Antiphospholipid Syndrome


Prof Graham HughesThis autoimmune disease with multi-organ symptoms was described in 1983 by Prof Dr Graham Hughes in London. It is characterized by excessive clotting (thrombosis in blood vessels) of blood leading to lack of oxygen supply in the affected organ. A thrombus can form in arteries (vessels carrying oxygenated blood) or veins (vessels carrying de-oxygenated blood) of any size – small or large. Phospholipids are important constituents of membranes of various cells including those circulating in blood. Platelets are the main cells responsible for blood clotting.
Antibodies to phospholipids attack membrane phospholipids in platelets and other circulating cells and increase risk of thrombosis. Not all people with anti-phospholipid antibodies (APLA) develop thrombosis. It seems that some factors like infections (HIV, Hepatitis C and few other viruses) trigger clotting events in these cases. 40% of APS cases are associated with various autoimmune diseases, especially systemic lupus erythematosus (SLE), Sjogren’s syndrome and rheumatoid arthritis. Drugs (chlorpromazine, hydralazine, procainamide, phenytoin, quinine, etc) and diseases (diabetes, sarcoid and cancers) can also lead to elevations of APLA in low titres.

Clinical Features:
As blood circulates through entire body and supplies oxygen to every organ, APS can manifest as diverse features with enormous variations. The most frequent ones are listed below.

  1. Stroke (paralysis of one side or part of body) is a common manifestation of APS. One out of five young stroke patients are APLA positive. Stroke is due to blockage of an artery in brain. Blockage of smaller arteries in brain can cause headache, migraine, forgetfulness, and lack of concentration. It can also lead to serious problems like involuntary movements (chorea) and diminished vision. Some of these patients may be wrongly labeled as psychiatric disease, Alzheimer’s disease or multiple sclerosis.
  2. Heart disease – 18% of heart attacks (coronary artery disease) in young patients are due to APS and can lead to premature death. Thrombus within heart, valve defects (5% can require valve replacement surgery) and heart dysfunction can also occur in APS.
  3. Deep vein thrombosis – Two-third cases of APS manifest as blockade in veins especially those of limbs (more common in legs), lungs, liver, kidneys and eyes. Any occlusion in venous blood flow results in oozing of serous fluid. Occlusion of leg veins manifests as sudden pain, swelling and tightness of the limb. This can be easily diagnosed by Doppler ultrasound examination.
  4. Other organs such as lungs (embolism, hemorrhage), liver (abnormal function, thrombosis), bowel (infarct and perforation), kidneys (dysfunction and arterial or venous occlusion), bones (avascular necrosis-‘dead’ bone) and endocrine glands can also be involved in APS.
  5. Skin changes called as ‘livedo reticularis’ are important feature (though not specific) of APS. The skin (usually around knees and over thighs or arms) appears blotchy with lacy prominent blood vessels. Livedo is a marker of severe disease and poor prognosis. Some patients can get ulcers around shins and ankles which are very difficult to heal. Gangrene (‘dead black area’) of fingers and toes, redness of palms and soles, rashes and painful nodules are rarer features of APS.
  6. Pregnancy loss – 15% of women with more than 3 consecutive miscarriages (
APS can be catastrophic in about 1% patients leading to simultaneous failure of multiple organs within a few days. Such event can be triggered by intercurrent infections, delivery, surgery, drugs or flare of an autoimmune disease (e.g. SLE). Mortality in these cases is very high (upto 50%) despite aggressive therapy.
Laboratory Tests:- APLA can be easily measured. Only IgG fraction (and not IgM or IgA) of APLA has clinical implications. 1% of normal population and about 3% of elderly people are APLA positive. They do not require any treatment. IgG APLA of more than 40 is predictive of thrombosis. Beta-2 GP1 is an antibody to phospholipid binding protein. It can also be measured and appears to be more specific in predicting thrombosis. Lupus anticoagulant test (LAc) measures the ability of APLA to interfere blood clotting. LAc is also reported to be positive in normal population. Higher levels are commonly associated with thrombosis. All these tests, though expensive, must be repeated after 3 months to confirm the diagnosis of APS.

A False positive VDRL test (which tests syphilis infection) can also indicate APS. Platelet count is usually low in 25% cases and may cause bruising of skin. Haemolytic anaemia (destruction of red cells) can also occur. Prothrombin time is usually prolonged whereas bleeding time and partial thromboplastin time are normal.
A false Treatment: Although there is no satisfactory treatment to suppress APLA, clotting tendency can be corrected by use of anti-coagulant drugs such as low dose aspirin (75-100 mg/day) and warfarin or heparin. Dipyridamol can be used in patients intolerant to aspirin. Long term anticoagulation with heparin (low molecular weight preferable though costlier) followed by warfarin is the treatment of choice in all major thrombotic events. Patients on anticoagulants must check blood regularly for INR (internationally normalized ratio) which indicates thinning of blood. INR should be maintained between 2 and 3, although a higher INR (3-4) is required in few critical cases. Newer anticoagulants (fondaparinux) are now available for patients intolerant to heparin. Anticoagulants can cause bleeding (which settles with vitamin K and temporary withdrawal of drug) and bone loss (osteoporosis). All patients on anticoagulants must receive calcium and vitamin D.


 
 Associated diseases such as SLE need to be treated with hydroxychloroquin, azathioprin and other suitable drugs.

Although pregnancy in APS indicates high risk, 90% live birth rate can be achieved with proper obstetric care and medical management.

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