Antiphospholipid syndrome: antibodies and antigens

Elucidation of the antibodies and antigens involved in the antiphospholipid syndrome has provided many new insights and research opportunities. The major autoantibodies associated with the syndrome and detected in clinical laboratory assays for antiphospholipid antibodies are directed against prothrombin and beta2-glycoprotein I beta2GPI), a phospholipid-binding plasma protein whose physiological function is unknown. Recent advances in our understanding of these antibodies and antigens include discovery of the crystal structure of beta2GPI, identification of a plasmin cleavage site in beta2GPI, genetic studies of beta2GPI polymorphisms, development of clinical laboratory assays using purified protein antigens, and the identification of antigen specific T cells.     

Antiphospholipid antibodies in acute coronary syndrome

Antiphospholipid (aPL) antibodies entailing anticardiolipin (aCL) and anti-beta2 glycoprotein I (anti-beta2GPI) antibodies may be involved in a number of vascular diseases including coronary artery diseases (CAD) or stroke. Here we assessed the presence of aPL antibodies in acute coronary syndrome (ACS). The frequency of anti-beta2GPI antibodies was significantly higher (14.4%) in ACS in comparison to control healthy subjects (2%). In addition, serum concentrations of anti-beta2GPI antibodies were also increased in ACS. Anti-beta2GPI antibodies of the IgA isotype might be the most relevant for the onset and outcome of ACS. Regarding subclasses of ACS, anti-beta2GPI IgA antibodies were elevated in unstable angina (UA) and myocardial infarction with ST elevation (STEMI), but not in myocardial infarction without ST elevation (NSTEMI). The involvement of anti-beta2GPI antibodies in ACS was more pronounced in men than women, and in younger rather than older patients. Finally, anti-beta2GPI antibodies in ACS were associated with previous stroke, but not with hypertension or previous myocardial infarction. Thus, anti-beta2GPI antibodies may be involved in the thrombotic events underlying ACS.     

Antiphospholipid antibodies and stroke in Down syndrome

Two patients with Down syndrome and the primary antiphospholipid antibody are described. One patient had a vasculopathy similar to that previously described as Moyamoya. Down syndrome is characterized by immune defects including a tendency to autoimmune phenomena. This report extends the scope of these observations and particularly draws out the potential role of antiphospholipid antibodies. Indeed antiphospholipid antibodies may well explain the well-known association of Down syndrome and stroke.     

Antiphospholipid antibodies, antiphospholipid syndrome and viral infections

Since the association between antiphospholipid antibodies and syphilis was first described, many other viral, bacterial and parasitic infections have been shown to induce antiphospholipid antibodies, notably anticardiolipin antibodies. These aPL are usually associated neither with anti-beta2 glycoprotein I antibodies (anti-beta2-GPI) nor with thrombotic events, even if cases of arterial and deep venous thrombosis have been reported in such circumstances. A literature review shows that anticardiolipin antibodies occur frequently in viral infections, particularly in HIV (49.8%), HBV (24%) and HCV (20%). The prevalence of anti-beta2 glycoprotein I antibodies (anti-beta2GPI) is lower (HCV: 1.7%, HIV: 5.6%, HBV: 3.3%) and there is no demonstrated association with a risk of thrombotic events or hematological manifestations defining antiphospholipid syndrome (APS). Regarding other viral infections, including viral hepatitis A, herpes virus (CMV, EBV, VZV), parvovirus B19 and HTLV-1 infections, only a few studies are available but data confirm the high prevalence of antiphospholipid antibodies at the acute phase. Finally, antiphospholipid antibodies, mainly anticardiolipin, are frequently associated with viral infections. Their presence may probably reflect an intense or chronic antigenic stimulation of the immune system. However, their evolution under antiviral therapy and correlation with the quality of the virological control and/or the immune restoration remain to be determined.     

Antiphospholipid syndrome, antiphospholipid antibodies, and atherosclerosis

The antiphospholipid syndrome is characterized by arterial and venous thrombosis, as well as pregnancy morbidity, in the presence of elevated levels of antiphospholipid antibodies. These autoantibodies have procoagulant activity, as they affect platelets, humoral coagulation factors, and endothelial cells. In addition, they are proatherogenic, as demonstrated by animal models and by the increased prevalence of cardiovascular diseases in patients with systemic lupus erythematosus and antiphospholipid syndrome. Moreover, antiphospholipid antibodies, including anticardiolipin, anti-β2-glycoprotein-1, and anti-oxidized low-density lipoprotein, are associated with atherosclerosis and its consequences in the general population as well. This autoimmune aspect of atherosclerosis in the presence or absence of an autoimmune disease suggests benefit from development of immunomodulating therapies.     

Antiphospholipid syndrome

Antiphospholipid syndrome is an autoimmune systemic disorder characterized by arterial, venous, or small vessel thrombosis and/or recurrent early pregnancy loss, fetal loss, or pregnancy morbidity in the setting of documented persistent antiphospholipid antibodies that include the lupus anticoagulant, or moderate-high titer anticardiolipin, or anti-β2Glycoprotein I antibodies. Associated clinical manifestations include livedo reticularis, cutaneous ulcerations, thrombocytopenia, hemolytic anemia, valvular heart disease, and nephropathy. The degree of risk associated with antiphospholipid antibody depends on the characteristics of the antiphospholipid antibody profile and on the presence of additional thrombotic risk factors. Current standard treatment for unprovoked thrombosis is long-term warfarin or other vitamin K antagonist therapy. Treatment to prevent recurrent obstetric complications is low-dose aspirin and prophylactic heparin, usually low-molecular-weight heparin. Optimal treatment for standard therapy failures or for certain nonthrombotic manifestations is uncertain, although nonanticoagulation therapies that address multiple demonstrated mechanisms of disease are being explored.     

