WHAT ARE ANTIPHOSPHOLIPID ANTIBODIES ?

Antibodies are proteins produced by white blood cells known as lymphocytes. We are all programmed to produce these antibodies which assist us in fighting foreign invaders, particularly viruses, bacteria etc. They form part of the "immune response ".which occurs normally when we are faced with a challenge. As we get older, some of us start to produce what is termed "autoantibodies", which are antibodies directed against our own tissues. The commonest of these is rheumatoid factor. Antibodies directed towards phospholipids which are ubiquitous, occurring as part of the envelope of many types of blood cells (mainly the platelets) as well as other proteins which are responsible for maintaining our blood in a fluid non-clotted state are formed in patients with certain "autoimmune" diseases such as Systemic Lupus Erythematosus (SLE) , accompanying other autoantibodies seen in this disease. They are also formed in patients who have a condition known as the "Primary" Antiphospholipid Syndrome who do not have SLE, as well as in other rheumatic diseases, infections, after certain drug ingestion and more uncommonly in patients with cancer and certain types of vasculitis.

WHAT DO THEY CAUSE ?

High levels of antiphospholipid antibodies are associated predominantly with clotting, affecting usually affecting the deep veins of the lower limbs, arteries of the brain, causing transient losses of consciousness (termed transient Ischaemic attacks) or strokes, limb arteries causing gangrene, heart attacks and miscarriages, because of clotting of placental vessels. The clotting may affect any large or small vessels in the body, and affect any organ. Since the discovery of the antiphospholipid antibodies, many existing syndromes and several new syndromes have been linked to their presence. The association of thrombosis, miscarriages and ,often a decrease in the blood platelets themselves has been termed "The Antiphospholipid Syndrome" These events are often recurrent and frequent and such patients may require energetic and longterm,sometimes lifelong therapy.

WHEN ARE THESE EVENTS LIKELY TO OCCUR ?

Clotting may occur at any time, but patients are at most risk when they are faced with situations which either slow the circulation (e.g. longhaul flying, prolonged bed rest) or at times when the normal mechanisms which ordinarily prevent clotting are disturbed. These times are during pregnancy,(and particularly during the 6 weeks following delivery, the puerperium),following particular surgical operations (e.g. hip replacement) or even biopsies (e.g. lung, kidney) .

WHICH PATIENTS ARE AT RISK ?

There are other patients, besides those with SLE or the "Primary Antiphospholipid Syndrome" who may also be at an increased at risk for clotting should they develop antiphospholipid antibodies. There are several groups of such patients: · Those patients who already have an inherited clotting disorder due to a deficiency of other proteins such as Protein C, S and Antithrombin C. · Patients with certain diseases such as increased fats in their blood e.g. high cholesterol or triglyceride levels, diabetes or patients with kidney disease who have developed what is known as a "nephrotic syndrome" where they lose excessive amounts of these essential proteins in their urine. · Obese patients, particularly if they are sedentary.

HOW DO DOCTORS TEST FOR ANTIPHOSPHOLIPID ANTIBODIES ?

Three major tests are now used by most laboratories.

Negativity in one test does not imply negativity in others and therefore the complete range of tests is now advised. These tests consist of : · Lupus Anticoagulant Test: This is done on plasma and the patient therefore has to present herself at the laboratory personally as the blood has to be spun to extract the plasma. Usually a modified Russel Viper Venom Test and the Kaolin Cephalin Thromboplastin Tests are used by most laboratories today. · Anticardiolipin Antibody Tests. these are measured by a procedure known as ELISA. here are three main classes of anticardiolipin antibody, the IgG, IgM and IgA. It is the IgG which is considered the most important as a screen for clotting. The IgM antibody is less threatening but cases have been reported with this class who have also presented with clotting. The level of these antibodies as well as the clot is important, those patients with the highest levels being more at risk than those with lower levels generally. · Beta 2 Glycoprotein Antibodies. This protein initially known as the co-factor has been recently shown to be even more important than phospholipids in the causation of clotting and antibodies directed towards it are now also being measured in patients who are negative for lupus anticoagulants or anticardiolipin antibodies. · Antimitochondrial Antibodies. On rare occasions these may be positive rather than tests for other antibodies · VDRL. or "false positive test for syphilis .This was one of the earliest tests used to identify patients at risk for clotting and may still be used if other tests are negative. · Tests for other antiphospholipids e.g. antiphosphatidylserine, ethanolamine.These may also be performed by specialized laboratories if other tests prove negative.

