Posted by Dr. Bijoykumar Barik on Thursday, 22nd July 2010ANTIPHOSPOLIPID ANTIBODY SYNDROME
Antiphospholipid Syndrome (APS , APLS), also known as Antiphospholipid antibody syndrome or ‘Sticky blood Syndrome’or Hughes syndrome is a disorder characterized by elevated level of multiple different antibodies that are associated with arterial and venous thrombosis and pregnancy related complications. This syndrome occurs due to auto antibodies against phospholipids (aPL), a cell membrane substances. The antibodies are found against cardiolipin (anticardiolipin antibodies) and β2 glycoprotein I (β2 GP1).
These aPL antibodies were first seen in some patients with positive test for syphilis without infection out of which few developed SLE(Systemic Lupus Erythematosus ) and other similar conditions. Later lupus anticoagulant was detected in few cases of SLE. A case report in 1956 showed repeated pregnancy loss,thrombophlebitis and lupus anticoagulant. In 1980 the rheumatologist Dr. Graham R. V. Hughes of St. Thomas’ Hospital , London provided the details including the test for anticardiolipin antibodies. Later anticardiolipin antibodies were found to act against β2GP1,while lupus anticoagulant was found to act against β2GP1 and more recently prothrombin.
It can be classified as
1. Primary - without any related disease.
2. Secondary – in conjunction with autoimmune diseases like SLE .
3. Catastrophic APS (CAPS) – Rapid multi organ failure due to thrombosis leading to death.
Normal person may have antibodies. The triggering factors are:-
1. Infections- People with Syphilis ,HIV infection, Hepatitis C, Malaria.
2. Medications- Antihypertensive like hydralazine , antiepileptic like phenytoin, antibiotics like amoxicillin. Cocaine, procainamide, quinine may cause.
3. Genetics – Although APS has been reported to occur in multiple members of the same family, no clear inheritance pattern has been identified and no gene has been found to be the sole cause of this condition. One report in 1999 studied families with more than one affected member, examined possible modes of inheritance, and examined links with certain genes. In seven families 30 out of 101 family members met diagnostic criteria for the syndrome. The data were fitted best by either a dominant or co dominant models.
Antiphospholipid syndrome is an autoimmune disease in which “antiphospholipid antibodies”(Anticardiolipin antibodies and Lupus anticoagulant) react against protein 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 are associated with thrombosis and vascular disease.
Anti-ApoH and a subset of Anti-cardiolipin antibodies bind to ApoH , which in turns inhibits Protein C, a glycoprotein with regulatory function upon the common pathway of coagulation(by degrading [Va factor]).
LAC antibodies bind to prothrombin, thus increasing its cleavage in thrombin, its active forms.
In APS there are also antibodies binding to Protein S, which is a co-factor of protein C. Thus Anti-Protein S antibodies decrease Protein C efficiency.
Annexin A5, which forms a shield around negativity-charged phospholipids molecules, thus reducing their availability for coagulation. Thus Anti-annexin A5 antibodies increase phospholipids-dependent coagulation steps.
The Lupus anticoagulant antibodies are those that show the closest association with thrombosis, those that target β2GP1 have a greater association with thrombosis than those that target prothrombin. Anticardiolipin antibodies are associated with thrombosis at moderate to higher titres (> 40 GPLU or MPLU). Patients with both Lupus anticoagulation antibodies and moderate/high titer anticardiolipin antibodies show a greater risk of thrombosis than with one alone.
The aPL antibodies are found in 30% cases of SLE. The aPL antibodies may be found in 1-5% of normal individuals. There is no racial predisposition of Primary type. It is more common in young adults(30-45 yrs). Primary APS accounts for over 50% cases. Some studies indicate that aPL antibodies may play a role in approximately one third of strokes in persons under age of 50.A female predominance causing secondary APS parallels APS with SLE and other connective tissue disease .After age of 60 incidence is rare.
APS usually shows up for the first time as vascular thrombosis or embolism or as recurrent pregnancy loss. Thrombocytopenia , certain skin problems, neurological signs, heart valve disease and certain autoimmune diseases have also have been noted in association with APS. Pulmonary hypertension and sensory- neural hearing loss have been noted in some individuals with APS as well.
Conditions associated with APS include:
1. Systemic Vascular Thrombosis
While the deep veins of the legs are most frequent sites of thrombosis, thromboemblism can involve virtually any vein or artery. Deep vein thrombosis tends to be most common finding, occurring in half of affected individuals. Other sites of venous thrombotic events include the veins of the lungs (due to pulmonary embolism, a clot that typically has dislodged from a vein below the pulmonary veins and lodged in a pulmonary veins), thoracic veins(veins in or above the chest that carry blood to the heart including the superior vena cava, or jugular vein), and abdominal or pelvic veins.
