Classification Criteria For Antiphospholipid Syndrome Research Articles

Antiphospholipid Syndrome

The antiphospholipid syndrome (APS) is an autoimmune systemic disease that is diagnosed when there is vascular thrombosis and/or pregnancy morbidity occurring with persistently positive antiphospholipid antibodies (aPL) (lupus anticoagulant test, anticardiolipin antibodies, and/or anti– β 2-glycoprotein I antibodies). Although International APS Classification Criteria have been formulated to provide a uniform approach to APS research, aPL may cause a spectrum of clinical manifestations, some of which are not included in these criteria. The main aPL-related cardiac manifestations include valve abnormalities (vegetations and/or thickening), myocardial infarction (MI), intracardiac thrombi, and myocardial microthrombosis. In this article, we will review the definition, etiopathogenesis, clinical manifestations, diagnosis, and treatment of aPL-related clinical events with emphasis on cardiac manifestations.

Thromboprophylaxis and obstetric management of the antiphospholipid syndrome

There is consensus in treating patients with antiphospholipid syndrome (APS) and first venous thrombosis with oral anticoagulation to a target international normalized ratio of 2.0 – 3.0. A recent systematic review recommended a target international normalized ratio > 3.0 in the group of patients with APS and arterial thrombosis. The approach for women with obstetric manifestations of APS is based on the use of aspirin plus heparin. In addition, we summarize the evidence-based information about management of catastrophic APS and some difficult cases, such as ‘seronegative’ APS, patients who do not display formal classification criteria for APS, and recurrent thrombotic events despite optimal anticoagulation.

Neonatal effects of maternal antiphospholipid syndrome

Antiphospholipid antibodies (aPL) can impair the physiologic development of a fetus during pregnancy not only by causing thrombosis of the placental vessels, but also by directly binding throphoblast cells and modifying their functions. Consequently, the presence of aPL in pregnant women is linked to an increased rate of pregnancy complications. These include recurrent early miscarriages, late fetal losses, and hypertensive disorders of gestation. In this clinical setting, preeclampsia is usually early and severe and can be complicated by the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome). The close association between aPL and obstetric pathology supports the inclusion of these manifestations in the clinical classification criteria of antiphospholipid syndrome. About 30% of children born to mothers with aPL passively acquire these autoantibodies; fortunately, the occurrence of thrombosis seems extremely rare in these babies. The prospective ongoing studies of children born to antiphospholipid syndrome patients reassure us about their general good health; however, some data suggest that learning difficulties might occur, possibly related to in utero exposure to aPL.

How we diagnose the antiphospholipid syndrome

AbstractThe antiphospholipid syndrome (APS) is an acquired thrombophilia, characterized by the occurrence of venous and arterial events. This article examines the laboratory and key clinical aspects of APS. Particular focus is given to anti–beta 2-glycoprotein I (β2GPI) antibodies in view of their recent inclusion in the APS classification criteria. The clinical utility of using the β2GPI enzyme-linked immunosorbent assay, in conjunction with the established lupus anticoagulant assays and cardiolipin enzyme-linked immunosorbent assay, for diagnosing and risk stratifying patients suspected of having APS is discussed. The relative importance of the various assays in diagnosing obstetric APS (early and late gestation miscarriages) is explored. The implications of recent epidemiologic findings for possibly understanding the underlying pathophysiologic mechanisms of obstetric APS are highlighted. Insights into which patients with obstetric APS may be at most risk of thrombotic complications are presented.

Primary, Secondary, and Catastrophic Antiphospholipid Syndrome: What's in a Name?

