Antiphospholipid syndrome

Synonyms: lupus anticoagulant, Hughes' syndrome, sticky blood

Antiphospholipid syndrome (APS) is an autoimmune disorder characterised by arterial and venous thrombosis, adverse pregnancy outcomes (for mother and fetus), and raised levels of antiphospholipid (aPL) antibodies¹.

Pathogenesis

• The cause of APS is not known. Although aPL antibodies are clinically linked to APS, it is not known whether they are involved in pathogenesis, as up to 5% of healthy individuals have aPL antibodies.

• Proposed mechanisms for the hypercoagulable effect of aPL antibodies include complement activation, the production of antibodies against coagulation factors (including prothrombin, protein C, protein S), activation of platelets, activation of vascular endothelium and a reaction of antibodies to oxidised low-density lipoprotein.

Diagnostic criteria

The aPL antibody syndrome is present if at least one of the clinical criteria and one of the laboratory criteria are present²³.

Clinical criteria

• Vascular thrombosis: one or more episodes of arterial, venous or small vessel thrombosis.

• Pregnancy morbidity: at least one unexplained death of a normal-appearance fetus at or beyond the 10th week of gestation; at least one preterm birth of a neonate of normal appearance before 34 weeks of gestation, because of eclampsia or severe pre-eclampsia or with signs of placental insufficiency; three or more unexplained consecutive spontaneous miscarriages before 10 weeks of gestation where anatomical, hormonal and chromosomal causes have been excluded.

Laboratory criteria

• Lupus anticoagulant (LA) is present on two or more occasions at least 12 weeks apart.

• Anticardiolipin (aCL) antibody is present in serum or plasma, in medium or high titre (ie ≥40 GPL units or MPL units or ≥99th centile), on two or more occasions at least 12 weeks apart.

• Anti-b2-glycoprotein I antibody in serum or plasma (in titre ≥99th centile) is present, on two or more occasions, at least 12 weeks apart.

Epidemiology

• In systemic lupus erythematosus (SLE) 30% have aPL antibodies¹.

• They are also found in 1-5% of the healthy population. In the elderly, aCL antibodies occur more frequently.

• There is a higher prevalence in black people. A female predominance reflects the association of APS with SLE and other connective tissue diseases, which also have a female predominance.

• APS occurs most commonly in young women of fertile age - male:female 1:3.5.

• The condition accounts for about 20% of recurrent thrombosis in young people and 15% of cases of recurrent fetal loss⁴.

• There is a familial association in some cases of APS, with apparently increased risk associated with HLA DR7, DR4, DQw7 and DRw53.

Associated disorders

APS may be found secondary to several inflammatory or autoimmune conditions:

• SLE.

• Rheumatoid arthritis.

• Systemic sclerosis.

• Behçet's disease.

• Giant cell arteritis.

• Sjögren's syndrome.

• Psoriatic arthropathy.

Other clinical associations

aPL antibodies are also found in association with:

• Infections, including acute self-limiting and chronic infections - eg, HIV, varicella, hepatitis C, syphilis, malaria.

• Lymphoproliferative diseases: malignant lymphoma, paraproteinaemias.

• Drug exposure: phenothiazines, phenytoin, hydralazine.

• Autoimmune thrombocytopenia.

• Autoimmune haemolytic anaemia.

• Sickle cell disease.

• Intravenous drug abuse.

• Livedo reticularis or Sneddon's syndrome.

• Guillain-Barré syndrome.

Presentation

APS has varied clinical features and a range of autoantibodies. Virtually any system can be affected, including¹⁴⁵:

• Peripheral artery thrombosis, deep venous thrombosis.

• Cerebrovascular disease, sinus thrombosis.

• Pregnancy loss: loss at any gestation - recurrent miscarriage or prematurity can be seen in APS.

• Pre-eclampsia, intrauterine growth restriction (IUGR).

• Pulmonary embolism, pulmonary hypertension.

• Livedo reticularis (persistent violaceous, red or blue pattern of the skin of the trunk, arms or legs; it does not disappear on warming and may consist of regular broken or unbroken circles), purpura, skin ulceration.

• Thrombocytopenia, haemolytic anaemia.

• Libman-Sacks endocarditis and cardiac valve disease:
  

  • Usually mitral valve disease or aortic valve disease and usually regurgitation with or without stenosis.

  • Mild mitral regurgitation is very common and is often found with no other pathology. There may also be vegetations on the heart and valves.