A risk of recurrent thrombi is associated with APS as well. Most studies suggest that individuals who have a recurrent episode will have it in a similar blood vessel type. For example, indivisuals who have a stroke initially will most often have a stroke if they have a recurrence. Nonetheless, individuals are reported who have had different types of thrombosis events.
A deep vein thrombosis( DVT) can form in the arm or leg after a long journey, or in some women, after starting the contraceptive pill. Clots in the veins can cause thrombophlebitis of the legs with pain in the thigh or calf, swelling of the leg , and sometimes a visible red, thickening blood vessel. Damage to the valves of lower limbs may impair the upward venous flow leading to chronic venous insufficiency causing chronic swelling and discoloration of leg. Thrombosis can also affect vital organs such as the eye, liver and kidney.
2. Pregnancy Loss and Other Complications
APS is associated with miscarriages as well as other complications of pregnancy. Most studies have estimated the prevalence of aPL antibodies among pregnant women at 5 percent or less, most of these women do not have any signs or symptoms of APS. Around 10-20 percent of women with multiple pregnancy loses are thought to have APS.
Women with APS often have a history of recurrent (usually defined as three or more) pregnancy losses. Pregnancies occurring in women with APS are at increased risk of prematurity , slower than expected growth of the fetus, and preeclampsia. Pregnant women with APS are also more prone to develop deep vein thrombosis during pregnancy or puerperium .
One miscarriage is a disaster. Two is worse. Imagine the suffering of women who have 3,5,7 or even 12 pregnancy losses, and sometimes as late as the late few weeks of their pregnancy.
We now know that Hughes Syndrome is the most common treatable cause of recurrent miscarriage. Future more, late pregnancy loss, fortunately an unusual problem in pregnancy, is very strongly associated with Hughes Syndrome as is pre-eclampsia, placental abruption and intra-uterine growth restriction.
For the sake of a simple blood test, patients with miscarriage or late pregnancy loss can be tested for Hughes Syndrome. Treatment of these patients has proved one of the true success of modern medicine , the successful pregnancy rate rising from a previous low of fewer than 20% to figures now in the region of 75-80% success rate.
An association with immune thrombocytopenia has been established. This occurs to varying degrees in many as 50% of individuals with APS. Because platelets help the blood to clot, thrombocytopenia can sometimes cause a bleeding disorder in an otherwise healthy person as bleeding from gum, nose and skin. However in APS thrombocytopenia is usually moderate and is rarely significantly enough to cause bleeding complications or affect anticoagulant therapy.
4. Skin Disorders
Certain skin conditions have also been observed in APS. These include livedo reticularis (mottled discolouration of the skin), ulcers on the skin, usually on the legs, and sometimes skin necrosis .
Many Hughes Syndrome patients complain of ‘cold circulation’ and this sometimes manifest as a blotchy appearance of the skin of the arms and legs, described in medical textbooks as “livedo reticularis” or “corned beef skin”. It can also cause repeated sores and bumps (nodules) of the skin.
5. Stroke and Other Neurological Disorder
Stroke is associated with APS as are some other neurological conditions. In addition to cerebrovascular thrombosis , embolic stroke can also occur. Multiple strokes can sometimes leads to a condition called multi-infarct dementia.
Other neurological problems have been reported in people with aPL antibodies, although they are not as strongly associated with APS as stroke. These include seizures, chorea , migraines, Guillain-Barre syndrome, diabetic peripheral neurotherapy, transverse myelitis and conditions similar to multiple sclerosis. Evidence for an association with cognitive dysfunction is growing.
There are many cause of strokes- for instance hypertension but most surveys show that 1 in 5 young strokes (under the age of 45) are now associated with Hughes Syndrome(APS). Now, in the age of easy diagnoses of Hughes Syndrome, many patients are not receiving adequate anti-coagulant treatment of their “sticky blood” , and suffering from early mini-strokes or TIAs (transient ischemic attacks) or more permanent strokes.
Some people with Hughes Syndrome develop a syndrome which is very similar to multiple sclerosis where they have numbness or pins and needles, double vision or loss of part of the field of vision, and have difficulty in walking. Consequently one of the main alternative diagnosis in patients with Hughes syndrome is multiple sclerosis.
6. Heart Disease
A type of heart valve disease called Libman-Sacks endocarditic is sometimes seen in individuals with aPL antibodies. In this condition, growth on the heart can break off and travel through the blood streams, causing embolic events. Hughes Syndrome can lead to heart attacks and heart valve problems that can mimic bacterial endocarditic, and create clots in the upper chambers of the heart. Up to20% of young people (under 45) who have a heart attack have antiphospholipid antibodies.
