Antiphospholipid Antibody Syndrome

I’m going to talk about antiphospholipid antibody syndrome. I’ll be using the abbreviation APS for this talk. At the end of this talk, you should be able to define APS, describe the clinical presentation, identify the autoantibodies specific to the disorder, and summarize key points in the management. Here’s the outline for the talk. The term antiphospholipid antibody syndrome, APS, was coined in the early 1980s and described patients with recurrent thrombosis and pregnancy complications such as miscarriages, fetal death, and premature births and association with detectable autoantibodies directed against phospholipid-binding protein that interfere with coagulation. Antiphospholipid antibodies act as inhibitors binding to phospholipid portions of clotting factors and slow down coagulation cascade. APS can be primary, meaning the disease occurs without an associated autoimmune disease and contrast, secondary APS occurs in association with another disorder, most commonly systemic lupus erythematosus. Please note, not all patients with APS have lupus and not all patients with lupus have APS. In APS, auto antibodies are against phospholipids, portions of proteins involved in the coagulation cascade and act as inhibitors to clotting factors to slow down to coagulation cascade. They also activate and endothelial cells, monocytes, and platelets that lead to a state deep vein thrombosis or clot. You see listed three specific autoantibodies that define APS and we will go through each of them. The first antiphospholipid antibodies described are known as lupus anticoagulant, which, unfortunately, is a misnomer. First, not all patients with lupus anticoagulant have lupus. Second, we know the antibody causes clots and is not an anticoagulant. However, the autoanibody, in vitro, prolongs the clotting time or activated partial thromboplastin time by binding to phospholipids interfering with their ability to function as the cofactor in the calculation cascade. When a patient has a prolonged APTT, the next step is to perform a mixing study. In the case the lupus anticoagulant, mixing normal plasma that doesn’t have an antibody will not correct the prolongation of the APTT caused by the patient’s plasma that contains an antibody. To confirm the prolongation as due to lupus anticoagulant, there are additional laboratory tests available that are beyond the scope of this presentation. Of the three major classes of autoantibodies seen in APS, lupus anticoagulant is most strongly associated with thrombosis. The second class of autoantibodies are termed anticardiolipin antibodies, which is directed against a type of phospholipid called cardiolipin. The auto antibodies can come in three flavors, IgG, IgM, and IgA. Often laboratory will also quantify auto antibodies in international units with 40 units or higher considered clinically significant. Of the three types, anticardiolipin IgG is the most strongly associated with thrombosis, but not as strongly as is the lupus anticoagulant. The third class, Anti-Beta2-glycoprotein I antibodies are a subset of anticardiolipin antibodies. They interact with an apolipoprotein that is part of the phospholipid complex. These antibodies were not included in the original diagnostic criteria. Unfortunately, the laboratory assays are not standardized so the quality of the tests can vary by laboratory. Further, there is no strong evidence showing association between having these antibodies and developing thrombosis or pregnancy complications. Now, we’re going to look at the rates of these autoantibodies. The importance here is looking at the population which was studied. In a general population of healthy blood donors, we find about 6% to 9% of donors have at least one of these three antiphospholipid antibodies, but when checked again over time, only about 2% of these donors will have persistence of the autoantibodies. Antiphospholipid antibodies are seen in a high percentage of patients with lupus, but only about 10% to 20% of those patients will develop thrombosis. Additionally, a significant portion of individuals who suffer thrombotic cerebral vascular accidents a young age and women with recurrent miscarriages have antiphospholipid antibodies. There is about a 1% risk per year of developing a thrombosis with antiphospholipid antibodies and no prior history of thrombosis. In APS, clots in the venous circulation with deep venous thrombosis or pulmonary embolism are the most common. However, clots can occur in any venous or arterial vascular bed. In the arterial circulation, a cerebral vascular accident, CVA, is most common. Other manifestations include pregnancy complications such as miscarriages, fetal loss, and preeclampsia, which can result in premature delivery and adverse fetal outcomes. Less common manifestations include heart valve disease, typically mitral aortic regurgitation and coronary artery disease. The