Antiphospholipid Antibody-Mediated Reproductive Failure in Antiphospholipid Syndrome

The association of elevated titers of circulating antiphospholipid (anti-PL) Abs in antiphospholipid syndrome (APS) and reproductive failure is well established in the literature. The clinical features include recurrent abortions at various stages, including implantation, placentation in the first trimester, miscarriages in the second and third trimesters, intrauterine growth retardation, preeclampsia with placental insufficiency and growth restrictions, arterial and venous thrombosis, and possibly also infertility. APS-mediated recurrent pregnancy loss and other features of reproductive failure might result from diverse autoimmune factors, inflammation, involving different mechanisms, which encompass pathogenic anti-PL Abs. Herein, we discuss the association of anti-PL Abs with reproductive failure with special emphasis on antiphospholipid autoantibodies characterizing APS. This association is evident from either human studies or murine models.     

Antiphospholipid syndrome

Antiphospholipid syndrome (APS) is a disease characterized by venous and arterial thromboses or spontaneous abortions and the repeated detection of antiphospholipid antibodies (aPL). APS may be associated with another autoimmune disease (secondary APS), particularly systemic lupus erythematosus (SLE), or unrelated to an underlying disease (primary APS). APS affects almost all organs. In addition to the clinical criteria, lupus anticoagulant testing and immunological aPL determinations are required to establish the diagnosis of APS.     

Antiphospholipid antibodies

The concept of antiphospholipid syndrome(APS) has been widely accepted. Antiphospholipid antibodies originally included anticardiolipin antibodies and lupus anticoagulants as serological marker of APS. However, recent advances have shown that most pathogenic antiphospholipid antibodies are directed to phospholipid binding proteins such as beta 2-glycoprotein I and prothrombin as well as phospholipids. The preliminary classification criteria for definite APS have been advocated as the "Sapporo criteria". Further prospective investigations are required to re-evaluate the clinical significance of so-called antiphospholipid antibodies.     

Antiphospholipid antibodies

OBJECTIVE: To review the role of lupus anticoagulants in the pathogenesis of both venous and arterial thromboembolic events, as well as in recurrent spontaneous abortions. The pathophysiology of lupus anticoagulants and associated antiphospholipid antibodies (eg, anticardiolipin antibodies) is also discussed. DATA SOURCES: Review of the recent medical literature. DATA EXTRACTION AND SYNTHESIS: Key articles in the recent medical literature dealing with lupus anticoagulants and their role in pathogenesis of thromboembolic events were reviewed. Plasma proteins that have an affinity for binding to "perturbed cellular membranes" have been identified as the antigenic targets for antiphospholipid antibodies. Thus, the concept of antiphospholipid antibodies needs to be reevaluated. Perhaps a better term is antiprotein-phospholipid antibodies. The principal antigenic protein targets are beta(2)-glycoprotein I, prothrombin, and a wide range of additional proteins that interact with activated cellular membranes, including protein C, protein S, annexin V, etc. Most research reported in the literature has focused on beta(2)-glycoprotein I and human prothrombin.     

Antiphospholipid antibodies

Conclusion Confirmatory evidence that aPL (the LA or aCL) are associated with an increased risk for arterial and venous thrombosis, recurrent spontaneous abortions, and fetal loss has led to increased laboratory requests for identification of these antibodies. Criteria for the definition of the APS is now well established. At present both the pathogenesis and the optimal management of the syndrome are uncertain. Treatment directed against the secondary thrombotic event is proving more successful than that directed against the underlying immunological abnormality. It is hoped that the results of various controlled therapeutic trials in the APS will indicate better ways of managing these difficult manifestations.     

Antiphospholipid syndrome

Abstract. The antiphospholipid syndrome (APS) was reported in the early 1980s as the association of thrombosis, recurrent pregnancy loss in the presence of anticardiolipin antibodies (aCL) and/or lupus anticoagulant (LA). Since then, many other clinical manifestations have been associated with aPL. Almost any organ and tissue may be involved in the disease, including the brain, the heart, the kidneys, the placenta and many more. aPL are a heterogeneous group of autoantibodies that are detected by immunoassays and functional coagulation tests. The antigenic targets are negatively charged phospholipids and serum phospholipid-binding proteins. Despite the strong association between aPL and thrombosis, the pathogenic role of aPL in the development of thrombosis has not been fully elucidated. Proposed mechanisms include antibody-mediated interference with coagulation homeostasis, activation of platelets and endothelial cells and a T-cell immune response to serum phospholipid-binding proteins. The mainstay of therapy is anticoagulation, whereas immunosuppression seems to be ineffective. Recommendations for the management of thrombosis in the antiphospholipid antibody syndrome have been based largely on retrospective case series. Several prospective clinical trials are currently underway and their results will probably lead to a more precise therapeutic approach of this problem.     