7. Lupus and Other Autoimmune Disorder
APS is classified within the category of autoimmune disorders . Individuals with aPL antibodies sometimes have an additional autoimmune disorder, most commonly SLE. About 30-40 percent of individuals with SLE have elevated aPL antibodies. APS has also been associated with a number of other autoimmune disorders, including myasthenia gravis, Graves’ disease, autoimmune hemolytic anemia and Evan’s syndrome.
8. Headache or migraine
Often this is one of the major features of the illness. Sometimes the headaches disappear in the 20’s to return with a vengeance in the 30’s or 40’s. This is a most important feature of Hughes Syndrome and symptoms sometimes improve dramatically when treatment is started. Often migraine features such as flashing lights and zigzag patterns accompany the headaches found in Hughes Syndrome.
For reasons not completely understood the brain appears particularly sensitive to the clotting effects of antiphospholipid antibodies and one of the ways in which it reacts to “Sticky blood” affecting its oxygen supply is to cause balance disorders. Many patients complain of feeling giddy or “slightly drunk” and this can naturally lead to accidents.
10. Memory loss
When the brain is starved of oxygen it only has a limited number of ways of complaining and a common symptoms of Hughes Syndrome is memory loss. Many patients feel that they are developing Alzheimer’s disease when they can’t remember names of friends and family , forget their shopping lists and get their word and sentences muddled. One of the most dramatic observations is the improvement of the memory (and the disappearance of the headaches and ‘fog’) which patients observe when blood thinning medicine is started.
11. Visual disturbance
In addition to the flashing lights and zigzag patterns which can accompany headaches and migraines, the person with Hughes Syndrome can experience double vision or sudden visual loss. This can be caused by the brain reacting to disturbances in its supply of blood or by the veins and arteries in the eye being affected.
12. Pulmonary embolism
A pulmonary embolism occurs when a blood vessel supplying the lung becomes clogged up by a clot. Blood clots in the lung can cause chest pain, shortness of breath and rapid breathing. Repeated clots can cause pulmonary hypertension which may cause the person to be constantly short of breath. Larger emboli in the lungs can be lethal.
13. Gastrointestinal disorder
Hughes Syndrome can affect the blood supply to the intestine causing abdominal pain, fever and blood in the stool. Antiphospholipid antibodies can also cause a condition called Budd-Chiari syndrome, in which a blood clot prevents blood from flowing out of the liver and the person may then experience nausea, vomiting, jaundice, dark urine and the swelling of the abdomen.
Diagnosed on the basis of clinical and laboratory findings. History of episode of thrombosis and pregnancy loss is important.
Laboratory Test- APS is diagnosed if an individual experiences one or more episodes of thrombosis or pregnancy loss and if aPL antibodies are detected through laboratory testing of the individual’s blood.
There are two main types of antiphospholipid antibody tests- immunological tests, like the anticardiolipin ELISA (enzyme-linked immunoassay), and coagulation-based tests for the lupus anticoagulant. ELISA are immunologically based tests, or immunoassays in which an antigen-antibody reaction is used to detect the antibodies. In contrast, lupus anticoagulant tests detect antibodies based on their ability to slow down phospholipids-dependent clotting reactions. Most individuals with APS have antibodies that can be detected in both tests. However a significant percentage of patients are positive in one test but not the other. Therefore to diagnose APS it is standard practice for both tests to be performed. The tests are then repeated six to eight weeks later to confirm the presence of aPL antibodies.
Antiphospholipid syndrome is tested 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 consists of :
• Future studies for Factor V Leiden variant and the prothrombin mutations. Factor VIII levels, MTHFR mutation.
• Levels of proteins C , free and total protein S, Factor VIII, antithrombin , plasminogen, activator(TPA) and plasminogen activator inhibitor-1(PAI-1)
The testing of antibodies to the possible individuals targets of aPL such as β2 GP1 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 in vivo target for antiphospholipid antibodies.
This is tested for by using a minimum of two coagulation tests that are phospholipid sensitive, 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. The tests must be carried out on a minimum of two occasions at least 6 weeks apart and be positive on each occasion demonstrating persistent positively to allow a diagnosis of antiphospholipid syndrome. This is to prevent patient with transient positive tests (due to infection etc) being diagnosed as positive.
Distinguishing a lupus antibody from a specific coagulation factor inhibitor (e.g. 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 pathways 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.
These can be detected using an enzyme-linked immunosorbent assay(ELISA) immunological test which screens for the presence of β2GP1 dependent anticardiolipin antibodies(ACA).
