|
Primary Biliary Cirrhosis |
|
Home |
|
About Us |
|
What is PBC |
|
Areas of Support |
|
Research |
|
Education |
|
Picture Gallery |
|
PBC Videos |
|
PBCers Store |
|
Links |
|
Make a Donation |
|
Site Map |
|
Strokes & Antiphospholipid Antibody Syndrome |
|
Antiphospholipid Antibody Syndrome Also known as APL, APLA, APS & Hughes Syndrome Primary APLA: no underlying systemic disorder Secondary APLA: presence of an underlying disease, most commonly SLE. Antiphospholipid Antibody Syndrome is a disease which involves the immune system. Common to autoimmune diseases, auto-antibodies are proteins produced by the body to attack itself, rather than invading viruses and bacteria. Normally antibodies are good and they help fight germs or viral infections from outside, however, occasionally the immune system makes the wrong kind - a type that acts against the body itself. These unusual auto-antibodies in APLA are detected by a blood test and when they are present make a person more likely to get specific problems. APLA doesn't make you feel unwell or stop your immune system from working to fight disease. You can't catch it or give it to someone else and it certainly isn't a terminal disease or anything like that. Many people go throughout life without even knowing their body makes these antibodies. Its just that there's more chance of certain problems. APLA is associated with systemic lupus erythematosis (SLE) and other autoimmune diseases. It is only recently that these antibodies were discovered and their significance understood, so the information available is somewhat limited, but more research is being carried out on this all the time. We still don't know exactly how the antibodies bring about the effects described below, although we have some good ideas. Patients with antiphospholipid antibody syndrome can develop abnormal symptoms while having antiphospholipid antibodies detectable in the blood. The antiphospholipid antibody syndrome involves abnormal clotting. Antiphospholipid antibody syndrome is also referred to as Hughes syndrome in honor of the doctor who first described it. It is important to note that antiphospholipid antibodies can also be found in the blood of individuals without any disease process. In fact, antiphospholipid antibodies have been reported in up to 2 percent of the normal population. Harmless antiphospholipid antibodies can be detected in the blood for a brief period occasionally in association with a wide variety of conditions, including bacterial, viral (hepatitis, HIV), and parasite (malaria) infections. Certain drugs can cause antiphospholipid antibodies to be produced in the blood, including antibiotics, cocaine, hydralazine, procainamide, and quinine. Neverthelss, the antiphospholipid antibody (a protein) is not considered a normal blood protein and has been found in patients with a number of illnesses. These illnesses include abnormal clotting (thrombosis) of arteries and/or veins, phlebitis, premature miscarriages (spontaneous abortions), abnormally low blood platelet counts (thrombocytopenia), slowly progressing memory problems/dementia, strokes, optic changes, Addison's disease, and skin rashes (purplish mottling discoloration of the skin-livedo reticularis), migraine headaches, a rare form of inflammation of the nervous tissue of the brain or spinal cord, called transverse myelitis and a form of "atypical multiple sclerosis". Antiphospholipid antibodies have been detected in over half of patients with the immune disease systemic lupus erythematosus. How common is APLA? The auto-antibodies are found in about 2% of women. Not all of these will have had one of the associated problems, so they do not necessarily have the disease. The levels of antibody can go up and down, and even disappear, so to definitely say someone has APLA, the blood tests need to repeated at least 8 weeks from the first and still be positive. The decision on treatment at a particular time (such as pregnancy) depends upon the levels and what previous medical problems there were. APLA may run in families, although not all members are necessarily affected. It isn't exactly clear to what extent this happens, but it is certainly suggestive, for example, if several people have had a series of miscarriages or thromboses. Who Gets Apla? About 30-50% of patients with SLE (lupus) will have APLA. These antibodies can also be found in patients with other autoimmune diseases. Patients without lupus or other autoimmune disease can have symptomatic APLA ("Primary APLA syndrome"). Children will often develop transient APLA after viral infections. These often come to clinical attention during pre-operative evaluation for tonsillectomy. Up to 30% of patients with HIV infection will also develop APLA. The infection associated APLA are not associated with thrombosis. Medication may also induce APLA. Chlorpromazine is the most common but APLA have also been associated with procainamide, dilantin