The association of the lupus anticoagulant with thrombosis and recurrent pregnancy loss was first recognized over a 20-year period between the early 1960s and early 1980s. The introduction of the anticardiolipin test in 1983 and the recognition of its association with clinical features similar to the lupus anticoagulant led to an exponential growth of interest in this disorder. The belief that anticardiolipin antibodies and lupus anticoagulant belonged to the family of antiphospholipid antibodies led to the disorder being named the antiphospholipid syndrome (APS). Efforts by individual investigators to introduce criteria for classification of APS and to standardize anticardiolipin antibody and lupus anticoagulant tests were started in the mid-1980s to ensure more reliable recognition and treatment of affected patients. Another layer of complexity was introduced with recognition that many anticardiolipin antibody-positive sera also bound the antigen beta (2) glycoprotein I. With increasingly sophisticated epidemiologic and prospective studies in the 1990s, more structured and better-documented criteria for APS were introduced in 1999 and modified in 2006. These criteria have been widely adopted. Whereas data supporting subclassification of APS into primary and secondary subgroups remain tenuous, a small percentage of patients do appear subject to clinical features termed the catastrophic antiphospholipid syndrome. Introduction of classification criteria for APS has enabled more reliable prospective studies, the promise of better management, and more valid tests for recognition of the disorder.

Update on Pregnancy in Autoimmune Diseases

The 12th International Congress on Matucci Cerinic (University of FlorAntiphospholipid Antibodies and the 5th International Conference on Sex Hormones, Pregnancy and Rheumatic Diseases offered the unique opportunity to bring together the world leaders in the field of pregnancy and rheumatic diseases. The management of pregnancy in women suffering from rheumatic diseases is becoming a common clinical situation. Moreover, we now have more information on the pathogenic mechanisms responsible for pregnancy complications: negative pregnancy outcomes, disease flares and consequences of the mother’s disease or treatment on the offspring. A specific and interdisciplinary expertise is required to avoid such manifestations. An additional aspect is represented by the use of the newly introduced antirheumatic drugs. The correct pregnancy planning, the use of widely validated therapeutical regimens and the careful administration of safe drugs can offer the chance for term pregnancies in rheumatic patients. The program, which attracted attendees from 50 different countries, was drafted by an international committee, cochaired by Pier Luigi Meroni (University of Milan, Milan, Italy), Angela Tincani (University of Brescia, Brescia, Italy), Maurizio Cutolo (University of Genoa, Genoa, Italy) and Marco ence, Florence, Italy). The aim was to provide physicians with updated information on the management of pregnancy in women suffering from autoimmune diseases. The conference was organized in combination with the 12th International Congress on Antiphospholipid Antibodies. Antiphospholipid antibodies (aPL) are in fact one of the most frequent causes of pregnancy complications in autoimmune patients, but are also one of the few known causes of pregnancy loss in the general population. Miscarriages and other obstetrical complications represent one of the most important features of the antiphospholipid syndrome (APS) and are formal classification criteria for APS. Most of the systemic autoimmune diseases display a high female:male ratio and have their peak of incidence in the childbearing age. Moreover, the improved prognosis of systemic autoimmune diseases favors a planned pregnancy. Hence, pregnancy in women suffering from systemic autoimmune diseases is becoming a clinical situation more and more common. The problem of pregnancy in autoimmune patients can be addressed from different points of view:

Revised classification criteria for antiphospholipid syndrome and the thrombotic risk in patients with autoimmune diseases.

