The antiphospholipid syndrome is defined as a clinical disorder with recurrent arterial and venous thrombotic events, pregnancy wastage and/or thrombocytopenia in the presence of the lupus anticoagulant and/or moderate to high positive anticardiolipin test. Both a primary form, in patients without clinically or serologically evident autoimune disorders, and a secondary form, usually in patients with systemic lupus erythematosus, are recognized. This separation is solely for academical purposes.
Thrombosis may be present in small, medium, or large venous or arterial sites. The presentation is episodic and unpredictable. Venous thrombosis of a leg or arm, renal vein thrombosis, the Budd-Chiari syndrome, pulmonary embolism, AddisonÂ’s disease, retinal , sagital, pelvic, mesenteric, portal and axillary vein thrombosis have all been described. When an arterial site is involved, the manifestations may vary between the clinical features of a stroke or transient ischemic attack. When other arterial vascular beds are affected, such as the retinal, coronary, brachial, mesenteric, renal (interlobular arteries, arterioles and glomerular capillaries) and dermal arterioles, the clinical presentations are directly related to involved site.
B) Pregnancy Loss
Some patients may present with recurrent pregnancy losses often, but not always, in late second or third trimester of gestation. Both preeclampsia and intrauterine growth retardation have been observed concomitantly. Patients who present a history of previous pregnancy loss are subject to a new event more frequently.
C) Nervous System Disorders
Most neurologic abnormalities are consequent to cerebrovascular thrombosis which result in reversible or fixed focal deficit. The neurological manifestations of the patient with antiphospholipid antibody syndrome are much wider transient ischemic attacks, cerebral infarcts and cerebral venous thrombosis. Other neuralgic presentations include epilepsy, transverse myelopathy, Guillain-BarrÃ© syndrome and chorea.
D) Other Features
Association of antiphospholipid antibodies with renal vein thrombosis, AddisonÂ’s disease, gut ischemia, Budd-Chiari syndrome, thrombocytopenia, autoimune hemolytic anemia, idiopathic thrombocytopenic purpura, cardiac valve abnormalities (insufficiency mitral and aortic) and Libman-Sacks endocarditis have all been described. Dermatologic manifestations are extremely frequent. The most common of them is livedo reticularis while others such as leg ulceration, distal cutaneous ischemia or necrosis, superficial thrombophlebitis, blue-toe syndrome, splinter hemorrhage and porcelain-white scars are also seen.
A) Venereal Disease Research Laboratory(V.D.R.L.)
This was the first test to detect an antiphospholipid antibody. Reviews of patients with biologic false-positive test for syphilis, however, did not identify an increased risk of thrombosis or fetal loss. Therefore, this test is not diagnostic and the biologic false-positive test for syphilis is not even considered a strong associate of antiphospholipid syndrome.
B) Lupus Anticoagulant (LA):
The lupus anticoagulant is an immunoglobulin, either IgG or IgM, that prolongs clotting time in vitro because they agglutinate phospholipids present in the plasma thereby preventing their participation as cofactors in coagulation steps. Its in vitro action appears to be the inhibition of the conversion of prothrombin to thrombin.
Since phospholipids are not very antigenic, the true antigen for the lupus anticoagulant antibody probably includes a plasma protein. The heterogeneity of the lupus anticoagulant can therefore be explained by the concept that the lupus anticoagulants are a family of antiphospholipid-plasma antibodies, with subgroups defined by both the phospholipids and plasma protein involved. Accordingly, no lupus anticoagulant test is 100% sensitive. Therefore, the following criteria are required for a positive lupus anticoagulant test: 1-prolonged partial thromboplastin time, Russel Viper Venom time, or Kaolin clotting time; 2-failure to correct the test by mixing patient plasma with normal plasma (suggesting a clotting inhibitor is present); 3-normalization of the test with freeze-thawed platelets, or phospholipids.
C) Anticardiolipin Test (Acl):
Realizing that cardiolipin was the major antigenic component of the false-positive test for syphilis, a radioimmunoassay was created directed against this phospholipid. Over time, an enzyme-linked assay (ELISA) replaced the radioimmunoassay. Cardiolipin, which is found in the mitocondria is unlikely the antigen against which the antibody reacts in vivo. Nevertheless, because antiphospholipid antibodies cross-react with other negatively charged phospholipids, cardiolipin can serve as a representative antigen in the system.
