Antiphospholipid Syndrome

Synonyms: APS, Lupus anticoagulant, Hughes' syndrome, sticky blood

Antiphospholipid syndrome (APS) alters the homeostatic regulation of blood leading to hypercoagulability and recurrent thrombosis which can affect virtually any organ system:¹

• The cause of APS is not known. Although antiphospholipid (aPL) antibodies are clinically linked to APS, it is not known whether they are involved in pathogenesis (up to 5% of healthy individuals have aPL antibodies).
• Proposed mechanisms for the hypercoagulable effect of aPL antibodies includes 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.

APS is diagnosed when arterial or venous thrombosis, or recurrent miscarriage occurs in a person in whom laboratory tests for antiphospholipid antibody (aCL, LA or both) are positive.^2,3

• There may be lupus anticoagulant (LA), moderate to high levels of anticardiolipin (aCL) or both.
• APS has been traditionally called primary if there is no clinical or serological evidence of an autoimmune disorder.
• In patients with recognised autoimmune disorders, usually systemic lupus erythematosus (SLE), APS has been called secondary.
• There is little clinical or biochemical difference between primary and secondary except that those with secondary disease are more likely to have endocarditis, valve disease and haemolytic anaemia.⁴
• A recent international consensus statement and update on the criteria for APS suggested that the distinction of primary and secondary was not helpful and that the interface between antiphospholipid syndrome (APS), systemic lupus erythematosus (SLE) and lupus-like disease (LLD) needs further consideration.⁵

• In SLE, 35 to 40% have anti-phospholipid antibodies (aPL) but they are found in 1-5% of the healthy population. Anti-cardiolipin antibodies (aCL) occur more frequently in the elderly.
• 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 to middle-aged adults but it can present in children and elderly people. The condition accounts for about 20% of recurrent thrombosis in young people and 15% of cases of recurrent fetal loss.
• There is a familial association in some cases of APS, with apparently increased risk associated with HLA DR7, DR4, DQw7 and DRw53.

• Systemic lupus erythematosus
• Rheumatoid arthritis
• Systemic sclerosis
• Behcet's syndrome
• Temporal arteritis
• Sjogren's syndrome
• Psoriatic arthropathy

Other clinical associations with antiphospholipid antibodies

• Infections, including acute self-limiting and chronic infections, e.g. 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
• Guillain-Barre syndrome

APS has varied clinical features and a range of autoantibodies. Virtually any system can be affected, including:¹

• Peripheral artery thrombosis, deep venous thrombosis
• Cerebrovascular disease, sinus thrombosis
• Thrombocytopenia (despite the lupus anticoagulant and thrombocytopenia, the risk in APS is of thrombosis rather than haemorrhage), haemolytic anaemia
• Pregnancy loss:
  • There may be a history of recurrent fetal loss, usually in the late 2nd or 3rd trimester but can be much earlier.
  • Early 1st trimester loss is not associated with APS.⁶
  • Late loss of a morphologically normal fetus is usually due to placental infarction and should lead to tests for APS.
• Eclampsia, intrauterine growth retardation
• Pulmonary embolism, pulmonary hypertension
• Livedo reticularis (persistent violaceous, red or blue pattern of the skin of trunk, arms or legs; it does not disappear on warming and may consist of regular broken or unbroken circles), purpura, skin ulceration
• 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 renal failure
• Adrenal infarction
• Avascular necrosis of bone

• The American College of Rheumatology proposed preliminary clinical classification criteria at Sapporo in 1999 but these were updated in Sydney in 2006.⁵
• At least 1 clinical criterion and 1 laboratory criterion must be present for a patient to be classified as having APS.
• The laboratory results should be found at least 12 weeks after the clinical event; otherwise the event may produce a false positive result.

