Antiphospholipid syndrome

Antiphospholipid syndrome (APS or APLS) or antiphospholipid antibody syndrome is a disorder of coagulation, which causes blood clots (thrombosis) in both arteries and veins, as well as pregnancy-related complications such as miscarriage, preterm delivery, or severe preeclampsia. The syndrome occurs due to the autoimmune production of antibodies against phospholipid (aPL), a cell membrane substance. In particular, the disease is characterised by antibodies against cardiolipin (anti-cardiolipin antibodies) and β2 glycoprotein I.

The term "primary antiphospholipid syndrome" is used when APS occurs in the absence of any other related disease. APS is commonly seen in conjunction with other autoimmune diseases; the term "secondary antiphospholipid syndrome" is used when APS coexists with other diseases such as systemic lupus erythematosus (SLE). In rare cases, APS leads to rapid organ failure due to generalised thrombosis and a high risk of death; this is termed "catastrophic antiphospholipid syndrome".

Antiphospholipid syndrome is sometimes referred to as Hughes syndrome after the rheumatologist Dr. Graham R.V. Hughes (St. Thomas' Hospital, London, UK) who worked at the Louise Coote Lupus Unit at St Thomas' Hospital in London.

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Signs and symptoms

The presence of antiphospholipid antibodies (aPL) in the absence of blood clots or pregnancy-related complications does not indicate APS (see below for the diagnosis of APS).

Antiphosphilipid syndrome can cause (arterial/venous) blood clots (in any organ system) or pregnancy-related complications (especially miscarriage in the second or third trimester). In APS patients, the most common venous event is deep vein thrombosis of the lower extremities (blood clot of the deep veins of the legs) and the most common arterial event is stroke.

Other common findings, although not part of the APS Classification Criteria, are thrombocytopenia (low platelet count), heart valve disease, and livedo reticularis (a skin condition). Some patients report headaches and migraines. Antiphospholipid syndrome can rarely mimic multiple sclerosis with an estimated 10% of patients misdiagnosed.

Very few patients with primary APS go on to develop SLE.

Diagnosis

Antiphospholipid syndrome is tested for in the laboratory using both liquid phase coagulation assays (lupus anticoagulant) and solid phase ELISA assays (anti-cardiolipin antibodies).

Genetic thrombophilia is part of the differential diagnosis of APS and can coexist in some APS patients. Thus genetic thrombophilia screening can consist of:

• Further studies for Factor V Leiden variant and the prothrombin mutation, Factor VIII levels, MTHFR mutation.
• Levels of protein C, free and total protein S, Factor VIII, antithrombin, plasminogen, tissue plasminogen activator (TPA) and plasminogen activator inhibitor-1 (PAI-1)

The testing of antibodies to the possible individual targets of aPL such as β₂ Glycoprotein 1 and antiphosphatidyl serine is currently under debate as testing for anticardiolipin appears to be currently sensitive and specific for diagnosis of APS even though cardiolipin is not considered an invivo target for antiphospholipid antibodies.

Lupus anticoagulant

This is tested for by using a minimum of two coagulation tests that are phospholipid sensitive this is due to the heterogeneous nature of the lupus anticoagulant antibodies. The patient on initial screening will typically have been found to have a prolonged APTT that does not correct in an 80:20 mixture with normal human plasma (50:50 mixes with normal plasma are insensitive to all but the highest antibody levels). The APTT (plus 80:20 mix), dilute Russell's viper venom time (DRVVT), the kaolin clotting time (KCT), dilute thromboplastin time {TDT/DTT) or Prothrombin time (using a lupus sensitive thromboplastin) are the principal tests used for the detection of lupus anticoagulant. These tests must be carried out on a minimum of two occasions at least 6 weeks apart and be positive on each occasion demonstrating persistent positivity to allow a diagnosis of antiphospholipid syndrome. This is to prevent patients with transient positive tests (due to infection etc) being diagnosed as positive.

Distinguishing a lupus antibody from a specific coagulation factor inhibitor (eg: Factor VIII). This is normally achieved by differentiating the effects of a lupus anticoagulant on factor assays from the effects of a specific coagulation factor antibody. The lupus anticoagulant will inhibit all the contact activation pathway antibodies (Factor VIII, Factor IX, Factor XI and Factor XII). Lupus anticoagulant will also rarely cause a factor assay to give a result lower than 35 iudl (35%) where as a specific factor antibody will rarely give a result higher than 10iudl (10%). Monitoring IV anticoagulant therapy by the APTR is compromised due to the effects of the lupus anticoagulant and in these situations is generally best performed using a chromogenic assay based on the inhibition of Factor Xa by Antithrombin in the presence of Heparin.