The classification criteria for antiphospholipid syndrome (APS) were updated in 2006. The aim of the study was to analyze associations between clinical complications and laboratory test abnormalities typical for APS in a group of patients with autoimmune diseases, based on the recently updated criteria. Three hundred and thirty-six patients were enrolled into the study, with the majority (n = 235) suffering from systemic lupus erythematosus. Laboratory determinations included: lupus anticoagulant (LA), anticardiolipin (aCL) and anti-beta(2)-glycoprotein I (anti-beta(2)GPI) antibodies (ABs) [of both immunoglobulin G (IgG) and IgM class]. A significant association was found between laboratory and clinical features of APS; odds ratios (ORs) for thrombosis associated with the presence of LA, aCL, and anti-beta(2)GPI Abs were 4.04 [95% CI: 2.44-6.68], 3.71 (95% CI 2.32-5.92) and 2.57 (95% CI 1.60-4.1), respectively. Detailed analysis showed marked differences between the risk of clinical complications associated with the presence of an antibody in the IgG class (OR 4.15, 95% CI 2.42-7.12, and OR 4.77, 95% CI 2.37-9.61 for aCL and anti-beta(2)GPI, respectively) and in the IgM class (OR 2.2, 95% CI 1.31-3.70, and OR 1.9, 95% CI 1.15-3.14 for aCL and anti-beta(2)GPI, respectively). The postulated inclusion of anti-beta(2)GPI antibody positivity into the previous laboratory criteria changed only slightly the number of patients diagnosed with APS (from 112 to 117). The updated APS classification criteria clearly represent a step forward. However, our results argue against the use of overall positivity for aCL or anti-beta(2)GPI, and favor a clear distinction between the IgG and IgM classes of antiphospholipid ABs. Patients with both LA and anti-beta(2)GPI IgG or LA and aCL IgG positivity may represent the subgroups at the highest risk of thrombotic complications.

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.

Thrombotic Risk Factors In Primary Antiphospholipid Syndrome

Because thromboembolic events are frequently observed in primary antiphospholipid syndrome (PAPS), we assessed the risk factors for new thrombotic episodes. Fifty-six PAPS patients (mean age, 37+/-10 years) were prospectively studied for 5 years. The preliminary Sapporo classification criteria for antiphospholipid syndrome (APS; a medium-high anticardiolipin antibody [aCL] titer and/or a positive lupus anticoagulant [LA] test in the presence of vascular thrombosis and/or pregnancy morbidity) were used to confirm the diagnosis. Thrombotic episodes or pregnancy losses before a diagnosis of PAPS were considered events, and any new disease manifestation other than thrombocytopenia was considered a recurrent event. Only patients with objectively verified thrombotic events were included in the study. Twenty-one new thrombotic events were observed in 15 subjects (26.8%), including 3 (5.4%) who died during the follow-up. The patients with IgG aCL levels of >40 IgG phospholipid unit (GPL-U) showed a higher incidence of new thrombotic events (43.3%) than those with levels of < or =40 GPL-U (7.7%). Univariate analysis identified a history of recurrent clinical events (P=0.004), a highly positive aCL titer (P=0.007), and the presence of cardiac abnormalities (P=0.036) as significant risk factors for new thrombotic events. A multivariate regression model confirmed that an IgG aCL titer of >40 GPL-U was an independent risk factor for thrombosis (odds ratio, 9.17; 95% confidence interval, 1.83 to 46.05). A high IgG aCL titer is the strongest predictor of new thrombotic events in PAPS patients.

Antiphospholipid syndrome nephropathy in patients with systemic lupus erythematosus and antiphospholipid antibodies: prevalence, clinical associations, and long-term outcome.

To evaluate the prevalence, clinical associations, and outcome of antiphospholipid syndrome (APS) nephropathy in patients with systemic lupus erythematosus (SLE) and antiphospholipid antibodies (aPL) and in SLE patients without aPL. Kidney biopsy specimens obtained from 81 patients with aPL (18 of whom had APS) and 70 patients without aPL were retrospectively examined for the presence of APS nephropathy. Clinical and serologic data obtained at the time of kidney biopsy and during a mean followup of 7 years were recorded. In cases for which serial kidney biopsy specimens were available, the evolution of APS nephropathy was examined. APS nephropathy existed in 39.5% of patients with aPL, compared with only 4.3% of patients without aPL. APS nephropathy was associated with both lupus anticoagulant and anticardiolipin antibodies. Among aPL-positive SLE patients, APS nephropathy was found in two-thirds of those with APS and in one-third of those without APS. A strong association between APS nephropathy and the presence of arterial thrombosis and livedo reticularis was noted. Patients with APS nephropathy had a higher frequency of hypertension and elevated serum creatinine levels at the time of kidney biopsy but did not have a higher frequency of renal insufficiency, end-stage renal disease, or death at the end of followup. Serial kidney biopsy specimens were available from 11 patients and showed progression of APS nephropathy lesions. During followup, manifestations of APS (especially arterial thromboses) developed more frequently in the SLE/non-APS patients with APS nephropathy than in those without APS nephropathy. Among patients with SLE, APS nephropathy occurs almost exclusively in those with aPL, suggesting an important role of aPL in the pathogenesis of APS nephropathy. Patients with APS nephropathy develop hypertension, raised serum creatinine levels, and progression of histologic lesions, all of which are associated with a poor renal outcome. Manifestations of APS also tend to develop in these patients. APS nephropathy should be included in the APS classification criteria, and the use of appropriate anticoagulant therapy should be tested.

