Transient global amnesia in a patient with high and persistent levels of antiphospholipid antibodies

Cerebrovascular disease is one of the most common symptoms associated with anticardiolipin antibodies (ACA) and lupus anticoagulant (LA), usually in the form of ischemic stroke. However, many other neurologic disorders have been described in patients with antiphospholipid syndrome or ACA. So far, the precise relation between the presence of antibodies and the development of the disease in many of these cases remain unknown. Transient global amnesia (TGA) is an infrequent neurologic disturbance whose precise pathophysiology is not known. It is characterized by a sudden inability to acquire new information, usually lasting no more than 12 h, and it is not accompanied by any other focal neurological signs or symptoms. We report a patient with TGA with persistent and high levels of ACA and LA and suggest that in patients with TGA, investigation of the possible presence of ACA and/or LA may be warranted because a higher prevalence of TGA in the patients with antiphospholipidic syndrome with respect to the general population may lead to further insights into pathogenesis of neurologic disease associated with antiphospholipidic antibodies.     

Pediatric antiphospholipid antibodies and antiphospholipid syndrome

Antiphospholipid syndrome (APS) can occur in children, like adults, with the same diverse spectrum of thrombotic sites but predominately with deep vein thrombosis and stroke. In contrast with adults, however, transient nonthrombogenic antiphospholipid (aPL) antibodies are seen more commonly, usually after childhood infections. In those with "true" aPL antibodies, recurrent thrombotic events seem less frequent than in adults, perhaps reflecting the less prothrombotic hemostatic state of childhood. Children with thrombotic events in APS present difficult management problems, as there is little evidence-based medicine. The duration and intensity of anticoagulation are unresolved management issues, but a target international normalized ratio of 2 to 3 is used by most. Multicenter randomized controlled trials would provide answers to some of these issues but are difficult to organize due to ethical issues and the rarity of the condition. A pediatric APS registry such as the Ped-APS Register is more easy to organize and can yield informative data.     

Managing antiphospholipid antibodies and antiphospholipid syndrome in children

Antiphospholipid antibodies (aPL) and antiphospholipid syndrome (APS) are increasingly being recognized in children. Transient non-pathogenic aPL are often seen after childhood infections, while thrombotic events seem rare in those with true aPL. We discuss the main scenarios faced when dealing with children with aPL--asymtomatic aPL, primary APS and secondary APS. Children with thrombotic events present difficult management problems, as there is little evidence-based medicine in this area. We discuss the manifestations and management of childhood aPL--asymptomatic aPL, primary and secondary APS elucidated with case histories. Insufficient safety data on anticoagulation and limited information on the effects of warfarin, use of aspirin, duration and intensity of anticoagulation are some of the unresolved issues in managing aPL and APS in children. Multicenter randomized controlled trials may provide answers to some of these issues.     

Origin of antiphospholipid antibodies

Our observations and those from others give further support to our hypothesis that "autoimmune aPL" may be generated by immunization with products from bacteria or viruses after incidental exposure or infection. We also were able to generate an APS-like syndrome in a strain of mice susceptible to autoimmunity, indicating that other factors such as genetic factors are likely to be involved in development of APS. Furthermore, not all aPL generated by immunization with bacterial or viral products were pathogenic. Based on the clinical experience and on the numerous reports indicating the presence of aPL in large number of infectious diseases, it may be expected that not all aPL produced during infection are pathogenic. We hypothesize that a limited number aPL induced by certain viral or bacterial products would be pathogenic in certain groups of predisposed individuals. Identification of those bacterial or viral agents may help to find strategies for the prevention of production of "pathogenic" aPL. Alternatively, free peptides may be used to induce tolerance against aPL production.     

Pathophysiology of antiphospholipid antibodies

The presence of antiphospholipid antibodies in plasma is a risk factor for thromboembolic complications. In vitro, however, the same antibodies can prolong dotting times in coagulation assays, a classic marker for a bleeding tendency. For years this contradiction has puzzled many scientists. Recently new insights into the interaction between antiphospholipid antibodies and their main target, the protein beta-2-glycoprotein I, have opened new avenues for the understanding of the pathology of this syndrome.     

Accelerated atheroma, antiphospholipid antibodies, and the antiphospholipid syndrome

Indirect data coming from animal studies and in vitro observations support the contention that the mere presence of antiphospholipid antibodies may be sufficient to increase atheroma development, regardless of other predisposing factors. It seems that humoral and cellular immune responses to beta 2-glycoprotein I can play an important role in mediating the increased propensity to atherosclerosis.     

Update on antiphospholipid antibodies

The association of antibodies with an apparent specificity for anionic phospholipids with thrombosis, fetal loss, thrombocytopenia, and certain other clinical manifestations is now well-recognized as the antiphospholipid syndrome (APS). Recent advances in our understanding of the antibodies and antigens involved include discovery of the crystal structure of beta2-glycoprotein I, (beta2GPI), genetic studies of beta2GPI polymorphisms, and the development of anti-beta2GPI and antiprothrombin immunoassays as clinical laboratory tests. The identification of antigen-specific T cells in APS patients has stimulated interest in the role of the cellular immune response in the syndrome. Clinical research in APS will also benefit from the development of preliminary classification criteria.     

