Rarer clinical associations of antiphospholipid antibodies

Detection of antiphospholipid antibodies (aPL) are central to the definition of the antiphospholipid (antibody) syndrome (APS). Thrombosis in certain vascular beds, such as the cerebral circulation, the veins of the lower legs and cutaneous vessels, and/or fetal loss, are common manifestations of APS. However, aPL have been found in association with a large range of other clinical conditions-these conditions constitute a rather heterogeneous group and are the subject of this review. Thus, aPL may rarely be found in association with thromboses of vascular beds other than those commonly associated with APS. The combination of thrombosis and aPL still satisfies the criteria for APS, and management of this group of patients is the same as that of APS associated with the more common manifestations of the disease. Alternatively, aPL may be detected in a range of conditions where thrombosis cannot be clearly demonstrated, such as duodenal ulcer or transverse myelopathy. The approach to management of patients who have aPL in association with these conditions is less clear, although in some cases interventions to remove the associated antibody have been associated with amelioration of the condition. Finally, in several studies, aPL have been detected in a proportion of patients with conditions occurring commonly in the normal population-these findings have to be treated with caution in view of inconsistent findings between the reported results and methodological limitation of studies purporting to show positive results.     

Multiorgan failure due to rapid occlusive vascular disease in antiphospholipid syndrome: the ‘catastrophic’ antiphospholipid syndrome

The term ‘catastrophic’ antiphospholipid syndrome (CAPS) is defined as an accelerated form of antiphospholipid syndrome (APS) usually resulting in multiorgan failure. These patients have in common: (i) clinical evidence of multiple organ involvement developing in a very short time period; (ii) histopathological evidence of multiple small vessel occlusions (a minority also have large vessel thrombosis); and (iii) laboratory confirmation of the presence of antiphospholipid antibodies (aPL), usually in high titres. Although less than 1% of patients with the APS develop this complication, its potentially lethal outcome emphasizes its importance in clinical medicine.     

Antiphospholipid antibodies in rheumatoid arthritis: Identifying the dominoes

Antiphospholipid antibodies (aPL) occur in a variety of autoimmune, malignant, and infectious diseases, with or without the thrombotic or obstetric sequelae that characterize the antiphospholipid syndrome. Although many studies have focused on the clinical implications of aPL in systemic lupus erythematosus, few have specifically addressed the questions facing rheumatologists caring for rheumatoid arthritis patients who are concomitantly positive for aPL. Such a clinical scenario requires current knowledge of antiphospholipid syndrome diagnosis criteria, test reliability, conditions causing temporal positivity of aPL, and treatment risks and benefits. Recently researched factors possibly integral to rheumatoid arthritis’s increased morbidity and mortality and related to aPL include oxidatively modified low-density lipoprotein antibodies, homocysteine, annexins, infectious agents, β estradiol, and specific gene polymorphisms. This review presents current scientific research addressing the pathophysiologic mechanisms and clinical implications of aPL in rheumatoid arthritis.     

Antiphospholipid antibody associated thrombocytopenia and the paradoxical risk of thrombosis

The pathogenesis of thrombocytopenia in patients with antiphospholipid syndrome (APS) is heterogeneous. Patients with antiphospholipid antibodies (aPL) and thrombocytopenia in the absence of clinical manifestations of APS will be diagnosed and treated as idiopathic thrombocytopenic purpura. However, the presence of aPL places those individuals at particular risk for developing both bleeding and thrombotic complications. Therefore, we propose the inclusion of such patients in the subgroup 'aPL-associated thrombocytopenia'. More attention should be devoted to this subgroup of patients to elucidate the role of aPL in the development of thrombocytopenia and to facilitate the adequate monitoring of its potential thrombotic risk.     

Prothrombotic mechanisms based on the impairment of fibrinolysis in the antiphospholipid syndrome

Antiphospholipid syndrome (APS) is a clinical autoimmune disorder characterised by thrombosis, venous or arterial, and recurrent pregnancy morbidity in association with the persistence of antiphospholipid antibodies (aPL). The clinical variety of aPL ranges from asymptomatic individuals to those with multiple organ thromboses and failure developing over a short period, also known as catastrophic APS. An increasing number of phospholipid-binding proteins with crucial functions in the regulation of blood coagulation and fibrinolysis are targeted by APS-related autoantibodies. Disruption of fibrinolysis is one of the proposed pathophysiological mechanisms for the APS. There are some experimental data for an association between impaired overall fibrinolytic activity and autoimmune aPL; however, evidence is still inconclusive and more studies are needed in this area. In this article, we review the evidence by which aPL may disturb fibrinolysis.     