Anticardiolipin, other antiphospholipid antibody tests and diagnosis of the antiphospholipid syndrome

The frequent occurrence of false positive results in the anticardiolipin (aCL) enzyme linked immunosorbent assay (ELISA) hampers its application in identifying the antiphospholipid syndrome (APS), a condition characterized by a myriad of clinical presentations. This study highlights some of the pitfalls in the use of assays for antiphospholipid (aPL) antibody in clinical practice. The aCL ELISA, commercially prepared anti-beta2-gylcoprotein 1 (beta2-GP1) and antiphospholipid (APhL) assays were evaluated in the diagnosis of antiphospholipid syndrome (APS) in 94 pregnant women who had spontaneous abortion and a group of 177 healthy blood donors. Serological tests were used to rule out syphilis as the cause of false positive results in the aCL ELISA. The prevalences of positive aCL ELISA results (29/94, 31% v 26/177, 14%; p = 0.001) and aCL antibodies of the IgM isotype (19/94, 20% v 6/177, 3%; $p = 0.001$) were significantly higher in aborters compared to healthy subjects. The majority of the sera which were positive in the aCL ELISA were shown to be false positives as 93% (27/29) of aCL positive aborters and 67% (8/24) of aCL positive healthy subjects were negative in the anti-beta2-GP1 assay. Similarly, the sensitivity of the APhL ELISA was low and only 1% (1/94) of the sera of aborters and 6% (11/177) of healthy subjects were positive in this assay. The frequent occurrence of anticardiolipin antibodies of the authentic non-autoimmune variety and the low sensitivity of the other more specific aPL assays make the positive aCL ELISA difficult to interpret. We recommend that the diagnosis APS be made with strict adherence to the preliminary criteria for classification of APS.

Antiphospholipid syndrome nephropathy in systemic lupus erythematosus.

In the course of the antiphospholipid syndrome (APS), the existence of vaso-occlusive lesions capable of affecting numerous organs is now well established. The renal involvement attributable to primary APS, APS nephropathy (APSN), corresponds to vaso-occlusive lesions of the intrarenal vessels, associating side-by-side, acute thromboses with chronic arterial and arteriolar lesions, leading to zones of cortical ischemic atrophy. A retrospective study of 114 lupus patients undergoing renal biopsy was undertaken to determine the following: (1) if APSN can be found in the course of systemic lupus erythematosus (SLE); (2) if certain clinical and biologic factors can permit the prediction of the presence of APSN; and (3) if APSN is a superadded renal morbidity factor in lupus patients. This study shows the following: (1) APSN occurs in SLE (32% of patients with renal biopsies) in addition to, and independently of, lupus nephritis; (2) APSN is statistically associated with lupus anticoagulant but not with anticardiolipin antibodies; (3) APSN is associated with extrarenal APS, mainly arterial thromboses and obstetrical fetal loss, but not with the venous thromboses of APS; (4) APSN is an independent risk factor, over and above lupus nephritis, that contributes to an elevated prevalence of hypertension, elevated serum creatinine, and increased interstitial fibrosis. Thus, it seems likely that, because of its associations with hypertension, elevated serum creatinine, and increased interstitial fibrosis, APSN may worsen the prognosis in these patients. APSN may also have therapeutic significance in that its recognition should permit a better balance between immunosuppressor and antithrombotic and/or vasoprotective therapy. Finally, this study suggests that APSN should be considered as an element to be included in the classification criteria of APS.