and quinidine. In screening studies of blood donors, up to 8% of normal people will have APLA. However the APLA in these people are usually low titer and most often occur in young women. Strokes. APLA is found 10-46% of young patients with strokes and in 10% of stroke patients overall. Stroke patients with APLA tend to be younger (42 years vs 62 years). These patient also have a recurrence rate of 6-30%/year and a mortality rate of 10%/year. Certain groups of patients appear to be at even higher recurrence rates. These would include SLE patients with APLA and patients with Sneddon's syndrome (described below). Early-Onset Dementia. This is becoming a more recognized and feared feature of APLA. Thirty-five patients with APLA and dementia are followed at OHSU and dozens are reported in the literature. The dementia is multi-infarct in nature and occurs often without a history of major stroke episodes. APLA-related dementia on the average occurs a decade earlier (52 years) than non-APLA dementia. Sneddon's syndrome is a combination of livedo reticularis and cerebral ischemic events. It is a form of APLA that often results in major morbidity and mortality. The skin involvement in Sneddon's may be severe enough to result in ulceration. Patients with Sneddon's syndrome seem also to have a higher incidence of thrombocytopenia. Venous Thrombosis. Venous thrombosis was the first described manifestation of APLA and still one of the most clinically predominant. Overall, retrospective studies show that 31% of patient with APLA have venous thrombosis. Patients with lupus and SLE have a thrombosis rate of 42% while those with infections and drug-induced APLA the rate is less then five percent. Patients with APLA are over represented in young patients with deep vein thrombosis. Prospective studies have demonstrated a relative risk for venous thrombosis of 5.3 for patients with IgG ACLA. Patients with APLA venous thrombosis can be difficult to treat. Many patients (?1/3-1/2) are resistant to low intensity warfarin (INR 2.0-3.0) and need to be treated with high intensity warfarin therapy (INR= 2.5-3.5) or chronic subcutaneous heparin. These patients have high rates of recurrent thrombosis if anticoagulation is stopped with recurrence rates of 20-50%/year of repeat thromboses have been reported if therapy is stopped. Rarely patients may be refractory to warfarin and will need to be on long-term heparin therapy. Arterial Disease. APLA are increased in young patients with myocardial infarctions and strokes. They are also found in higher proportion in patients with peripheral vascular disease and may predict graft failure. Prospective studies have demonstrated that patients have APLA have higher rates of saphenous by-pass vein occlusion and re-occlusion of PTCA. One confounding factor is that anticardiolipin antibodies will cross-react with oxidized-LDL. Since raised levels of ox-LDL are found in patients with atherosclerosis the anticardiolipin antibodies sometimes found in these patients may be an epiphenomenon of their atherosclerosis. Neurological Disease. A variety of neurological disorders have been associated with APLA. The underlying cause of these symptoms appear to be thrombosis. Some patients have large vessel disease while many patient have small vessel involvement. Patients with APLA often will have multiple MRI abnormalities consistent with small white matter infarcts. The neurological diseases include: Ocular Events. Amaurosis fugax, retinal artery and vein thrombosis have been reported in multiple case reports to be a part of the APLA syndrome. Other. APLA are found in as many as 50% of patients who get migraines. As will be discussed below, patients may have encephalopathy as part of severe APLA. Fetal Loss. Fetal loss is seen in 38% of SLE patients with APLA. The incidence of fetal loss in non-SLE APLA is controversial. When women who have recurrent fetal loss (>3) are screened the incidence of APLA is 30%. The pathophysiology is thought to be due to micro-thrombosis in the placenta. Thrombocytopenia. Certain APLA will react with activated platelets leading to thrombocytopenia. Since it is only activated platelets that expose the proper epitopes, often it is the patients with the thrombotic manifestations of APLA who will also get the thrombocytopenia. The treatment of these patients is clinically challenging since the thrombocytopenia often occurs in patients who are anticoagulated for thrombosis. Danazol appears to be uniquely effective for these patients. Hypoprothrombinemia Patients with APLA (almost always ones with lupus inhibitors) may have an elevated prothrombin time (PT) for 2 reasons. One is that the APLA are present in such high titer that will also interfere with the PT test. The other is that 10% of patients with lupus inhibitors will develop non-neutralizing antibodies to prothrombin. This leads to increased clearance of prothrombin from the plasma and hypoprothrombinemia. Since