Antiphospholipid syndrome

The antiphospholipid syndrome (APS) was reported in the early 1980s as the association of thrombosis, recurrent pregnancy loss in the presence of anticardiolipin antibodies (aCL) and/or lupus anticoagulant (LA). Since then, many other clinical manifestations have been associated with aPL. Almost any organ and tissue may be involved in the disease, including the brain, the heart, the kidneys, the placenta and many more. aPL are a heterogeneous group of autoantibodies that are detected by immunoassays and functional coagulation tests. The antigenic targets are negatively charged phospholipids and serum phospholipid-binding proteins. Despite the strong association between aPL and thrombosis, the pathogenic role of aPL in the development of thrombosis has not been fully elucidated. Proposed mechanisms include antibody-mediated interference with coagulation homeostasis, activation of platelets and endothelial cells and a T-cell immune response to serum phospholipid-binding proteins. The mainstay of therapy is anticoagulation, whereas immunosuppression seems to be ineffective. Recommendations for the management of thrombosis in the antiphospholipid antibody syndrome have been based largely on retrospective case series. Several prospective clinical trials are currently underway and their results will probably lead to a more precise therapeutic approach of this problem.     

Antiphospholipid antibody syndrome

Antiphospholipid antibodies are directed against phospholipid-protein complexes and include lupus anticoagulant, anticardiolipin antibodies, and anti-beta-2 glycoprotein I antibodies. Antiphospholipid antibody syndrome is a common cause of acquired thrombophilia and is characterized by venous or arterial thromboembolism or pregnancy morbidity and the presence of antiphospholipid antibodies. Antibodies should be demonstrable on at least 2 occasions separated by 12 weeks. Heterogeneity of the autoantibodies and absence of gold standard assays makes interpretation of laboratory results a challenge for both laboratorians and clinicians. This review discusses the key laboratory and clinical aspects of antiphospholipid antibody syndrome. Particular focus is given to lupus anticoagulant detection, in view of recently updated laboratory guidelines.     

Antiphospholipid antibodies and atherosclerosis

Antiphospholipid antibodies (APA) are present in a variety of autoimmune disorders, including systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS). Increasing evidence suggests that a subset of APA can also be detected in patients with atherosclerosis. In this review, we discuss the specificities of the autoantibodies that are present during both APS and atherosclerosis. A critical and unresolved question is whether these APA are specific for epitopes that result from lipid oxidation. Despite the fact that APA are present in patients with systemic autoimmunity and that they may participate in the pathogenesis of APS, recent studies have paradoxically proposed a beneficial role for some APA in atherosclerosis. We review the evidence that some APA specificities may be protective against plaque formation, and we discuss the putative mechanisms by which some APA could be useful in the prevention of atherosclerosis.     

Management of Women with Antiphospholipid Antibodies or Antiphospholipid Syndrome during Pregnancy

Antiphospholipid syndrome (APS), which is characterized by the presence of antiphospholipid antibodies (aPL), is associated with increased risk of thrombosis and obstetric complications, including preterm delivery and recurrent pregnancy losses. APS shows diverse clinical manifestations and the risk of complications varies among clinical subtypes. Although these patients are usually treated with aspirin and anticoagulants, the optimal treatment in various clinical settings is unclear, as the risk of complications vary among clinical subtypes and the management strategy depends on whether the patient is pregnant or not. Also, there are unmet needs for the evidence-based, pregnancy-related treatment of asymptomatic women positive for aPL. This review focuses on the management of positive aPL or APS in pregnant and postpartum women, and in women attempting to become pregnant. For asymptomatic aPL positive women, no treatment, low dose aspirin (LDA) or LDA plus anticoagulants can be considered during antepartum and postpartum. In obstetric APS patients, preconceptional LDA is recommended. LDA plus low molecular weight heparin is administered after confirmation of pregnancy. Vascular APS patients should take frequent pregnancy test and receive heparin instead of warfarin after confirmation of pregnancy. During pregnancy, heparin plus LDA is recommended. Warfarin can be restarted 4 to 6 hours after vaginal delivery and 6 to 12 hours after cesarean delivery. Most importantly, a tailored approach and patient-oriented treatment are mandatory.     