Anticardiolipin antibody is one of the few autoantibodies that have assays which allows the identification and quantification of specific isotypes (IgG, IgM and IgA).The IgG isotype was the major predictor of thrombosis and pregnancy loss while the IgM class was associated especially with hemolytic anemia in addition to thrombosis. Besides the identification of different isotypes, the antibody titer seems an useful predictor of pathogenicity (even though it is still not clear that quantity of antibody is the best or the only one). The higher-titer of IgG anticardiolipin antibody (>40GPL) correlates strongly with thrombosis and fetal loss. Most patients with antiphospholipid syndrome have medium to high IgG anticardiolipin antibody levels with or without other isotypes.
D) Relationship of the LA and aCL:
Both lupus anticoagulant and anticardiolipin antibody are associated with each of the clinical manifestations of the antiphospholipid syndrome. There are controversy between the relation of aCL and LA, thus the test may be positive for one, negative for other, or positive for all.
The differential diagnosis will vary depending on the clinical manifestations. In cases in which thrombosis is the main presentation, other procoagulation states – such as protein C, protein S or antithrombin III deficiency, malignancy, oral contraceptives, nephrotic syndrome, polycytemia, thrombocitosis, dysfibrinogemia, paroxysmal nocturnal hemoglobinuria, homocystinuria – should be in mind and excluded. In the case of pregnancy loss, other mechanisms may be responsible for the fetal loss. These include fetal chromossomal abnormalities, anatomic anomalies of the maternal reproductive tract and others such as endocrine, infectious, autoimmune, drug induced disorders.
Acute management of arterial or venous thrombosis in patient with antiphospholipid syndrome is no different from the treatment of other patients with similar complications. Thus the patient should receive heparin (1000 units/h). Prophylactic oral anticoagulant is advised following venous thrombosis for a prolonged period of time since patients with antiphospholipid syndrome are prone to recurrent thrombosis. In patients with stroke or other arterial thrombotic event, aspirin (80-100 mg/day), aspirin plus dipyridamole, or oral anticoagulation have been used by various groups. When venous thrombosis occurs an INR>3,5 should be achieved with warfarin. In cases in which thrombosis continues despite adequate anticoagulation high doses of corticosteroids, initially, and cyclophosphamide have been used in addition to anticoagulation.
B) Recurrent Pregnancy Losses:
Management of women during pregnancy is controversial. Subcutaneous heparin (5000-15000 units) twice daily prophylaxis is recommended for patients with antiphospholipid syndrome. Some centers have reported successful pregnancy outcome with prednisone (20-60 mg/day) and aspirin (80-100 mg/day). The essential is the frequent monitorization of the patient. Another alternative management is immunoglobulin therapy (0.5 mg/kg/day) for 3-5 day each month. The follow-up is multidisciplinary.
More info on Anti-phospholipids.
ANTIBODY ASSOCIATED WITH AUTOIMMUNE DISORDERS
FOUND TO “CLUSTER” IN FAMILIES
Finding May Be First Step In Preventing
Premature Stroke, Heart Attack and Miscarriage
An antibody traditionally associated with rheumatic autoimmune diseases such as lupus, has been identified as a “common thread” in families where at least one member suffers from an autoimmune disorder associated with high levels of the antibody.
The research, conducted by investigators at Yale University School of Medicine and St. Mary’s Hospital in Waterbury, Connecticut, was published in the November issue of the American Journal of Medicine.
The antibody, known as the antiphospholipid antibody (APL), is one of a class of antibodies referred to as auto-antibodies. Common to autoimmune diseases, auto-antibodies are proteins produced by the body to attack itself, rather than invading viruses and bacteria. APL is made to fight certain good body fats called lipids. When the level of APL is high and these proteins float freely throughout the blood, a disease state occurs.
The antiphospholipid antibody syndrome (APS) is associated with recurrent clotting events (thrombosis) including premature stroke, repeated miscarriages, phlebitis, venous thrombosis (clot in the vein) and pulmonary thromboembolism (blockage of an artery found in the lung due to a clot that has traveled from a vein). It is also associated with low platelet or blood elements that prevent bleeding.
