A glimpse into the history of description of the antiphospholipid syndrome.

Prior to 1983, several landmark reports prepared the stage for a detailed description of the Antiphospholipid (Hughes) syndrome (APS). Formerly depicted as lupus-like, APS exhibits a wide spectrum of symptoms that overlap with Sjogren's, Hashimoto, and other autoimmune diseases. In this review, we take a glimpse into the history of description of APS, discussing the events that led to its recognition as one of the most common autoimmune diseases and the enormous impact of that recognition in the rheumatology field.

The chequered history of the antiphospholipid syndrome.

Consideration of the chronology of advances in medical knowledge can provide useful insights into the pathogenesis, diagnosis and treatment of diseases. The antiphospholipid syndrome is an enigmatic disorder and this is reinforced by the misleading associated terminology, the adoption of which results directly from early discoveries relating to the condition. Thus the target antigen of the causative autoantibodies in antiphospholipid syndrome does not reside on phospholipid, and the frequently associated lupus anticoagulant is not restricted to subjects with systemic lupus erythematosus and, paradoxically, despite causing prolongation of clotting times in vitro it is associated with a pronounced tendency to thrombosis. Recognition of the antiphospholipid syndrome has its origins in the identification of subjects with so-called biological false-positive serological reactions for syphilis in the middle years of the last century. Since that time there have been considerable advances in our understanding of the pathogenesis of the disease and the clinical manifestations and associations, improved diagnostic accuracy and an evolving evidence base for optimal therapy. However many gaps in our knowledge remain.

A quarter of a century in anticardiolipin antibody testing and attempted standardization has led us to here, which is?

The anticardiolipin (aCL) test has been widely used by physicians since the mid-1980s for diagnosing patients with antiphospholipid syndrome (APS). Establishment of this diagnosis has enabled effective management of patients with recurrent thrombosis and recurrent pregnancy losses. The test was first established in 1983 as a radioimmunoassay and soon thereafter converted into an enzyme-linked immunosorbent assay (ELISA). The other test commonly used in the diagnosis of APS is the lupus anticoagulant (LA) test. The aCL ELISA is sensitive for the diagnosis of APS but lacks specificity. On the other hand, the LA assay, although more specific, is not as sensitive as the aCL ELISA. More specific tests are now available such as the anti-beta2 glycoprotein I (anti-beta2GPI) assay, the antiprothrombin assay, and other ELISAs that use negatively charged phospholipids instead of cardiolipin to coat the plates. In the past 25 years, there have been numerous efforts to standardize aCL, LA, and anti-beta2GPI tests but there are still reports of significant intra- and interlaboratory variation in results for all three assays. This article discusses in detail the clinical value of these tests, technical problems associated with their use, the current laboratory classification criteria for diagnosis of APS, and possible new and better assays that will be available in the near future for diagnosis of APS.

Attempts to make sense of the antiphospholipid syndrome.

Many investigators have been intrigued by the paradoxical association of a circulating anticoagulant, first called lupus anticoagulant by Feinstein and Rapaport [1], with a tendency to develop thrombosis, as initially described by Walter Bowie [2]. Work in Leuven on this topic started when Luis Carreras, an Argentinian hematologist, joined the laboratory of blood coagulation at this university in 1979. At that time, the head of the laboratory was Marc Verstraete. Luis had a particular interest in antibody-mediated coagulation disorders, and had prepared reviews on thrombosis and thrombocytopenia induced by heparin [3] and on the lupus inhibitor [4]. In Leuven, he joined Jos Vermylen, senior member of the laboratory, and an internist with particular interest in hemostasis, thrombosis and vascular disease. As such, Professor Vermylen was involved in both laboratory research and patient care.

Queen Anne (1665-1714) and her health.

The contemporary records of Queen Anne's health and disease are reviewed, including the strange diagnoses made and the treatments prescribed. A correct diagnosis is suggested.

New basic aspects of the antiphospholipid syndrome.

This article reviews recent changes in our understanding of the basic aspects of the Antiphospholipid syndrome (APS) with special emphasis on interactions with phospholipid binding proteins. We survey the history of the development of tests for the APS, and discuss current methods of detection of antiphospholipid antibodies, clinical events associated with APS, and new concepts regarding the immunological specificity of the antibodies.

Antiphospholipid antibody syndrome: new insights on thrombogenic mechanisms.

