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

Pathogenesis

• The cause of antiphospholipid syndrome (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 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.

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

• There may be LA, moderate-to-high levels of aCL or both.
• APS was first described in systemic lupus erythematosus (SLE), but it was also recognised as a primary APS (PAPS) form. These forms are not always distinguishable, since they show some common clinical/serological manifestations.⁴ The patients may initially be classified as PAPS and gradually develop SLE, or have SLE and associated APS (whose complications generally affect morbidity and mortality) or have SLE and positive aPL antibodies without APS manifestations.

Epidemiology¹

• In systemic lupus erythematosus (SLE) 35-40% have antiphospholipid (aPL) antibodies but they are found in 1-5% of the healthy population. Anticardiolipin (aCL) antibodies occur more frequently in the elderly.
• There is a higher prevalence in black people. A female predominance reflects the association of antiphospholipid syndrome (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.

Antiphospholipid syndrome in rheumatic and connective tissue disorders³

• Systemic lupus erythematosus (SLE)
• Rheumatoid arthritis
• Systemic sclerosis
• Behçet's disease
• Temporal arteritis
• Sjögren's syndrome
• Psoriatic arthropathy

Other clinical associations with aPL 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 or Sneddon's syndrome.
• Guillain-Barré syndrome.

Presentation

Antiphospholipid 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 (LA) 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 at any gestation. 1st trimester loss is associated with APS.⁵
  • Late loss of a morphologically normal fetus is usually due to placental infarction and should also lead to tests for APS.
• Pre-eclampsia, intrauterine growth restriction.
• 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 kidney disease.
• Adrenal infarction.
• Avascular necrosis of bone.

Diagnostic criteria

• The American College of Rheumatology proposed preliminary clinical classification criteria at Sapporo in 1999 but these were updated in Sydney in 2006.⁶
• At least 1 clinical criterion and 1 laboratory criterion must be present for a patient to be classified as having antiphospholipid syndrome (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:
  • 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 postmortem 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 with 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 (LA):
    This should be found in plasma on at least 2 occasions at least 12 weeks apart.
  • Anticardiolipin (aCL) antibody:
    The aCL antibody may be immunoglobulin G (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-beta₂ glycoprotein I (GPI) 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-beta₂ GPI, antiphosphophatidylserine (aPS) antibodies, antibodies against prothrombin (aPT-A) and antibodies to the anti-beta₂ GPI antibody/antiphosphatidylserine-prothrombin (aPS/PT) complex.

Investigations¹

• For diagnosis, patients must have medium-to-high levels of IgG or IgM anticardiolipin (aCL), anti-beta₂ GPI or lupus anticoagulant (LA) on at least 2 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 sclerosis.⁷

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.

Management of thrombosis

• 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).³
• Prophylactic treatment should be long-term after venous thrombosis since patients with antiphospholipid syndrome (APS) are liable to recurrent thrombosis.³
• 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 (aPL) antibody test result and prior stroke, aspirin and warfarin appear equally effective for preventing recurrent stroke.⁸
• 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.⁹
• Valvular heart disease may require surgery.

Improving outcomes in pregnancy

In women with aPL antibodies and recurrent miscarriage with no history of thrombosis, consensus guidelines recommend low-dose aspirin in combination with prophylactic or intermediate-dose unfractionated heparin or prophylactic dose low molecular weight heparin, administered antenatally.^10,11 The evidence is significant for unfractionated heparin and aspirin, but further controlled trials are required for low molecular weight heparin plus aspirin.¹²

Complications

• Antiphospholipid syndrome (APS) may produce cerebrovascular event 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 patients¹³ 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).¹⁴

Prognosis

• 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.

Document references

1. Belilos E et al; Antiphospholipid Syndrome, eMedicine, Aug 2009
2. Love PE, Santoro SA; Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. Ann Intern Med. 1990 May 1;112(9):682-98. [abstract]
3. Guidelines for the investigation and management of antiphospholipid syndrome, British Committee for Standards in Haematology (2000)
4. Tincani A, Andreoli L, Chighizola C, et al; The interplay between the antiphospholipid syndrome and systemic lupus Autoimmunity. 2009 May;42(4):257-9. [abstract]
5. Rai R, Regan L; Recurrent miscarriage. Lancet. 2006 Aug 12;368(9535):601-11. [abstract]
6. Miyakis S, Lockshin MD, Atsumi T, et al; International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006 Feb;4(2):295-306. [abstract]
7. IJdo JW, Conti-Kelly AM, Greco P, et al; Anti-phospholipid antibodies in patients with multiple sclerosis and MS-like illnesses: MS or APS? Lupus. 1999;8(2):109-15. [abstract]
8. Lim W, Crowther MA, Eikelboom JW; Management of antiphospholipid antibody syndrome: a systematic review. JAMA. 2006 Mar 1;295(9):1050-7. [abstract]
9. Otsubo S, Nitta K, Yumura W, et al; Antiphospholipid syndrome treated with prednisolone, cyclophosphamide and double-filtration plasmapheresis. Intern Med. 2002 Sep;41(9):725-9. [abstract]
10. Lim W; Antiphospholipid antibody syndrome. Hematology Am Soc Hematol Educ Program. 2009:233-9. [abstract]
11. The investigation and treatment of couples with recurrent miscarriage, Royal College of Obstetricians and Gynaecologists (RCOG), 2003
12. Ziakas PD, Pavlou M, Voulgarelis M; Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: a Obstet Gynecol. 2010 Jun;115(6):1256-62. [abstract]
13. Cervera R, Piette JC, Font J, et al; Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 2002 Apr;46(4):1019-27. [abstract]
14. Asherson RA, Cervera R, de Groot PG, et al; Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus. 2003;12(7):530-4. [abstract]

Acknowledgements