Novel considerations in the pathogenesis of the antiphospholipid syndrome: involvement of the tissue factor pathway of blood coagulation

The antiphospholipid syndrome (APS) is characterized by clinical manifestations such as venous and arterial thrombosis, thrombocytopenia and/or recurrent pregnancy loss, as well as the persistent presence of laboratory markers of antiphospholipid (aPL) antibodies detected in laboratory assays. Though it is generally accepted that aPL antibodies, such as anticardiolipin (aCL), anti-beta2 glycoprotein I (anti-beta2GPI), and lupus anticoagulants (LA) contribute to the pathogenesis of APS, precise mechanism(s) are yet to be fully described. It is probable that aPL antibodies bind to a range of cellular targets (e.g., platelets, endothelial cells, and monocytes), leading to thrombosis and obstetric complications. There is now increasing evidence that alterations to the tissue factor (TF) pathway of blood coagulation contribute toward hypercoagulability in patients with aPL antibodies. This article reviews current evidence that suggests changes and/or interference to the major pathway of blood coagulation may represent a novel mechanism that contributes to the development of APS.     

Antiphospholipid antibodies in primary Sjögren's syndrome: prevalence and clinical significance in a series of 74 patients

The aim of this study is to determine prevalence, clinical significance of antiphospholipid antibodies (aPL) including anticardiolipin antibodies (aCL), anti-beta2GP1 and lupus anticoagulant (LA) in a cohort of 74 patients with primary Sj?gren's syndrome (pSS) according to revised European criteria. aPL were found in 25 (34%) patients; IgG in 23 (12 had low titres, six moderate titres and five high titres) and IgM in five (three and two had respectively moderate and high titres). Eight (11%) patients were found to have LA; anti-beta2GP1 antibodies were detected only in three (4%) patients. Only two patients with LA, aPL and beta2GP1 had recurrent venous thrombosis. One patient with moderate titres of aPL exhibited recurrent spontaneous foetal losses. Peripheral neuropathies without cryoglobulinemia were more frequent in the aPL group. Other systemic involvements of pSS were the same in both groups with or without aPL. Patients with aPL have more concurrent immunological diseases such as thyroiditis and primary biliary cirrhosis and a higher prevalence of hypergammaglobulinemia (P < 0.05). Even if aPL prevalence reached 30% in pSS, titres were usually low, with a close correlation with hypergammaglobulinemia but not with antiphospholipid syndrome, which is related to positivity of both LA and aPL.     

Syndrome des antiphospholipides « séronégatif » : mythe ou réalité ?

The antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombosis and/or obstetrical manifestations and the persistent presence, at least 12 weeks apart, of antiphospholipid antibodies (aPL) such as lupus anticoagulant (LA) and/or anticardiolipin antibodies (ACL) and/or anti-β2 glycoprotein I antibodies (aβ2GPI). The finding of patients with clinical profile highly suggestive of APS but who are negative for conventional biological criteria has led to the concept of seronegative APS. In the last few years, new antigen targets and methodological approaches have been employed to more clearly identify this syndrome in patients with thrombosis or obstetrical complications without conventional aPL. Although seronegative APS is still controversial, there is increasing recognition of the existence of this subgroup. However, clinical relevance of non conventional aPL need to be confirmed by efforts toward standardizing new biological tools and longitudinal studies involving large cohort of patients.     

Neurologic manifestations of the antiphospholipid syndrome

Antiphospholipid syndrome is an important cause of neurologic morbidity. The clinical criteria for antiphospholipid syndrome include only cerebrovascular arterial and venous thrombosis, but many other neurologic manifestations have been associated with antiphospholipid antibodies (aPL). This review discusses the role of aPL in cerebrovascular manifestations and in some of the other neurologic manifestations commonly associated with these antibodies, as well as data pertaining to the pathophysiology of aPL-associated neurologic manifestations and treatment issues.     