Antiphospholipid Syndrome and Cognition

In addition to the well-defined neurologic events due to arterial and venous thrombotic vascular occlusions of antiphospholipid syndrome (APS), a broad spectrum of neuropsychiatric has been related to antiphospholipid (aPL). Experimental evidence of a pathogenic role of aPL in mice with impaired neurological function disclosed inflammatory reaction as a hallmark. The process that leads to neurological dysfunction seems to be both structurally destructive and functionally impairing. The most modern resources of neuroimmaging also suggest that, in addition to the micro-infarcts that occur in strategic areas, other metabolic impairments are related to progressive dementia and aPL presence. Although there is a lot of confusion among APS and lupus’ cognitive involvement, there is a body of experimental and clinical evidence that aPL causes this kind of damage.     

Antiphospholipid Syndrome Infectious Origin

Antiphospholipid syndrome (APS) is characterized by the presence of pathogenic autoantibodies against beta 2-glycoprotein-I (beta 2GPI). The factors causing production of anti-beta 2GPI remain unidentified, but an association with infectious agents has been reported. Studies on experimental APS models proved that molecular mimicry between beta 2GPI-related synthetic peptides and structures within bacteria, viruses, tetanus toxoid, and CMV are a cause for experimental APS. Any explanation of how microbial infections might set off APS must take into account the observation that all individuals appear to harbor potentially autoreactive lymphocytes, as well as natural antiphospholipid antibodies, but that these cells or antibodies remain innocuous unless somehow activated. Herein, we discuss the association of antiphospholipid antibodies in the infectious state, molecular mimicry as a proposed cause for development of APS, and the contribution of the database to this topic.     

Antiphospholipid Syndrome and Cancer

Thrombosis is a frequent complication of cancer that is a substantial cause of morbidity and mortality. The association of antiphospholipid antibodies (aPL) and cancer has been under investigation for several years. Recent findings suggest an increased prevalence of certain cancers in aPL-positive patients; thus, an intensive search for an occult malignancy is prompted in these patients. In addition, several studies reported on elevated levels of aPL in various malignancies; it seems, however, that aPL levels do not reflect their pathogenicity; therefore, their pathological significance in these subset of patients is still elusive. Continuing research on the association between the antiphospholipid syndrome/aPL and malignancies is important, given the potential impact on the understanding and treatment of both antiphospholipid syndrome and cancer.     

Antiphospholipid antibodies and reproduction

Antiphospholipid antibodies (APAs) may be identified in the laboratory by using either coagulation studies or solid-phase immunologic assays (ELISA; RIA). These methodologies do not necessarily evaluate the same antibody; consequently, it is appropriate to screen a patient's plasma by utilizing both assays. APAs have been associated with a variety of obstetrical complications including recurrent spontaneous abortion, intrauterine fetal death, early onset preeclampsia, deep vein thrombosis, and postpartum serositis syndrome. The Kaolin Clotting Time appears to be the most sensitive coagulation test for identifying the lupus anticoagulant. However, preliminary studies would suggest the presence of anticardiolipin antibodies as detected by solid-phase assays are more sensitive and predictive of the clinical course. Although there are no prospective trials to analyze treatment of patients with APA, preliminary data suggest the use of prednisone in combination with aspirin significantly improves the probability of delivery of a viable infant. In addition, heparin, intravenous gammaglobulin, and exchange plasmaphoresis have all been tried with varying degrees of success in individual patients in small series.     

Antiphospholipid antibodies and cancer

Antiphospholipid antibody (APLA) is a family of antibody that exhibits a broad range of target specificities and affinities all recognizing various combination of phospholipids binding proteins. Laboratories diagnosis of APLA can be difficult due to heterogeneity of APLA and a poor standardization of the laboratory tests. The antiphospholipid syndrome (APS) is a form of immune mediated thrombophilia occurring as a recurrent thrombotic event in association with positive laboratory test for antiphospholipid antibodies. The syndrome may be isolated, then defined as primary or secondary when it is associated to different diseases (like malignancies). The thrombotic events associated with APLA can be the first manifestation of malignancy. In patients with malignancy the presence of antiphospholipid antibodies increased the risk of thrombosis. Less than 1% of the patients with APS present a life threatening condition involving multiple organ thrombi and failure named as catastrophic antiphospholipid syndrome.