Anticardiolipin antibodies

These can be detected using an enzyme-linked immunosorbent assay (ELISA) immunological test, which screens for the presence of β₂glycoprotein 1 dependent anticardiolipin antibodies (ACA).

A Low platelet count and positivity for antibodies against β₂-glycoprotein 1 or phosphatidylserine may also be observed in a positive diagnosis.

Criteria

The diagnosis of APS is made in case of a clinical event (vascular thrombosis or pregnancy event) and repeated positive tests of aPL performed 12 weeks apart (repeat aPL testing is necessary due to the naturally occurring presence of transient low levels of aPL following infections).

The Updated Sapporo APS Classification Criteria are commonly used for APS diagnosis.^[1] Based on these criteria, APS diagnosis requires:

• a) Vascular Thrombosis (blood clots) in any organ or tissue or Pregnancy Event (one or more miscarriages after 10th week of gestation, three or more miscarriages before 10th week of gestation, or one or more premature births before 34th week of gestation due to eclampsia) and
• b) Persistenly (12 weeks apart) Positive aPL (lupus anticoagulant test, moderate-to-high titer anticardiolipin antibodies, or moderate-to-high titer β₂-glycoprotein-I antibodies).

The International Consensus Statement is commonly used for Catastrophic APS diagnosis.^[2] Based on this statement, Definite CAPS diagnosis requires:

• a) Vascular Thrombosis in three or more organs or tissues and
• b) Development of manifestations simultaneously or in less than a week 'and
• c) Evidence of small vessel thrombosis in at least one organ or tissue and
• d) Laboratory confirmation of the presence of aPL.

Some serological tests for syphilis may be positive in aPL-positive patients (aPL bind to the lipids in the test and make it come out positive) although the more specific tests for syphilis that use recombinant antigens will be negative.

Pathogenesis

Antiphospholipid syndrome is an autoimmune disease, in which "antiphospholipid antibodies" (Anticardiolipin antibodies and Lupus anticoagulant) react against proteins that bind to anionic phospholipids on plasma membranes. Like many autoimmune diseases, it is more common in women than in men. The exact cause is not known, but activation of the system of coagulation is evident. Clinically important antiphospholipid antibodies (those that arise as a result of the autoimmune process) are associated with thrombosis and vascular disease. The syndrome can be divided into primary (no underlying disease state) and secondary (in association with an underlying disease state) forms. The main target of anti-cardiolipin antibodies is apolipoprotein H (commonly referred to as β₂Glycoprotein 1) and the main target of Lupus anticoagulant is prothrombin. Other targets of anti-phospholipid antibodies are protein S, protein C and annexin A5.

The Lupus anticoagulant antibodies are those that show the closest association with thrombosis, those that target β₂glycoprotein 1 have a greater association with thrombosis than those that target prothrombin. Anticardiolipin antibodies are associated with thrombosis at moderate to high titres (>40 GPLU or MPLU). Patients with both Lupus anticoagulant antibodies and moderate/high titre anticardiolipin antibodies show a greater risk of thrombosis than with one alone.

Treatment

Often, this disease is treated by giving aspirin to inhibit platelet activation, and/or Warfarin as an anticoagulant. The goal of the prophylactic treatment is to maintain the patient's INR between 3.0–4.0.^[3] It is not usually done in patients who have not had any thrombotic symptoms. During pregnancy, low molecular weight heparin and low-dose aspirin are used instead of Warfarin because of Warfarin's teratogenicity.

Women with recurrent miscarriage are often advised to take aspirin and to start low molecular weight heparin treatment after missing a period. This is the most effective treatment at the moment.

References

1. ^ Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295-306)
2. ^ Asherson RA, Cervera R, de Groot PG, et al (2003). "Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines". Lupus 12 (7): 530-4. PMID 12892393.
3. ^ Horton JD, Bushwick BM (1999). "Warfarin therapy: evolving strategies in anticoagulation". American family physician 59 (3): 635-46. PMID 10029789.

Further reading

• Triona Holden. "Positive Options for Antiphospholipid Antibody Syndrome" ISBN 0-89793-409-1.
• Kay Thackray. Sticky Blood. ISBN 1-898030-77-4. A personal account of dealing with the condition.

Resources

• APS Foundation of America, Inc.
• APS Friends & Support Forum
• Rare Thrombotic Diseases Consortium (RTDC)
• Lupus Patients Understanding & Support
• Lupus UK
• Women's health
• Louise Gergel Fellowship - Charity funding research into Hughes Syndrome
• Hughes Syndrome Foundation
• Association with pregnancy loss
• The London Lupus Centre
• Antiphospholipid.net: Information for patients and doctors, update on research and congresses

Congresses and Events

• 12th International Congress on Antiphospholipid Antibodies
• Conference for patients
• 6th Meeting of the European Forum on Antiphospholipid Antibodies