Antiphospholipid Syndrome

An autoimmune disorder characterised by recurrent arterial or venous thrombosis, or pregnancy morbidity, in the presence of persistently positive antiphospholipid antibodies. It occurs as a primary condition or secondary to another connective tissue disease, most often systemic lupus erythematosus, and is a leading acquired cause of recurrent pregnancy loss.

Pathophysiology

Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti beta 2 glycoprotein I) bind to phospholipid binding plasma proteins on cell surfaces, activating endothelium, platelets and the complement cascade, and interfering with natural anticoagulant pathways, producing a prothrombotic state affecting both arterial and venous circulations, along with placental vasculopathy that underlies the obstetric manifestations.

Catastrophic antiphospholipid syndrome

A rare, rapidly progressive and life threatening variant in which multiple organs suffer simultaneous microvascular thrombosis over days, often triggered by infection, surgery or anticoagulation withdrawal, carrying substantial mortality and requiring immediate aggressive multimodal treatment.

• Venous thromboembolism (deep vein thrombosis, pulmonary embolism) is the commonest manifestation, often recurrent and sometimes at unusual sites.

• Arterial thrombosis, particularly stroke and transient ischaemic attack in younger patients without conventional vascular risk factors, is a hallmark presentation warranting antiphospholipid testing.

• Obstetric morbidity comprises recurrent early miscarriage, one or more unexplained fetal deaths after ten weeks gestation, or premature birth due to severe preeclampsia, eclampsia or placental insufficiency.

• Livedo reticularis, thrombocytopenia (usually mild, not typically associated with bleeding), haemolytic anaemia, cardiac valve abnormalities (Libman Sacks endocarditis), and nephropathy from renal microvascular thrombosis are recognised associated features.

• Catastrophic antiphospholipid syndrome presents with rapid multiorgan failure over days, often with fever, encephalopathy, acute kidney injury, adult respiratory distress syndrome and cardiac involvement, and is a medical emergency.

Diagnosis requires at least one clinical criterion (vascular thrombosis or pregnancy morbidity) plus at least one laboratory criterion persistently positive on two occasions at least twelve weeks apart.

• Laboratory testing comprises lupus anticoagulant assay, anticardiolipin antibodies (IgG and IgM), and anti beta 2 glycoprotein I antibodies (IgG and IgM), with testing avoided during acute thrombosis or anticoagulation where possible given interference, and repeated at twelve weeks to confirm persistence and exclude transient positivity from infection or other causes.

• Triple positivity (all three antibody types positive) carries the highest thrombotic risk and informs decisions about treatment intensity and duration.

• Screen for underlying systemic lupus erythematosus and other connective tissue disease given the frequent association, with antinuclear antibody and complement testing.

• Imaging appropriate to the presenting thrombotic event (venous duplex, computed tomography pulmonary angiography, magnetic resonance imaging of the brain) as clinically indicated.

• Anticoagulation is the cornerstone of treatment for confirmed thrombotic antiphospholipid syndrome, typically with a vitamin K antagonist targeting an international normalised ratio of 2 to 3 for venous events, with higher intensity or the addition of aspirin considered for arterial events or recurrent thrombosis despite standard intensity anticoagulation.

• Direct oral anticoagulants are generally avoided in triple positive or high risk antiphospholipid syndrome given evidence of inferior efficacy compared with vitamin K antagonists in this population, particularly for arterial events.

• Duration of anticoagulation is indefinite in confirmed antiphospholipid syndrome with a thrombotic event, given the persistent underlying risk.

• Low dose aspirin plus prophylactic low molecular weight heparin during pregnancy is standard for women with obstetric antiphospholipid syndrome, substantially improving live birth rates, with therapeutic anticoagulation continued postpartum in those with a prior thrombotic event.

• Asymptomatic antiphospholipid antibody positivity without prior thrombosis or pregnancy morbidity does not routinely warrant anticoagulation, though low dose aspirin is often considered, particularly with additional risk factors or a lupus diagnosis.

• Catastrophic antiphospholipid syndrome requires immediate combination therapy with therapeutic anticoagulation, high dose corticosteroids, plasma exchange or intravenous immunoglobulin, and treatment of any precipitating trigger such as infection, managed in an intensive care setting given the high mortality.

• Address modifiable cardiovascular risk factors given their compounding effect on thrombotic risk, and provide clear counselling regarding the risks of oestrogen containing contraception and hormone therapy, which are generally avoided.