Clinical criteria

Clinical criteria fall into two groups:

• Vascular thrombosis:
  • There must be one or more episodes of arterial, venous or small vessel thrombosis in any tissue or organ.
  • Objective criteria must be used to make the diagnosis. This includes imaging and histopathology but for the latter, there should be no significant evidence of inflammation of the vessel wall.
• Pregnancy morbidity: either,
  • One of more unexplained deaths of a morphologically normal fetus at the 10th week of gestation or beyond. This should be confirmed by ultrasound or post mortem examination.
  • One or more premature births of a morphologically normal baby before the 34th week of gestation because of:
    • Severe pre-eclampsia or eclampsia, or
    • Placental insufficiency
  • Three or more unexplained consecutive spontaneous abortions with exclusion of gynaecological abnormalities or hormonal inadequacy as the cause and normal chromosomes in both parents.
  • Some patients may have features from more than one of these pregnancy criteria.

Laboratory criteria

• Laboratory criteria have three components:
  • Lupus anticoagulant; this should be found in plasma on at least 2 occasions at least 12 weeks apart.
  • Anticardiolipin antibody (aCL); the aCL antibody may be IgG or IgM. The titre should be medium or high being at least 40 GPL or MPL or above the 99th centile. This should be on two or more occasions at least 12 weeks apart.
  • Anti-β₂glycoprotein-I antibody; this can also be IgG or IgM and in a titre above the 99th centile on two or more occasions at least 12 weeks apart.
  Some authors feel that the need to have just one clinical and one laboratory criterion to make the diagnosis is too lax and results in excessive diagnosis. At the same time there is a problem of those who do not fulfil the criteria but who have other features that are associated with the disease.
• Other laboratory features include IgA aCL, IgA anti-β₂GPI, antiphosphophatidylserine antibodies (aPE), antibodies against prothrombin (aPT-A) and antibodies to the Anti-β₂glycoprotein-I antibody/anti-prothrombin (aPS/PT) complex.

• For diagnosis, patients must have medium to high levels of IgG or IgM anticardiolipin (aCL), anti–beta-2 glycoprotein I or lupus anticoagulant (LA) on at least 2 occasions at least 12 weeks apart.
• Full blood count; thrombocytopaenia, haemolytic anaemia.
• Clotting screen.
• CT scanning or MRI of the brain (CVA), 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.

This depends upon 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 strokes can produce a picture resembling multiple sclerosis.⁷

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

Management of thrombosis

• Acute management of arterial or venous thrombosis is the same as with other patients with similar problems. They should receive heparin (1000 units/h).³
• Prophylactic treatment should be long-term after venous thrombosis since patients with APS are liable to recurrent thrombosis.³
• In one study the presence of aCL in those who had suffered a DVT increased the rate of recurrence in the next 4 years from 14% to 29% and the risk of mortality from 6% to 15%.⁸
• Anticoagulation with warfarin with an INR of 2.0-3.0 reduces the risk of recurrent venous thrombosis by 80% to 90% and may be effective for preventing recurrent arterial thrombosis. For patients with a single positive antiphospholipid antibody test result and prior stroke, aspirin and warfarin appear equally effective for preventing recurrent stroke.⁹
• In cases in which thrombosis continues despite adequate anticoagulation, high doses of corticosteroids, plasmapheresis to remove antibodies and cyclophosphamide have been used in addition to anticoagulation.¹⁰
• Valvular heart disease may require surgery.

Recurrent pregnancy loss

• Management of women during pregnancy is controversial but a Cochrane review found that combined unfractionated heparin and aspirin may reduce pregnancy loss by 54%.¹¹
• Subcutaneous heparin (5000-15000 units) twice daily prophylaxis is recommended.
• A comparison of 4 groups, (1) prednisolone and low dose aspirin, (2) heparin and low does aspirin, (3) all three and (4) other combinations including immunoglobulin, showed little difference in outcomes.¹²
• Another trial¹³ found that heparin plus low dose aspirin was significantly better than aspirin alone.
• Another study compared low dose heparin with prednisolone 40 mg daily, both groups also receiving low dose aspirin. The outcome was similar in both groups except that the prednisolone group had a higher incidence of pre-term delivery and maternal morbidity.¹⁴

• APS may produce stroke in young individuals. It is usually thrombotic but it can 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 antiphospholipid syndrome (CAPS) is a serious and often fatal manifestation characterised by multiple organ infarctions over a period of days to weeks. It occurs in less than 1% of patients¹⁵ 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).¹⁶

• 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.