Antiphospholipid antibodies in response to infection

An association between infections and antiphospholipid antibodies (aPL) has been reported in several epidemiologic and experimental studies. Infection-induced aPL have been traditionally regarded as transient and were generally not associated with clinical features of antiphospholipid syndrome. The distinction between autoimmune and postinfectious aPL on the basis of requirement of binding cofactor is not absolute, and in recent years, several reports demonstrated that some patients can produce pathogenic antibodies in response to infection. Infections most frequently associated with antiphospholipid syndrome include parvovirus B19, cytomegalovirus, varicella-zoster virus, HIV, streptococcal and staphylococcal infections, gram-negative bacteria, and Mycoplasma pneumoniae.     

Recent advances in antiphospholipid antibodies and antiphospholipid syndromes in pediatric populations

In recent years, antiphospholipid antibodies (aPL) and their associated clinical features have been recognized increasingly in various pediatric autoimmune and non-autoimmune diseases. Pathogenic mechanisms involved in pediatric antiphospholipid syndrome (APS) appear to be the same as in adults. However, since pediatric patients do not have prothrombotic risk factors present in adults, there clearly are differences in the spectrum of clinical findings. The frequency of aPL-related thrombotic events is generally low in pediatric populations. On the other hand, various commonly acquired infections are likely to be responsible for higher percentage of non-pathogenic and transient aPL in childhood. Such points have to be considered in clinical judgment of elevated aPL in children. In this review we summarize the recent data on the prevalence and clinical significance of aPL in neonates, children and adolescents.     

Epilepsy as part of systemic lupus erythematosus and systemic antiphospholipid syndrome (Hughes syndrome)

The antiphospholipid syndrome (APS) is defined by the presence of antiphospholipid antibodies (aPL), demonstrated by ELISAs for antibodies against phospholipids and associated phospholipid-binding cofactor proteins and/or a circulating lupus anticoagulant (LA) together with diverse systemic clinical manifestations such as thrombosis, and recurrent spontaneous abortions. According to the criteria set out in Sydney the only neurological manifestations that can be suitable as APS classification criteria are ischemic events (stroke and transient ischemic attacks). However, other neurological manifestations, including seizures in particular, have been repeatedly reported in APS patients. The present review will summarize recent research on the association of aPL, as well as other autoantibodies, with seizure disorders, with or without concomitant SLE.     

Antiphospholipid syndrome, “the best prophet of the future”

The antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the occurrence of venous and arterial thromboses, often multiple, and obstetric-related adverse events in the presence of antiphospholipid antibodies (aPL). APS, first described in 1983, as thrombosis, abortion and cerebral disease, is nowadays recognised as a systemic disease with a wide constellation of clinical manifestations related to acute and chronic vascular lesions. The presence of aPL is the serological hallmark of APS representing a heterogeneous population of autoantibodies with many antigenic specificities directed to phospholipid-binding proteins, either alone or in combination with phospholipids. Many assays have been developed for aPL detection. Particularly, anticardiolipin antibodies, anti-β2-glycoprotein I antibodies and lupus anticoagulant are essential tools for APS diagnosis. The cumulative evidence indicates that aPL are pathogenic autoantibodies binding to target cells and promoting thrombosis and pregnancy complications through a wide range of pathological mechanisms not yet fully understood. Finally, the recognition of the important role of aPL to assess the individual risk of thrombosis or pregnancy complications has expanded the concept of aPL, and currently aPL profile is regarded as a major risk factor for clinical thrombotic events.     

Non-stroke neurological syndromes associated with antiphospholipid antibodies: evaluation of clinical and experimental studies

Although many types of neurological disorders and events have been described in association with antiphospholipid antibodies (aPL) and the antiphospholipid syndrome (APS), only ischaemic stroke is reasonably well established and accepted as a diagnostic criterion for the syndrome. We propose to evaluate, classify and rank the association of other neurological manifestations as possible, probable, or definite according to the data available from clinical studies and animal models. By these criteria, none of the neurological disorders or events such as epilepsy, psychiatric disease, dementia, transverse myelitis, multiple sclerosis-like disease, chorea, migraine, Guillian-Barrè syndrome, and sensory-neural hearing loss, can be definitely associated with aPL or APS.     

Ethnic and geographical variation in antiphospholipid (Hughes) syndrome

Investigation of the clinical epidemiology of the antiphospholipid syndrome (APS) is in its early stages. During the past 20 years, studies of antiphospholipid antibodies (aPL) and APS have been made in many countries and ethno-geographical groups. aPL appear to occur in all populations studied, with some variations noted in their frequency and in the clinical complications. Environmental and genetic factors contribute to ethnic variation and susceptibility to APS and thus inter-ethnic differences in disease patterns may be due to environmental or genetic factors, or both.     