Pathogenic role of antiphospholipid antibodies

The antiphospholipid antibody syndrome (APS) is characterized by recurrent arterial and venous thrombosis and/or pregnancy in association with antiphospholipid (aPL) antibodies. The pathogenic mechanisms in APS that lead to in vivo injury are incompletely understood. Recent evidence suggests that APL antibodies alter regulation of haemostasis and induce activation of complement. We will discuss the current knowledge on how aPL antibodies trigger increased inflammation and enhanced thrombotic tendency, and thereby lead to tissue damage.     

Clinical consequences of antiphospholipid antibodies

Antiphospholipid antibodies (aPL), notably the lupus anticoagulant and anticardiolipin antibodies, are the serological hallmarks of the antiphospholipid syndrome. Thrombosis and pregnancy complications are the most prominent clinical manifestations of this syndrome. This paper provides the clinician with guidelines for ordering and interpreting tests for aPL and discusses consequences for treatment if persistently positive tests are found.     

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.     

The significance of antiphospholipid antibodies

Antiphospholipid antibodies (APLA) present very heterogeneous groups of antibodies which can significantly influence processes on different levels of coagulation cascade depending on effects of phospholipid surfaces on blood coagulation. This usually leads to a particular level of thrombophylia. Clinical syndrome accompanying positive APLA, such as antiphospholipid syndrome, was defined by clinical and laboratory symptoms. This clinical syndrome can be a primary syndrome, if other disorders with ability to induce generation of antibodies can be excluded, or a secondary syndrome. The most often in cases of systemic tissue disease. APLA can be divided according to the presence of lupus anticoagulant and anticardiolipin antibodies. According to a definition lupus anticoagulants are antibodies able to inhibit and prolong in vitro one or more blood clotting processes dependent on phospholipid surfaces. Anticardiolipin antibodies are antibodies measured by ELISA method with cardiolipin used as an antibody. Findings show that some APLA are directed against proteins bound to phospholipid surfaces. Main cofactor proteins include beta 2-GPI and prothrombin. Because of their heterogeneous specificity, APLA are directed against negative phospholipids or proteins bound to phospholipid surfaces and have important pathophysiology role in development of antiphospholipid syndrome.     

Autoimmune antiphospholipid antibodies and cryoglobulinemia

In addition to their role in the thrombotic manifestations of the antiphospholipid syndrome (APS), autoimmune antiphospholipid (aPL) antibodies may also be responsible for direct injury to the blood vessel wall, although the mechanism is unclear. Cryoglobulinemia has been reported infrequently in patients with APS and is one potential means of blood vessel injury. The aim of the present study was to determine if autoimmune aPL antibodies and their target antigens contribute to the formation of cryoprecipitates. Cryoglobulins were identified and isolated from 5 of 8 patients with autoimmune aPL antibodies. Using identical concentrations of immunoglobulins isolated from matched sera and washed cryoprecipitates there was a significant enrichment (at least 100%) of aCL antibodies in the cryoprecipitates from 4 of 5 patients. This involved IgG, IgM and IgA isotypes with specificity for both beta2-glycoprotein I (GPI) and prothrombin (PT). The target antigens were detected in cryoprecipitates from all 5 aPL positive patients and in cryoprecipitates from 3 controls. These results suggest that anti-beta2-GPI and anti-PT antibodies in association with their target antigens are integrally involved in the formation of cryoprecipitates in patients with autoimmune aPL antibodies and provide insight into a potential mechanism for blood vessel injury.     

Cerebral haemostasis and antiphospholipid antibodies

One of the major clinical concerns of the antiphospholipid syndrome (APS) is the propensity of antiphospholipid (aPL) antibodies to cause thrombosis in both the large and small vessels of the brain. In this article, we review the current understanding of haemostasis in cerebral circulation and discuss this in the context of antiphospholipid antibodies. The systemic-defect-local-phenotype paradox is of particular importance in this discussion. In this paradigm, a systemic defect in thrombosis and haemostasis leads to a localized pattern of thrombotic disease because the regional physiological variations in the several prothrombotic and anticoagulant factors and the defect interact so as to favour thrombosis at a particular site. One possible mechanism of initiation of thrombosis in APS is the activation of endothelial cells by aPL that could occur in the cerebral vessels and provoke thrombosis. We review the evidence from gene knockout mice, other animal models and human postmortem examination studies as to which pro- and antithrombotic mechanisms are effecting haemostasis in the cerebral circulation. We conclude that there are large deficits in the understanding of the regulation ofhaemostasis in the human brain. As a consequence there is a lack of knowledge about the effect of aPL on cerebral endothelium and thrombosis. Recent developments in gene expression profiling may have an impact on our understanding of endothelial function in the brain. More research is required.