The antiphospholipid antibody syndrome is a thrombophilic condition manifested by vascular thrombosis or recurrent pregnancy loss together with the presence of antibodies against anionic phospholipid protein complexes. These antibodies are detected by their reactivity to the anionic phospholipids (or protein phospholipid complexes) in solid-phase immunoassays or by their property of inhibiting phospholipid-dependent coagulation reactions (the "lupus anticoagulant" effect). The pathophysiologic mechanisms of this syndrome have remained obscure because of the apparent multiplicity of antigenic determinants recognized by the antibodies and also because of the many effects which have been described for them. This article reviews current concepts of the antiphospholipid disease process and evidence for the hypothesis that thrombosis in this syndrome is a result of the displacement of annexin-V, an anionic phospholipid-binding protein with potent anticoagulant activity, from phospholipid surfaces. The authors propose that under physiologic conditions, annexin-V plays a thromboregulatory role at the vascular-blood interface by shielding anionic phospholipids from complexation with coagulation proteins in circulating blood. Thrombosis in the antiphospholipid syndrome is due to disruption of the annexin shield by antiphospholipid (and cofactor) antibodies which results in the increased exposure of thrombogenic phospholipids. Accumulated data are consistent with the hypothesis that the disruption of annexin-V binding to anionic phospholipid surfaces plays an important thrombogenic role in the antiphospholipid syndrome.

[The antiphospholipid syndrome]. / Das Phospholipid-Antikörpersyndrom.

Antiphospholipid syndrome (APS) is a thrombophilic disorder, which embraces almost all specialities. This article includes information about the history, classification, epidemiology, clinical manifestations and treatment of the APS. It is the aim of this article to introduce the APS with clinical features of all medical specialities to show the actuality of the syndrome which is not known everywhere.

Antiphospholipid antibodies and thrombosis.

Antiphospholipid syndrome is an autoimmune disease which combines vascular thrombosis and/or pregnancy complications with the presence of antiphospholipid antibodies. It could be a devastating and sometimes life-threatening condition. As vascular thrombosis presents as typical venous or arterial thromboembolism diagnosis is based on laboratory data. Therefore proper performance and interpretation of laboratory tests is crucial. Broader knowledge about clinical and laboratory aspects of the syndrome and their associations are essential for proper evaluation and management of the patients.

Hughes syndrome (the antiphospholipid syndrome): 25 years old.

The antiphospholipid (Hughes) syndrome (APS) is a unique thrombotic disorder, causing both arterial and venous thrombosis, linked to the presence of antibodies directed against phospholipid-protein complexes. The first papers describing the syndrome were published in 1983 and, over the next two years, a series of publications described in detail the various clinical manifestations of the syndrome. Laboratory standardisation workshops were also set up and, in 1984, the first "world" symposium on APS was held. The international APS conferences have continued to grow in numbers and in stature. The APS has already had an impact in obstetrics, in medicine, in psychiatry, and in surgery. The approximate figure of 1 in 5 is a useful guide -- 1 in 5 of all young strokes, 1 in 5 recurrent miscarriages, 1 in 5 DVTs. More precise data will become available in the worlds of epilepsy, migraine, Alzheimer's, and MS. The advent of newer "biologic" immunosuppressives such as rituximab may offer help in selected cases. Intravenous immunoglobulin has proved successful, especially in the emergency setting.

The primary, secondary, catastrophic, and seronegative variants of the antiphospholipid syndrome: a personal history long in the making.

Although many of the clinical features accompanying lupus anticoagulant positivity were documented in the early 1960s and many "non-lupus patients" were also published, it was not until the discovery of antibodies to cardiolipin in the 1980s that the existence and true ramifications of a distinct antiphospholipid syndrome was defined. A primary syndrome was in fact recognized in 1985 by the author while at the Hammersmith Hospital and comprised 25 patients who conformed to this new subset of disease, which has now overtaken lupus-associated (secondary) antiphospholipid syndromes in frequency. However, publication of this important milestone was in fact prevented, because of the purveying dogma at that time that "these patients were all suffering from 'lupus,'" which history has since proved to be incorrect. The syndrome was therefore only clearly defined AND published in 1988. Subsequently, in the following year, a new and more comprehensive multicenter series comprising 70 patients was documented (including the original 25 patients from 1985) as well as two smaller series by other units. The catastrophic variant of the syndrome with distinct triggering factors, clinical features, and a generally poor prognosis was then defined in 1992, with more than 300 patients with this devastating condition now summarized on the University of Barcelona online registry. The existence of a seronegative syndrome has also been suggested, but whether this is related to the presence of undetectable antiphospholipid antibodies or perhaps represents a similar type of vasculopathy or endotheliopathy is unclear at the present time. This article documents a personal account of the events that took place in relation to the description of these syndromes.

Diagnóstico en el síndrome antifosfolipídico: desde una perspectiva histórica a la aparición de nuevos autoanticuerpos / Diagnosis of antiphospholipid syndrome: From an historical perspective to the emergence of new autoantibodies

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