Recently, however, even more disease states have been linked with APL including premature heart attack, migraine headaches, various cardiac valvular abnormalities, skin lesions, diseases that mimic multiple sclerosis, vascular diseases of the eye that can lead to visual loss and blindness, and early peripheral vascular disease that can result in amputations of the extremities and digits.
The St. Mary’s/Yale study looked at 23 individual family members with APS, 87 of their blood relatives, 18 spouses and 37 controls. Overwhelmingly, it found clustering of the APL antibody in families. Of the 87 blood relatives, some 50 – or nearly 60% – had auto-antibodies, compared with only one spouse. Approximately 33 percent or one-third had antiphospholipid antibodies, while another 37 percent had other auto-antibodies, such as anti-nuclear antibodies. None of the controls tested positive.
The study also found that more relatives had suffered from one of the manifestations of APS than did either the spouses or controls. Indeed, several relatives were found to have either lupus (4) or lupus-like syndrome (4), premature stroke (2), recurrent fetal loss (3), recurrent thrombosis (1) or thrombocytopenia (2).
“While the study is relatively small, it is supported by other previous studies that suggest APL antibodies may actually be genetically transmitted from family member to family member, from generation to generation,” said Thomas Greco, M.D., assistant clinical professor of medicine, Yale University School of Medicine, and chief, Section of Inflammatory Diseases, St. Mary’s Hospital, who conducted the research, along with Nahum Goldberg, M.D., and Ann Marie Kelly, M.D. “More important, the APL antibody may be associated with one disease process in one family member and yet another disease process in another family member,” he added.
Collaborative studies looking into whether the various disease states may possibly occur in increased frequency in family members who carry the proteins are currently being planned by St. Mary’s, Yale University, and Duke University School of Medicine. In addition, other universities may participate in the joint research effort.
Previous independent research at Duke led by Michael Seldin, M.D., Ph.D., associate professor, supports this new data. Dr. Seldin’s team found strong evidence for genetic transmission of APS in analyses of 12 different families. Preliminary modeling in these studies has suggested the possibility that inheritance of this disease may be due to a single dominant genetic defect with variability in disease penetrance. The workers in
collaboration with Dr. Greco and other centers have initiated a study of the gene patterns in families with APL. It is hoped that this “gene hunting study” will ultimately define the genetic defect(s) in this disease.
Recent data presented by French researchers at the October meeting of the American College of Rheumatology also support the findings of Drs. Greco, Goldberg and Kelly. In a study on families with antiphospholipid antibodies, many relatives were found to have diseases related to these proteins as well as many other immunologic diseases, including rheumatoid arthritis, systemic lupus erythematosus, Sjogren’s syndrome, crohn’s disease, multiple sclerosis, low platelets (ITP), thyroid disease and others.
Dr. Greco pointed out that while the prevalence of these proteins among the patients nationwide is relatively low (between 1 and 2 percent), for given families it may be very high – as high as one in every two family members. “If an APL inheritance pattern can be firmly established in future studies, the good news is that we may be able to prevent premature stroke, heart attack, recurrent miscarriage and the other APL-associated diseases by performing simple and inexpensive tests and taking more thorough family
histories,” explained Dr. Greco. “It may be premature to say, but APL may end up being one of the common threads that ties together all of the seemingly unrelated 80 known autoimmune diseases,” said Virginia T. Ladd, president of the American Autoimmune Related Diseases Association (AARDA).
She said large studies of patients with neurologic autoimmune diseases such as multiple sclerosis and myasthenia gravis, endocrine autoimmune diseases such as thyroid, juvenile and type 1 diabetes, and rheumatic autoimmune diseases including rheumatoid arthritis, lupus, scleroderma and Sjogren’s syndrome, need to be conducted to confirm this theory. “If it turns out that APL is a common factor in autoimmune diseases, then the next step for researchers is to begin looking for an autoimmune gene.”
According to AARDA, approximately 50 million Americans,(20 percent of the population or one in five people) suffers from an autoimmune disease. Of these, the majority are women; some estimates say that 75 percent of those affected – well over 30 million people – are women. Autoimmunity is the underlying cause of all autoimmune diseases and the leading cause of chronic illness. While these illnesses cannot be cured, they can be treated.