renal mesenteric and portal vasculature are rarely involved. Livedo reticularis is a common clinical manifestation APS and literally means blue net, which describes the bluish or purplish lacy appearance of the skin. It is produced by dilated dermal and subcutaneous venules. It occurs in about 25% of APS patients and can be a marker for arterial thrombosis. Now that we have reviewed the autoantibodies and clinical presentation, we will learn how these are incorporated into the classification criteria for APS. The initial Sapporo criteria developed in 1998, were updated in 2006. It is a very important point that to diagnose someone with APS, they must meet both clinical and laboratory criteria. For the clinical criteria, a patient must have either a vascular thrombosis or pregnancy morbidity. Vascular thrombosis is defined by one or more clinical episodes of arterial, venous, or small vessel thrombosis in any tissue or organ confirmed by imaging or pathology. For pregnancy morbidity, a patient can fit one of three clinical scenarios. The first is fetal death beyond 10 week of gestation, second is one or more premature births before the 34th week of gestation because of eclampsia or sever preeclampsia. Third is three or more unexplained consecutive miscarriages before the 10th week of gestation. In addition to a thrombosis are pregnancy complication, a patient must meet the laboratory criteria. A patient can have a lupus anticoagulant or anticardiolipin, IgG or IgM at 40 international units or higher or anti-Beta2-glycoprotein I antibody, IgG or IgM on two or more occasions, at least 12 weeks apart. The importance is that the antibodies are persistent. Now we are going to discuss the management of APS. We will use the term secondary prophylaxis as the patient by definition, has already suffered a thrombosis or pregnancy complication. Patients with antiphospholipid antibodies are not anticoagulated in the absence of a clinical manifestation such as an adverse pregnancy outcome or a clot. You must first manage vascular risk factors such as encouraging smoking cessation, stopping estrogen in females on oral contraception, and also reducing cholesterol, although there are no published guidelines on the target. A patient will need indefinite anticoagulation with the goal INR of 2 to 3. Currently, most patients are managed with warfarin long term. Some patients develop thrombosis despite anticoagulation with warfarin and further management of these patients is controversial, though many recommend a higher goal INR of 3 to 4. Pregnant patients with APS cannot take warfarin due to the fetal malformations it causes. The intensity of anticoagulation is based on the patient’s clinical event. For recurrent miscarriages, lotus aspirin typically, 81 milligrams daily, is used alone or in combination with unfractionated heparin, 5,000 to 7,500 international units, subcutaneously twice a day or prophylactic dose of low molecular Heparin such as enoxaparin, 40 milligrams subcutaneous daily. For fetal loss and/or premature delivery, aspirin and a slightly higher dose of unfractionated heparin, 7,500 to 10,000 international units are used. For prior clot, aspirin and unfractionated heparin, 10,000 international units three times a day or therapeutic dose of low molecular weight heparin, for example, enoxaparin, 1 milligram per kilogram twice a day are used. Catastrophic APS is an accelerated form of APS characterized by widespread clotting resulting in multi-organ failure. Fortunately, it is a rare form of APS accounting for less than 1% of all cases. Catastrophic APS can be a complication of APS in patients with established disease or can be the presenting manifestation of APS. Mortality is up to 50% to 60% even with treatment, which includes both anticoagulation immunosuppression. Patients typically require care in an intensive care unit and are treated with high dose steroids, such as 1 gram of methylprednisolone daily for several days along with intravenous immunoglobulins or plasma exchange. In summary, APS is a syndrome with recurrent thrombosis and pregnancy complications with autoantibodies. Auto antibodies include lupus anticoagulant, anticardiolipin, and anti-Beta2-glycoprotein I. Most commonly, patients present with DVT and PE, however, clots can occur in any venous or arterial bed. Patients can also have adverse pregnancy outcomes such as miscarriages, fetal death, and premature delivery. Diagnosis of APS requires both a clinical event and autoantibodies on 2 or more occasions at least 12 weeks apart. Patients require indefinite anticoagulation. Here are the references.

One Reply to “Antiphospholipid Antibody Syndrome”

  1. spellbound! very nice. I think you can add about other treatment modalities such as eculizumab in refractory case/ aPL nephropathy, immunomodulator in autoimmune hemolytic anaemia/ thrombocytopenia.

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