Pathogenesis of the antiphospholipid syndrome

The presence of pathogenic antiphospholipid antibodies (aPL) is the characterizing feature of the antiphospholipid syndrome (APS), mediating the recurrent pregnancy loss and thrombosis typical of the disease, through their action on various antigenic targets. Despite the available knowledge regarding the mechanisms by which aPL induce a procoagulant phenotype in the vasculature and abnormal cellular proliferation and differentiation in placental tissues to cause the typical clinical features, these processes still remain incompletely understood. It is also known that inflammation serves as a necessary link between the observed procoagulant phenotype and actual thrombus development, and is an important mediator of the placental injury in APS patients. Even less well understood are the processes underlying the ontogeny of these pathogenic antibodies. This review seeks to highlight what is known about the mechanisms that contribute to the origin of pathogenic aPL and to the action of these antibodies on target antigens that produce the pathological features of APS. We will also examine the feasibility of classifying patients in clinical phenotypes related to underlying pathophysiological mechanisms, and how this could impact the management of patients with novel "targeted" therapeutic strategies.     

Laboratory diagnosis and management challenges in the antiphospholipid syndrome

The antiphospholipid syndrome (APS) is characterized by recurrent arterial and/or venous thrombosis and pregnancy morbidity manifested by early or late losses. Laboratory diagnosis ofAPS relies on the demonstration of a positive test for antiphospholipid antibodies (aPL). In clinical practice, the gold standard tests are those that detect anticardiolipin antibodies (aCL) and/or the lupus anticoagulant (LA). Although other specificities for aPL have been described their clinical utility and standardization has still to be established. Persistence of aPL positive tests must be demonstrated, and other causes and underlying factors considered. Although it is universally recognized that the routine screening tests (aCL and/or LA) might miss some cases, careful differential diagnosis and repeat testing are mandatory before the diagnosis of 'seronegative APS' can be made. Correct identification of patients with APS is important, because prophylactic anticoagulant therapy can prevent thrombosis from recurring, and treatment of affected women during pregnancy can improve fetal and maternal outcome.     

Anti-beta 2-glycoprotein I antibodies: a useful marker for the antiphospholipid syndrome

We studied anti-beta 2-glycoprotein I antibodies (a beta 2GPI) in autoimmune disease patients to evaluate their relationship to clinical findings. Seventy-nine systemic lupus erythematosus (SLE) patients [44 with antiphospholipid antibodies (aPL)], 21 with primary antiphospholipid syndrome (APS), eight asymptomatic individuals with aPL and 60 controls were studied. Sixteen SLE patients (14 with aPL and two without aPL) and six with primary APS had a beta 2GPI. A significant relationship was found between a beta 2GPI and aPL (P < 0.01). In SLE, a significant correlation was found between previous thrombosis or thrombocytopenia and a beta 2GPI or a beta 2GPI + aPL, but not between fetal losses and a beta 2GPI. These data suggest that a beta 2GPI may be useful in the study of APS.      

Drug treatment-induced downregulation of antiphospholipid antibodies in PAPS

Although low-dose methotrexate (MTX) has been used to treat several autoimmune diseases like lupus erythematosus, rheumatoid arthritis, etc., it has not yet been used to treat patients with primary antiphospholipid syndrome (PAPS). Parallel to clinical follow-up of female patient with a severe form of PAPS, antiphospholipid antibodies (aPL), blood coagulation, and hematological parameters in the peripheral blood have been monitored. MTX improved ulcers, livedo reticularis, decreased aPL titers, increased platelet counts, and improved blood coagulation parameters (e.g., factor VIII) and was well tolerated. Low-dose MTX was safe and effective in the presented case with PAPS. The clinical benefit may be due to the downregulation of increased aPL titers and amelioration of disturbed coagulation parameters.     

Cognitive impairment in antiphospholipid syndrome: evidence from animal models

Although antiphospholipid syndrome (APS) is a multisystem prothrombotic condition, its inflammatory nature has been increasingly recognized in recent years. Stroke and transitory ischemic attacks are the neurological manifestations included in APS criteria, however many other neurological involvements have been attributed to antiphospholipid antibodies (aPL), such as seizures, transverse myelitis, and cognitive impairment. In this article we will review evidence from animal model that explain the role of aPL in cognition.