed against a complex antigen that includes B2GPI.
Hudson et al. found a possible linkage between the HLA-DRB1*14 allele on chromosome 6p21.3 and familial primary APLS [17]. A meta-analysis recently showed that the B2GPI Val/Leu(247) polymorphism was associated with susceptibility to APLS and thrombosis and with anti-B2GPI positivity (OR 1.514, 95% CI 1.017–1.253, P = 0.041) [18].
Patients have one or more clinical episodes of arterial, venous or small vessel thrombosis. Venous thrombosis in APLS is most commonly lower limb deep-vein thrombosis or pulmonary embolism but any part of the venous system may be involved, including superficial, portal, renal, mesenteric and intracranial veins [1]. The most frequent site of arterial thrombosis in APLS is in the cerebral vasculature resulting in transient cerebral ischaemia/stroke. Myocardial infarction is less common, although subclinical myocardial ischaemia may be underrecognized [19].
Pregnancy morbidity [1] consists of:
Cutaneous lesions include thrombophlebitis, purpura and ecchymoses, livedo reticularis, leg ulcers, cutaneous necrosis, gangrene and subungual splinter haemorrhages. Histologically, non-inflammatory thrombosis of small dermal blood vessels can be demonstrated, but necrotizing vasculitis is usually not a feature.
Other prothrombotic thrombophilias should be considered. Conditions presenting with thrombocytopenia and thrombosis include heparin-induced thrombocytopenia, thrombotic thrombocytopenic purpura and disseminated intravascular coagulation.
In addition to thrombosis and pregnancy morbidity, thrombocytopenia, occult heart valve disease, chorea, cognitive impairment, haemolytic anaemia and nephropathy are potential complications of APLS. Transverse myelopathy occurs in SLE and may be more frequent in those with APLS [20]. In rare cases, APLS leads to rapid multiorgan failure due to generalized microvascular thrombosis; this is termed ‘catastrophic APLS’ (CAPS) and is associated with a high risk of mortality.
The long-term prognosis of APLS is largely dictated by the risk and effects of recurrent thrombosis and any underlying autoimmune condition in those with secondary APLS. Those with primary APLS have a poor prognosis, with one-third having organ damage and one-fifth unable to perform everyday activities [21]. APLS may contribute to an increased frequency of strokes especially in younger individuals [22]. Strokes may develop secondary to in situ thrombosis or embolization that originates from the valvular lesions of Libman–Sacks (sterile) endocarditis, which may be seen in patients with APLS. Valvular heart disease may be severe enough to require valve replacement. Recurrent pulmonary emboli or thrombosis can lead to life-threatening pulmonary hypertension.
When testing for APLS is indicated, testing for lupus anticoagulant and for immunoglobulin G (IgG) and/or IgM antibodies to cardiolipin and/or B2GPI (via ELISA assays) should be performed. Medium or high titres (especially at or above the 99th percentile) are deemed significant positives [1]. Initial positive tests should be repeated to check for persistence at least 12 weeks later. This is to prevent patients with transient positive tests (due to infection, etc.) being diagnosed as having APLS. Testing for IgA antibodies is not recommended [1].
Those with lupus anticoagulant typically have been found to have a prolonged activated partial thromboplastin time (APTT) that does not correct in an 80 : 20 mixture with normal human plasma (50 : 50 mixes with normal plasma are insensitive to all but the highest antibody levels). The APTT (plus 80 : 20 mix), dilute Russell's viper venom time (DRVVT), the kaolin clotting time (KCT), dilute thromboplastin time (TDT/DTT) or prothrombin time (using a lupus-sensitive thromboplastin) are the principal tests used for the detection of lupus anticoagulant.
Treatment and prevention of thrombosis is a major goal of therapy. The presence of antibodies without any clinical features of APLS is not deemed to be an indication for long-term anticoagulation. However, in such patients, attention might be paid to modifiable risk factors such as smoking, obesity and diabetes. The use of low-dose aspirin in asymptomatic patients (as primary prophylaxis) has been advocated by some [1].
Anticoagulation is typically instituted in those who have APLS (i.e. those who have definite strong positive APA and have had a thrombosis). Most commonly, heparin or warfarin is used in non-pregnant individuals [23]. The target international normalized ratio (INR) for warfarin therapy in APLS is typically 2.5 (target range 2.0–3.0), though some have advocated higher target ranges of between 3.0 and 4.0 in patients with a prior arterial thrombosis and/or recurrent venous thromboses, as opposed to patients who have only had a single venous thrombosis [1]. For pregnant women with APLS and a history of recurrent fetal loss, close liaison with an obstetrician and haematologist is advised. Antenatal administration of heparin combined with low-dose aspirin throughout pregnancy may be advisable – warfarin is avoided because of teratogenicity. In general, treatment is often begun as soon as pregnancy is confirmed.