A low platelet count and positively for antibodies against β2GP1 or phosphatidyl serine may also be observed in a positive diagnosis.
Research in 2009 suggest elevated IgA anti-β2GPI antibody titers may identify additional patients who have clinical features of APS but who do not meet current diagnostic criteria, thus testing for IgA anti-β2GPI antibodies when other aPL tests are negative and APS is suspected may be in order.
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 (1998,published in 1999)are commonly used for APS diagnosis.
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 more premature births before 34th week of gestation due to eclampsia) and
b).Persistency (6weeks apart) of positive aPL ( lupus anticoagulant test, moderate-to-high titer anticardiolipin antibodies or moderate-to-high titer β2GPI antibodies).
The International Consensus Statement is commonly used for Catastrophic APS diagnosis. Based on this statement CAPS diagnosis requires:
a) Vascular thrombosis in three or more organs or tissues
b) Development of manifestations simultaneously or in less than a week
c) Evidence of small vessel thrombosis in at least one organ or tissue
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.
There is no cure but medications may reduce the risk of thrombosis. Despite our increased understanding of the syndrome the cornerstone of therapy remains antiaggregant and anticoagulant agents.
• Very ill patients requires hospitalization. Usually may be treated in outdoor. A variety of specialists are required.
• Desirable to limit blood coagulation including quitting smoking, ceasing oral contraceptives, control BP.
• In cases of P/H of thrombosis long-term medication like warfarin.
• In pregnant cases need treatment and monitoring to avoid complication.
• Treatment for APS must be individualized according to the person’s current health status and the types of problems that has experienced due to their APS. In general, for a person who has aPL antibodies and had a thrombotic event a short-term course of heparin is followed by long-term( sometimes life-long) treatment with warfarin.
In women with moderate to high levels of aPL antibodies and a history of pregnancy loss who wish to get pregnant again individualized. After consulting with obstetrician and rheumatologist and /or hematologist women generally begin treatment with heparin and low-dose aspirin. For those individuals who have been found to have aPL antibodies but no signs or symptoms of APS low-dose aspirin is generally recommended. Hydroxychloroquin(HCQ) an antimalarial drug used for Lupus and Rheumatoid arthritis is under trial.
If you or someone you know has been diagnosed with APS, we recommend talking with a health care provider to determine a personalized course of management.
APS is an autoimmune disease associated with arterial and/or venous thrombosis and pregnancy related complications. The antibodies responsible are anticardiolipin antibody, lupus anticoagulant and anti β2GP1. They may be classified as Primary, Secondary or CAPS. Various types of infection, drugs or genetic factors are thought to be triggering mechanism. It is common in young with a female prepondence. It is found in -5% of normal persons. Incidence is high in association of SLE and other autoimmune diseases. It may present as recurrent systemic vascular thrombosis and embolism, pregnancy related complication specially recurrent miscarriage, thrombocytopenia, bleeding diathesis, skin manifestation, cardiac involvement, various neurological complications, psychiatric manifestation, pulmonary and gastrointestinal, ocular, renal complication. Diagnosis depends on history, clinical examination and laboratory investigation which demonstrate aPL antibodies through ELISA (anticardiolipin antibodies) and coagulation based test for Lupus anticoagulant. Thrombocytopenia and antibody against β2GP1 may be detected. There is no cure but treatment is individualized basing on preventing risk factors and ant platelet and anticoagulant therapy.
APS is an incurable autoimmune disease occurring in young. Recurrent thromboembolic episodes involving various organs, recurrent abortion and other manifestations like stroke in young, pulmonary hypertension, unexplained headache, dizziness, memory impairment, cardiac involvement with embolism, dermatological involvement and other neuropsychiatric disorders brings the patient to different clinicians. Basing on proper clinical history the diagnosis is confirmed by demonstrating antibodies like anticadiolipin, lupus anticoagulant and β2GP1. Treatment is symptomatic, prevention of risk factors and individualized use of anticoagulant.
• APS is an autoimmune disease due to presence of aPL antibodies like anticardiolipin, lupus anticoagulant and β2GP1.
• Recurrent thromboembolism in young leading to various clinical manifestation are to be kept in mind.
• Recurrent miscarriage in young females one has to think of APS.
• Incidence is high in association of SLE and other autoimmune diseases.
• Stroke in young or myocardial infarction, renal failure and other systemic complications do occur in young.
• Thrombocytopenia may occur in 50% cases of APS with bleeding manifestations.
• Diagnosed by demonstration of antibodies through ELISA &coagulation based test.
• Though there is no cure for the illness, prevention of risk factors and use of anticoagulants depending on clinical state and symptomatic treatment is useful.