WHAT IS PECULIAR ABOUT THESE ANTIBODIES ?

ANTIBODIES COMPRISE A "FAMILY OF ANTIBODIES AND PATIENTS MAY DEMONSTRATE ONE GROUP WITHOUT ANOTHER

SOME PATIENTS ONLY DEMONSTRATE THESE ANTIBODIES TRANSIENTLY .IN ORDER TO DEFINITELY DIAGNOSE AN ANTIPHOSPHOLIPID SYNDROME ,TESTS HAVE TO BE REPEATEDLY POSITIVE OVER 3 MONTHS

AT THE TIME OF THE THROMBOSIS THE ANTIBODY TESTS MAY BE NEGATIVE. THE TESTS SHOULD BE REPEATED AFTER THE ACUTE EVENT.

DO ALL PATIENTS WHO DEMONSTRATE ANTIPHOSPHOLIPID ANTIBODIES REQUIRE TREATMENT ?

NO. Patients who demonstrate these antibodies during the course of a connective tissue disease other than SLE or the "Primary" antiphospholipid syndrome (e.g. rheumatoid arthritis,scleroderma, Sjogrens syndrome and who have an IgM anticardiolipin antibody (usually) and who have not suffered a thrombotic event do not require treatment. Patient with infections (e.g. viral) who may demonstrate these antibodies transiently only, also do not require therapy.

WHAT TREATMENT IS AVAILABLE FOR PATIENTS ?

This is best covered by considering several groups of patients. The asymptomatic patient who has an IgG anticardiolipin antibody of a moderate to high titre DOES require treatment as they may thrombose at "risk" times Usually low dose aspiring is administered to this group. Patients who have suffered a thrombosis require anticoagulation therapy with coumadin. This may have to be life long, but new treatments now being developed (e.g. antiplatelet compounds) may supersede this type of treatment. Long term anticoagulation requires regular PI's and calculation of INR's (International Normalized Ratio) Some authorities recommend INR's of over 3. Others are satisfied with INR's of 2.5 - 3.The risk of bleeding with high INR's is fairly high. In patients with SLE, the use of antimalarials (e.g. hydroxychloroquin) which also has antiplatelet effects, reducing platelet "stickiness " is recommended. It also is helpful in joint pain and skin lesions.

ARE THERE SPECIAL TIMES WHEN TREATMENTS SHOULD BE ALTERED ?

Yes. Prior to surgical procedure, biopsies and during the puerperium (6 weeks after delivery) particularly when patients have previously suffered a thrombosis, the use of Heparin is recommended, It may be administered subcutaneously and preparations used are the Low Molecular Weight Heparin (LMWH) preparations.

WHAT ABOUT PREGNANCY?

If the patient has positive tests for antiphospholipid antibodies they are liable to recurrent miscarriages. However, many patients, even if they test positive, may have normal pregnancies. These pregnancies are termed "high - risk" pregnancies. Most authorities now use low dose aspirin and subcutaneous Heparin throughout the pregnancy. If they still miscarry despite this therapy, other options are available. Moderate doses of corticosteroids are administered from the second trimester. Coumadin is not to be used during the first trimester as it causes abnormalities in the foetus during this growth period. Some groups are now using warfarin/ coumadin from the second trimester without any ill effects. The use of intravenous Gammaglobulins may also achieve a full term pregnancy with this form of treatment but is very expensive. Close monitoring of blood flow to the fetus is required during these pregnancies and the use of Doppler Ultrasonic techniques used by people specialized in the field is mandatory and encouraged today. At the first sign of fetal distress, provided it is viable (after the 3Oth week) a Caesarian Section should be performed.