AARDA is the nation’s only organization dedicated to raising awareness of the early warning signs of autoimmune diseases, bringing a national focus to autoimmunity as a major health issue, and promoting a collaborative effort among researchers to find a cure for all autoimmune diseases.
Profiles – Families with APL
The Frey Family – Several years ago, Jennie Frey, one of the patients in Dr. Greco’s study, suffered severe headaches, arthralgia (joint pain) and tested positive for the antiphospholipid antibody (APL). In her workup she was found to have multiple small strokes on her MRI scan. While in care, her daughter was hospitalized and had a stroke. Other physicians who had been caring for her discontinued her Coumadin after a year and she had a second stroke. In Dr. Greco’s first family study, he found that not only was this daughter (age 31) suffering from the APL syndrome (APS), but that a second daughter who had pregnancy loss has APLs. In addition, a third daughter also has auto-antibodies in her serum.
The Santiago Family – Amarilis Santiago is a young woman who, in her teens, developed ITP (the low platelet syndrome associated with APLs). She was treated for that and then developed ischemia (gangrene) of her finger and toe. She then developed deep venous thrombosis and phlebitis of her leg. Later, she had a major lung clot and recurrent lung clots – despite aggressive therapy – and required a filter placed in her inferior vena cava
to prevent further clotting and stroke, and further pulmonary emboli.
The Santiago family, like the Frey’s, was one of the families in Dr. Greco’s study. Amarilis’ mother, Mrs. Santiago, tested positive for APLs. She also has experienced joint pain, myalgia, headaches, but has not yet had any major events.
Amarilis’ brother has not been as lucky. In the early 90’s, while at the Groton Submarine base, he developed ITP (low platelet), the exact same disease process that Amarilis had developed. He was sent to Bethesda Naval Hospital where he tested positive for other auto-antibodies, and upon further evaluation was diagnosed with aplastic anemia. After conferring with Dr. Greco about the other family members’ medical history, a bone marrow transplant was ruled out by the Bethesda physicians. Instead, they treated him with high doses of corticosteroid and were able to reverse the aplastic anemia. While he recovered from that, he has since developed other medical problems, including a lupus-like illness.
The Morgan Family – Sister Morgan is a nun at the Abbey of Regina Laudis in Waterbury, Connecticut. She was diagnosed with a multiple sclerosis-like illness. Because of atypical presentations for her neurologic syndrome, she was evaluated by Dr. Greco and found to have APLs antibodies (two types).
Multiple sclerosis-like illnesses have not been described in patients with APLs and work is being done currently to further study this patient population. While not part of Dr. Greco’s study, his team has seen her father, who was suffering from weakness, joint pain and swelling. At first, his platelet count, which normally is 150,000 to 250,000, was 1,000. He suffered from thrombocytopenia (low platelet count), a disease that is well established as a primary marker for the APS. He also had APLs. Hence, both the daughter and father had APLs and both had different disease processes. Mr. Morgan had numerous hospitalizations over the next year. Over that period, a classic picture of APS, with thrombocytopenia , positive lupus anticoagulant and anticardiolipin antibodies (two types of APLs). He then developed a perforated nasal septum. Currently in Dr. Greco’s care, he is doing well on a therapy that includes cortisone therapy and cytoxic (anticancer) agents.
The Berardi Family – Anthony Berardi is a husband and father and has been a patient of Dr. Greco’s for many years. He has had cutaneous skin lupus erythematosus and some other features of systemic lupus erythematosus (SLE), but has been healthy enough to maintain his job as an electrician. His daughter developed juvenile rheumatoid arthritis and had been followed by Dr. Greco. She has also had pregnancy loss and has tested positive for APLs.
Her gynecologist has been notified and she has been started on treatment with aspirin therapy throughout the current pregnancy (standard therapy now for one pregnancy loss with APL). Recently, Mr. Berardi developed dizzy spells, numbness of his face, and symptoms suggestive of a transient ischemic episode (compromised blood flow to his brain). Based on his daughter’s history, he was tested for APLs recently and tested positive. He is being treated with Coumadin in order to prevent further strokes. (The strokes have been documented on MRIs). Another family member recently died with systemic lupus erythematosus