Antiphospholipid syndrome

Antiphospholipid syndrome (APS) is characterized by recurrent arterial or venous thromboembolism or pregnancy loss in association with antibodies directed against anionic phospholipids or plasma proteins bound to anionic phospholipids. A common cause of the huge variety of clinical manifestations is vaso-occlusive disease and not vasculitis in venous or arterial blood vessels of different sizes and sites (i.e. deep vein thrombosis, pulmonary embolism, cerebrovascular disease). In accordance with this, fetal abortion, typically beyond the tenth week of gestation, is also caused by infarctions of blood vessels in the placenta. Establishing the correct diagnosis of APS is not easy. To estimate the risk of thrombotic complications is challenging, as well as the questions of, which, how long and in what strength anticoagulation is recommended. This paper should enable the reader to apply international consensus classification criteria correctly, to interpret the different laboratory tests for anti-phospholipid antibodies and to gain an awareness of the different forms of anticoagulation in order to stratify therapeutic decisions.     

Antiphospholipid syndrome

Antiphospholipid syndrome (APS), first described and termed in the early 1980's, is defined by its clinical and laboratory signs. If other disorders inducing antibody production are excluded, APS may be considered a primary disease. Or it can be a secondary condition that is usually seen in systemic diseases of connective tissues. The main concept of APS is based on strong association between its clinical and laboratory manifestations and patient's medical history. Clinical signs include recurrent arterial and venous thrombosis or repeated fetal losses; laboratory criteria involve lupus anticoagulant (LA) syndrome or medium and high titres of anticardiolipin (aCL) antibodies. Thus defined, APS represents the most common form of acquired thrombophilic conditions while the basic concept lies in strong association between specific clinical manifestations and repeated detection of LA or aCL. Antiphospholipid antibodies (LA and aCL) are extremely heterogeneous antibody groups whose effect on processes at different levels of coagulation cascade varies. Their effect can be analogical to the action of phospholipid surfaces at various points of blood coagulation. This process usually results in development of a certain degree of thrombophilia. Present level of understanding of APS indicates that characteristics of clinical signs and detection and evaluation of antiphospholipid antibodies have not been definitely established yet and are to be specified with the help of molecular geneticists, immunologists, biochemists, hematologists and rheumatologists.     

Antiphospholipid antibodies in practice

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the occurrence of thrombotic or obstetrical events associated with the presence in the serum of patients of antibodies that are associated with thrombosis. For the diagnosis of APS, the presence of either lupus anticoagulant, anticardiolipin or anti-β2-glycoprotein1 antibodies of IgG or IgM isotype is required through laboratory testing. Other autoantibodies such as antiphosphatidylethanolamin or antiphosphatidylserin/prothrombin complex antibodies may be interesting in the diagnosis of APS when common antiphospholipid antibodies are missing. These autoantibodies are still under evaluation for their diagnostic contribution. Despite numerous attempts, the assays that are available for the identification of antiphospholipid antibodies have not been standardized yet, which leads to high variability between reagents and laboratories. Thus, to optimize the biological monitoring of APS syndromes, it is mandatory to have consecutive samples analyzed in the same laboratory.     

Antiphospholipid antibodies in children

Lupus anticoagulant (LA) is made up of heterogeneous IgG and IgM antibodies that prolong clotting times in vitro and is associated with an increased rate of both thrombosis and hemorrhage in vivo, although thrombosis is far more common. Many mechanisms of action have been explored, but none explains the coagulation abnormality of every sample tested. Binding of these antibodies to protein phospholipid complexes provides a unifying model. Antiphospholipid antibodies (APAs) are found in adult patients with a variety of disorders or as an isolated finding. The association of LA and anticardiolipin antibodies (ACAs) with thrombosis in adults has been established, although there is no test as yet to predict thrombotic risk for an asymptomatic affected individual. The presentation of thrombosis with postinfectious APA is uncommon in adults. Children who present with thrombosis and LA are found to have underlying disorders similar to those of adults. Although the presentation of thrombosis in children with postinfectious LA is rare, the association is established. LA-positive children with thrombosis have manifested a severe acquired deficiency of protein S; LA-positive children with hemorrhage have manifested an acquired deficiency of prothrombin. The association of thrombosis with ACA-positive children has been reported. Further work to determine the epidemiology, mechanism of action, and thrombotic potential of APA in children is warranted to better understand, prevent, and treat thrombotic and hemorrhagic complications.     

Antiphospholipid antibodies and hypertension

Hypertension is a common manifestation of antiphospholipid syndrome (APS). Antiphospholipid antibodies (aPL) have been described in patients with hypertension secondary to renal artery stenosis (RAS). Twenty-six patients with RAS and 25 patients with severe essential hypertension (diastolic blood pressure > 110 mmHg or > or = 3 hypertensive drugs) were studied and compared to 61 age- and sex-matched healthy subjects. Serum samples were tested for lupus anticoagulant (LA), anticardiolipin (aCL) IgG and IgM, antiprothrombin (aPT) IgG and IgM, anti-beta2glycoprotein 1 (abeta2GP1) IgG and IgM. aPL were negative in all patients with RAS. Two patients with essential hypertension had positive aPL (8%) (LA in one patient confirmed in a second assay and abeta2GP1-IgG in the other patient confirmed one year later together with aCL IgG positivity). Among healthy subjects, one case (1.6%) was found to be positive for LA, aCL IgM, abeta2GP1 IgM, aPT IgG, aPT IgM. In conclusion, the association between RAS and aPL seems to be casual rather than an expression of an elective thrombotic localization ofAPS. The positive finding of aPL in 8% of patients with essential hypertension, a frequency higher than that of the control population, deserves further studies in larger series to better explore the relationship between aPL and hypertension.