• Myocardial infarction.

• Retinal thrombosis.

• Nephropathy: vascular lesions of the kidneys may result in chronic kidney disease.

• Adrenal infarction.

• Avascular necrosis of bone.

Investigations

Young adults (≤50 years old) with ischaemic stroke and women with recurrent pregnancy loss (≥3 pregnancy losses) before 10 weeks of gestation should be screened for aPL antibodies³.

• Levels of aCL, anti-beta₂ GPI or lupus anticoagulant (LA) on two occasions at least 12 weeks apart.

• FBC; thrombocytopenia, haemolytic anaemia.

• Clotting screen.

• CT scanning or MRI of the brain (cerebrovascular accident), chest (pulmonary embolism) or abdomen (Budd-Chiari syndrome).

• Doppler ultrasound studies are recommended for possible detection of deep vein thrombosis.

• Two-dimensional echocardiography may demonstrate asymptomatic valve thickening, vegetations or valvular insufficiency.

Differential diagnosis

This depends on the clinical features:

• If thrombosis predominates, other procoagulation states such as protein C, protein S or antithrombin III deficiency, malignancy, oral contraceptives, nephrotic syndrome, polycythaemia, thrombocytosis, dysfibrinogenaemia, paroxysmal nocturnal haemoglobinuria and homocystinuria should be considered.

• In the case of pregnancy loss, exclude other causes of recurrent miscarriage.

• Recurrent small cerebrovascular events can produce a picture resembling multiple sclerosis⁶.

Management

A healthy lifestyle in line with prevention of cardiovascular disease is recommended:

• Avoid smoking.

• Take regular physical exercise.

• Maintain a healthy diet and avoid overweight/obesity.

• Avoid excessive alcohol intake.

• Adequate management of cardiovascular risk factors, including diabetes, hypertension and hyperlipidaemia.

Thrombosis management

• Acute management of arterial or venous thrombosis is the same as with other patients with similar problems. They should receive heparin (1,000 units/hour).

• Prophylactic treatment (warfarin or antiplatelet therapy) should be long-term after venous thrombosis since patients with APS are liable to recurrent thrombosis³.

• Anticoagulation with warfarin with an INR of 2.0-3.0 reduces the risk of recurrent venous thrombosis and may be effective for preventing recurrent arterial thrombosis².

• New oral anticoagulant drugs (NOACs) are not currently recommended⁷.

• Women who are on long-term warfarin (because of previous thrombosis) should switch to heparin when trying to conceive or on confirmation of conception⁸.

• In cases where thrombosis continues despite adequate anticoagulation, high doses of corticosteroids, plasmapheresis and rituximab have been used in addition to anticoagulation⁹.

• Valvular heart disease appears to increase the risk of thrombosis in APS and may require surgery.

Pregnancy outcomes

APS in pregnancy may affect both mother and fetus throughout the entire pregnancy and is associated with high morbidity. Clinical complications are variable and include recurrent miscarriage, stillbirth, IUGR and pre-eclampsia¹⁰.

• For women with APS with recurrent (≥3) pregnancy loss, antenatal administration of low molecular weight heparin combined with low-dose aspirin is recommended throughout pregnancy¹¹. Treatment should begin as soon as pregnancy is confirmed.

• For women with APS and a history of pre-eclampsia or IUGR, low-dose aspirin is recommended.

• Women with aPL antibodies should be considered for postpartum thromboprophylaxis³.

Complications

• APS may produce a cerebrovascular event in young individuals. It is usually thrombotic but it may be embolic from Libman-Sacks endocarditis.

• APS can also produce myocardial infarctions in young people.

• Cardiac valvular disease may be severe enough to require valve replacement. Recurrent pulmonary emboli or thrombosis can lead to life-threatening pulmonary hypertension.

• Catastrophic APS (CAPS) is a serious and often fatal manifestation characterised by multiple organ infarctions over a period of days to weeks¹¹². It occurs in less than 1% of patients but requires intensive treatment including anticoagulation (usually intravenous heparin followed by oral anticoagulants), corticosteroids, plasma exchange, intravenous gammaglobulins and cyclophosphamide (if associated with a lupus flare).

Prognosis¹³

• The severity of the problem varies considerably and prognosis is therefore very variable.

• It can cause catastrophic and potentially lethal problems like massive pulmonary embolism, stroke and myocardial infarction. Long-term anticoagulation seems to improve outcome.