patients with hypoprothrombinemia can present with hemorrhagic complications, it is important to check for this when one is faced with an APLA patient with an elevated PT. This can be done by doing a 50:50 mix on the PT and measuring the plasma level of prothrombin. Plasma infusions and steroids are effective in raising the prothrombin levels in patients with prothrombin antibodies. Other Associated Diseases. Patients with APLA may have an assortment of skin findings included livedo, Raynaud's phenomena, ulcers, and superficial thrombophlebitis. Up to 26% of patients with SLE and APLA have cardiac valve vegetations and mitral regurgitation. Rarely patient have had valve destruction so extensive as to have required valve replacement. Myocardial dysfunction is seen in 5% of SLE-APLA patients. Primary pulmonary hypertension has been associated with APLA. Ten percent of patients with chronic thromboembolic pulmonary hypertension have APLA. Adrenal insufficiency from microvascular thrombosis has been seen also in APLA patients. Catastrophic Apla Rarely patients with APLA can present with fulminate multiorgan system failure. This is cause by widespread microthrombi in multiple vascular fields. These patient will present with renal failure, encephalopathy, ARDS (often with pulmonary hemorrhage), cardiac failure, dramatic livido reticularis, and thrombocytopenia. Many of these patients have pre-existing autoimmune disorders. It appears that the best therapy for these patients is aggressive immunosuppression with plasmapheresis then (perhaps) IV cyclophosphamide monthly. Early recognition of this syndrome can lead to quick therapy and resolution of the multiorgan system failure. How is APS treated? Each manifestation of the antiphospholipid antibody syndrome, and each individual patient with the condition, is treated uniquely. The discovery of the syndrome has made treatment decision much more precise. Many organs can be affected by APS/Hughes syndrome. Simple blood testing can point to much more appropriate treatment with anticoagulants where sticky blood is felt to be the cause. The three drugs most commonly used are aspirin, warfarin or heparin. Aspirin has long been known to make the blood platelets less ‘sticky’. In turn this has improved the outcome for people who have thrombosis. Low dose aspirin is now used throughout the world in patients who have suffered heart attacks or strokes. Aspirin Aspirin is clearly beneficial in milder cases (comparative trials are still going on). In recurrent miscarriage, the addition of aspirin alone has improved the success rate dramatically. In our combined lupus pregnancy clinic within St Thomas’ Hospital in London, for example, the success rate for pregnancy in patients with the syndrome has risen over the past five years from 19% to over 70% successful pregnancies. Whilst there are certainly many factors in this success, the addition of aspirin has been crucial. Heparin Heparin is less widely used, being administered by injection. It does have two potential advantages over warfarin: Its anticoagulant effects can easily be reversed and is therefore useful around the time of an operation. It can be used throughout pregnancy whereby warfarin cannot always be used. Warfarin Warfarin is an effective treatment for the Hughes’ Syndrome. It is the standard treatment for thrombosis and is relatively free from side effects, provided the blood thickness is regularly tested. In many patients it dramatically improves symptoms. It is now fifteen years since the clinical description of the syndrome. In that time, it has become an ‘established’ medical condition, meriting articles, textbook chapters, research, conferences and so on. More important, it has provided, by means of simple blood tests, a whole new approach to treatment. In those patients in whom Hughes’ Syndrome is diagnosed and treated early, the outlook has dramatically changed for the better. In main, the treatment for Hughes’ Syndrome (Antiphospholipid Syndrome) is to thin the blood i.e. with aspirin, warfarin or heparin. Difficulties in monitoring anticoagulation: Since APLA react with phospholipid both the aPTT and the protime can be affected. If one uses standard heparin to anticoagulate patients with APLA one needs to monitor with heparin levels (0.35 - 0.70 anti-Xa units 6 hours after the shot). The predictable dosing and anticoagulant effect is one advantage of using LMW heparin acutely for thrombosis in APLA patients. One should measure LMW heparin levels in patients with APLA for long term therapy (0.7 - 1.0 anti-Xa units) or those patients with renal failure. Often patients with APLA will have minor elevations of their protime. Those few patients with elevated protimes due to the inhibitor can be very difficult to manage with warfarin. One option is to perform prothrombin and proconvertin times ("P&P") to follow anticoagulation. The P&P is less dependent on phospholipids and one can