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Antiphospholipid syndrome: diagnosis and management

Dr Anisur Rahman and Dr Salma Ahmed discuss the diagnosis and management of antiphospholipid syndrome (APS).

Antiphospholipid syndrome (APS) is one of the most common non-inherited causes of thrombophilia. It is estimated to affect up to 1 in 100 people. APS is an autoimmune disease in which the immune system malfunctions, causing the production of pathogenic autoantibodies. These antiphospholipid antibodies interact with the clotting system, blood vessel walls and the uterus in pregnancy.

The main clinical features of the syndrome are venous or arterial thromboses and pregnancy morbidity, including early and late miscarriage and pre-eclampsia. However, it is important to be aware that patients with APS may suffer other, more chronic symptoms even when not pregnant and not suffering thrombosis. Such symptoms include fatigue, migraine, joint pain and rash.

APS can occur on its own, separate from any other disease (primary APS) or with another autoimmune disease, most commonly systemic lupus erythematosus (SLE).

Diagnosis

Primary care physicians should consider requesting antiphospholipid antibody tests in the following groups.

  • Patients with recurrent thrombosis
  • Patients with unprovoked large thrombosis and no obvious risk factors.
  • People under 50 with thrombotic stroke.
  • Women with a second trimester miscarriage.
  • Women with repeated first trimester miscarriages.
  • Women with repeated complications in late pregnancy.
  • Any patient with SLE who suffers clot, stroke or miscarriage.

A positive test in any of these groups suggests a likely diagnosis of APS and the patient should be referred to a specialist.

The three tests in common clinical use are:

  • Anti-cardiolipin antibody test – this assesses the presence of two types of antibody (IgG and IgM) that can bind to cardiolipin, a type of phospholipid. Results are given as a number in GPL units or MPL units. Values greater than 40 GPLU or MPLU are considered high.
  • Anti-beta-2-glycoprotein I test - this tests for the IgG and IgM that can bind to beta-2-glycoprotein I, a protein that is linked to phospholipids in the body. This test is usually not available to GPs. Results are given as a number – higher levels mean more risk of clotting.
  • The lupus anticoagulant test – despite the name, this is not a test for lupus. Results are given as either positive or negative. The test evaluates antiphospholipid antibodies (aPL), which interfere with clotting of the blood. Interestingly, the effect of these aPL in the laboratory is to make the blood clot more slowly whereas in the body the same aPL stimulate increased clotting. The important part to remember is that a patient with a positive lupus anticoagulant test has an increased risk of developing clots or miscarriages.

The risk of clotting is higher in patients for whom two or three of these tests are positive than in those in whom only one test is positive.

Interpreting results

APS can only be diagnosed if the patient’s blood tests positive for aPL on at least two occasions, at least 12 weeks apart.1 Two positive tests are required as transient positivity can occur after some infections. However, the tests are difficult to interpret and not all patients who test positive have the disease. Thus the diagnosis of APS should only be made by a specialist (usually a haematologist or rheumatologist).

At least 5% of the normal healthy population will be positive in one of the three aforementioned tests, and will suffer no adverse effects from those antibodies. In other words, positive aPL alone does not warrant a diagnosis of APS.

This means that it is important not to request these tests unless there is a good clinical reason. In this way, aPL tests are similar to anti-nuclear antibody and rheumatoid factor tests, which can also be positive in healthy people.

APS can be diagnosed in a person who has repeatedly positive tests, and has had at least one thrombosis or one or more late miscarriages or three or more successive first trimester miscarriages.1 A person who has a positive test but has not had thrombosis or miscarriage does not have APS but is at risk of developing it. People who are repeatedly positive in two or more of these tests or who have very high levels of anti-cardiolipin or anti-beta-2-glycoprotein I are at higher risk of developing APS.

Treatment

In many patients with APS, drug therapy aims to reduce the chance of a potentially serious outcome such as a stroke or the loss of a pregnancy. Thus specialists may be balancing side-effects of drugs given to a currently asymptomatic patient against the importance of preventing such outcomes. There are three different groups that need treatment.

Patients with APS and previous thrombosis

These patients are at high risk of further thrombosis. The only evidence-based treatment that prevents recurrent thrombosis is long-term anticoagulation.2 It is commonly difficult to maintain the target INR in patients with APS and they may need very high doses of warfarin and frequent monitoring of INR in an anti-coagulation clinic. Recently, new oral anticoagulants such as rivaroxaban (a direct Factor X inhibitor) are being used instead of warfarin in patients with APS.3 Patients on rivaroxaban do not need monitoring of INR and may experience fewer drug interactions.

Patients who have no thrombosis but suffer miscarriage or pregnancy complications (pure obstetric APS)

Warfarin cannot be used in pregnancy. Where a patient with APS has suffered adverse pregnancy outcomes previously, it is important for her to be referred to a specialist pregnancy clinic, preferably with haematology input. The standard management is daily low dose aspirin and daily subcutaneous low molecular weight heparin throughout the pregnancy.4 This results in a live birth rate of 70%+, though these mothers may still suffer late pregnancy complications such as pre-eclampsia and intra-uterine growth retardation. Opinions about whether anticoagulation is necessary following the birth are divided but many consultants would keep the heparin going for six weeks to prevent post-partum thrombosis. Long-term anticoagulation between pregnancies is not indicated in pure obstetric APS.

Patients with positive aPL but no history of thrombosis or pregnancy problems

There is no evidence base supporting primary prophylaxis in these patients. It is important to remember to avoid pro-thrombotic risk factors as much as possible – advise patients not to smoke, to avoid oestrogen-containing contraceptives, and to keep moving on long flights. Many of these patients are put onto low dose aspirin but, in general, anticoagulation is not considered justifiable.

Alternative medications

Steroids and immunosuppressant medications are not used in APS. They may be given to patients who have SLE as well as APS. Hydroxychloroquine may be beneficial in reducing symptoms such as fatigue and joint pain in some patients with APS but does not prevent clots or miscarriages.

  • Dr Anisur Rahman is a Professor of rheumatology at University College London
  • Dr Salma Ahmed is a GP in Tower Hamlets, London

Patient resources

APS Support UK

References

  1. 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;4(2):295-306.
  2. Lim W, Crowther MA, Eikelboom JW. Management of antiphospholipid antibody syndrome: a systematic review. JAMA 2006;295(9):1050-7.
  3. Cohen H, Hunt BJ, Efthymiou M, et al. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol 2016;3(9):e426-36.
  4. Mak A, Cheung MW, Cheak AA, et al. Combination of heparin and aspirin is superior to aspirin alone in enhancing live births in patients with recurrent pregnancy loss and positive anti-phospholipid antibodies: a meta-analysis of randomized controlled trials and meta-regression. Rheumatology (Oxford) 2010;49(2):281-8.
Key learning points
  • There are three different tests for antiphospholipid antibodies (aPL). One or more can be positive in up to 5% of healthy people.
  • A positive aPL test does not mean a person has APS.
  • APS can be diagnosed when a patient has persistently positive aPL and either thrombosis, stroke or pregnancy morbidity.
  • To prevent recurrent thrombosis in patients with APS, long-term anticoagulation is necessary; warfarin has been the standard of care but rivaroxaban is sometimes used.
  • In pregnancy, daily aspirin and daily subcutaneous heparin raise the live birth rate to 70%
  • All patients with APS should be managed in conjunction with secondary care specialists.
  • There is currently no convincing evidence for primary prophylaxis with drugs in aPL-positive patients who do not have APS.

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