Write a short note on antiphospholipid antibody syndrome.

Definition

Antiphospholipid antibody syndrome (APS) is an autoimmune prothrombotic disorder characterised by arterial and/or venous thrombosis and/or pregnancy morbidity, in the presence of persistently positive antiphospholipid antibodies. It is the commonest acquired cause of thrombophilia.

• Primary APS — occurring alone (about half of cases).
• Secondary APS — associated with an underlying autoimmune disease, most often SLE (present in 30–40% of lupus patients).

Pathogenesis

Antibodies are directed principally against beta-2 glycoprotein I bound to phospholipid, rather than against phospholipid itself. They promote thrombosis by activating endothelial cells, platelets and monocytes, upregulating tissue factor, inhibiting the protein C pathway and annexin A5 shield, and activating complement. In pregnancy they also cause defective trophoblast invasion and placental thrombosis.

Clinical Features

Thrombotic:

• Venous: deep vein thrombosis (commonest manifestation), pulmonary embolism, and thrombosis at unusual sites — cerebral venous sinus, hepatic (Budd–Chiari), portal, renal, retinal.
• Arterial: stroke and transient ischaemic attack in a young patient — a classic presentation, myocardial infarction, limb and mesenteric ischaemia.
• Recurrent thrombosis despite anticoagulation should always raise the possibility.

Obstetric:

• Three or more unexplained consecutive miscarriages before 10 weeks
• One or more fetal deaths after 10 weeks with a morphologically normal fetus
• Premature birth before 34 weeks due to severe pre-eclampsia, eclampsia or placental insufficiency

Non-criteria (but clinically important):

• Livedo reticularis — a mottled, net-like violaceous discoloration, and the commonest skin sign
• Thrombocytopenia (usually mild) and autoimmune haemolytic anaemia
• Libman–Sacks endocarditis with valve thickening and vegetations
• Nephropathy, migraine, cognitive dysfunction, chorea, transverse myelitis, avascular necrosis, and leg ulcers

Catastrophic APS (CAPS) — a rare, fulminant variant with multi-organ thrombosis affecting three or more organs within a week, with microthrombi on histology. Mortality approaches 50%; it is often precipitated by infection, surgery or anticoagulant withdrawal.

Investigations

Three antibody tests, and the timing rule matters:

1. Lupus anticoagulant — a functional clotting assay. It prolongs the aPTT in vitro, which fails to correct with mixing studies but corrects with added phospholipid. The name is a misnomer: in vivo it causes thrombosis, not bleeding.

2. Anticardiolipin antibodies — IgG and IgM, at medium or high titre.

3. Anti-beta-2 glycoprotein I antibodies — IgG and IgM.

Antibodies must be positive on two occasions at least 12 weeks apart to exclude transient positivity from infection, malignancy or drugs. "Triple positivity" (all three tests positive) carries the highest thrombotic risk.

Other findings: prolonged aPTT with a normal PT, thrombocytopenia, false-positive VDRL/RPR for syphilis (a classic clue), and positive ANA in secondary APS.

Management

• Thrombosis: lifelong warfarin after a first venous event, with the INR target set by event type and risk; warfarin with low-dose aspirin is often used after arterial events. Heparin is used for initial treatment and in pregnancy.
• Direct oral anticoagulants (DOACs) are NOT recommended, particularly in triple-positive patients and after arterial events, because trials demonstrated higher rates of recurrent thrombosis compared with warfarin.
• Pregnancy: low-dose aspirin plus prophylactic low-molecular-weight heparin substantially improves live birth rates. Warfarin is teratogenic and must be stopped before or in early pregnancy. Manage jointly with an obstetrician in a high-risk clinic.
• Asymptomatic antibody carriers: no routine anticoagulation; low-dose aspirin may be considered where risk is high (triple positivity, coexisting SLE), together with aggressive control of conventional cardiovascular risk factors.
• Hydroxychloroquine in SLE-associated APS — independently antithrombotic.
• Thromboprophylaxis at times of high risk — surgery, immobilisation, long travel, puerperium.
• Catastrophic APS: combined anticoagulation, high-dose corticosteroids, plasma exchange and/or intravenous immunoglobulin, with treatment of the precipitating trigger; rituximab or eculizumab in refractory cases.