monitor therapy. The other option is to use long-term heparin. One difficult issue it what to do with the patient with APLA but no thrombotic manifestations. Although some of these patients are at risk, especially those with SLE, many will never develop thrombosis. The current recommendation would be to do very careful search for thrombosis. This would include a brain MRI in patients with SLE and in patients with any neurological symptom. If this work-up is negative then the patient is followed very closely. Treatment to prevent thrombosis Treatment of patients with aPL Antibody is controversial. The problem seems to be mainly an abnormal hypercoagulable state that predisposes to thrombosis of arteries rather than true vasculitis. Asymptomatic patient with Antiphospholipid Ab: reduce risk factors for vascular disease. Those with high titers: avoid oral contraceptive. Life style change: maintain ideal weight, cholesterol level and physical activity. Control blood pressure, avoid smoking. Tests For Antiphospholipid Antibodies (Apla) There are two main groups of tests for APLA's: testing for presence of antibodies to cardiolipin and the coagulation based tests for APLA. Coagulation Based Tests: As you recall, APLA react with phospholipid. Phospholipids are used in coagulation tests to provide a surface for the coagulation reaction to occur. The basis for all these tests is that if there are antibodies binding to the phospholipid, it will interfere with the coagulation reaction and prolong the clotting time. Platelet Neutralization Test: This test takes a reaction that is prolonged by plasma which does not correct with a 50:50 mix and adds extracts of platelet. If it corrects to normal this is very specific for APLA. Hexagonal Phase Phospholipid: Same principles as the platelet neutralization test but used hexagonal phase phospholipids. This is the only valid test for lupus inhibitors when patients are on anticoagulants. Anticardiolipin Antibodies: This is an ELISA test for antibodies to cardiolipin. Therefore, unlike the coagulation based tests, it can be performed on plasma which has been anticoagulated. Unfortunately there is no one test that can screen a patient for APLA. One must do the whole panel on patients suspected with APLA. A good screen is to perform the hexagonal phospholipid assay and ACLA assay. If these are negative and one is very suspicious then one order further tests. These would include 1) Anticardiolipin antibodies, 2) Kaolin clotting time 3) dRVVT 4)"Lupus Inhibitor Screen" (different aPTT reagents). One of the largest obstacles to emergency treatment is that many people don't even know it when they are having a stroke. The very word "stroke" indicates that no one is ever prepared for this sudden, often catastrophic event. Stroke survivors and their families can find workable solutions to most difficult situations by approaching every problem with patience, ingenuity, perseverance and creativity. 10 percent of stroke survivors recover almost completely 25 percent recover with minor impairments 40 percent experience moderate to severe impairments requiring special care 10 percent require care in a nursing home or other long-term care facility 15 percent die shortly after the stroke. A stroke or "brain attack" occurs when a blood clot blocks a blood vessel or artery, or when a blood vessel breaks, interrupting blood flow to an area of the brain. When a stroke occurs, it kills brain cells in the immediate area. Doctors call this area of dead cells an infarct. These cells usually die within minutes to a few hours after the stroke starts. When brain cells in the infarct die, they release chemicals that set off a chain reaction called the "ischemic cascade." This chain reaction endangers brain cells in a larger, surrounding area of brain tissue for which the blood supply is compromised but not completely cut off. Without prompt medical treatment this larger area of brain cells, called the penumbra, will also die. Given the rapid pace of the ischemic cascade, the "window of opportunity" for interventional treatment is about six hours. Beyond this window, reestablishment of blood flow and administration of neuroprotective agents may fail to help and can potentially cause further damage. When brain cells die, control of abilities which that area of the brain once controlled are lost. This includes functions such as speech, movement, and memory. The specific abilities lost or affected depend on where in the brain the stroke occurs and on the size of the stroke (i.e., the extent of brain cell death). For example, someone who has a small stroke may experience only minor effects such as weakness of an arm or leg. On the other hand, someone who has a larger stroke may be left paralyzed on one side or lose his/her ability to express and process language. Some people recover completely from less serious strokes, while other individuals lose their lives to very severe strokes. |