International classification criteria for antiphospholipid syndrome: synopsis of a post-conference workshop held at the Ninth International (Tours) aPL Symposium.

An international workshop on classification criteria for antiphospholipid syndrome (APS) was held on 16 September 2000 in Tours, France, following the Ninth International APS Symposium. The workshop addressed issues that were not resolved by the previous (1998) international workshop on the classification criteria. Participants at the workshop agreed that no changes should be made to the international (Sapporo) criteria at the present time. However, to improve the criteria, future efforts should be focused on the following: (1) further evaluation of the international (Sapporo) criteria for definite APS; (2) definition of other categories of APS such as 'probable' and 'possible' APS; (3) guidelines for the clinical diagnosis as distinct from classification of APS; (4) strategies to improve the compliance of laboratories worldwide, with recommended procedures for Lupus anticoagulant (LA) and anticardiolipin (aCL) assays; (5) development of monoclonal antibody standard reagents for aCL and LA assays; and (6) refinement and subsequent evaluation of antibeta2GPI assays for use in idenfitication of APS.

Lithology of the Kennebec Valley esker

<h3></h3> Antiphospholipid syndrome (APS) is prothrombotic systemic autoimmune disorder characterized with multisystem manifestation, most commonly venous and arterial thromboembolism and/or recurrent pregnancy loss. The varying clinical phenotype is associated with heterogeneity in the pathogenic antiphospholipid antibodies (aPL) that are central to the diagnosis of APS. According to the international consensus statement on classification criteria, APS is classified when persistently elevated levels of specific aPL, such as lupus anticoagulant (LA), anti-cardiolipin (aCL) and anti-β2 glycoprotein I (anti-β2GPI) antibodies, are confirmed in addition to clinical manifestations (1, 2). The exact pathogenesis of APS is unknown, but aPL have been described to activate monocytes, neutrophils, dendritic cells and placental tissue (3). Despite the fact that many different proteins have been identified as being involved in the pathogenesis of APS, accumulating evidence from in vitro experiments as well as animal studies has revealed that β2GPI is the main target for aPL. It was also shown that triple aPL positivity, defined by detection LA, high titres of aCL and anti-β2GPI antibodies, correlates better with both thrombosis and pregnancy morbidity than any other aPL profile (4). Several autoantibodies outside those included in APS classification criteria could be also relevant to APS pathogenesis (5) and therefore, antibodies against other antigen targets have been investigated. Current evidence shows that some of these antibodies, particularly antibodies against domain I of β2GPI (anti-DI-β2GPI) and phosphatidylserine dependent anti-prothrombin antibodies (aPS/PT) might be relevant in the better recognition of APS patients. These antibodies are commonly referred as non-criteria aPL (6) because they have not been yet accepted as laboratory criterion for the diagnosis of APS. The DI of β2GPI has been identified as the most relevant antigenic target involved in β2GPI/anti-β2GPI antibody binding. Anti-DI-β2GPI antibodies were found to be strongly related to thrombosis and pregnancy complication and are more frequently detected in patients with APS than in asymptomatic aPL carriers (7). High titres of anti-DI-β2GPI are also frequently present in triple aPL positive patients. Nevertheless, it is far too soon to recommend replacement of anti-β2GPI testing with an anti-DI-β2GPI antibody assay because it was shown that about 30% of patients with anti-β2GPI antibodies are negative for anti-DI-β2GPI antibodies (8). The clinical significance of autoantibodies reacting with epitopes other than DI was also investigated in multicenter study (9). The results showed a diverse clinical association with reactivity to different epitopes on β2GPI, suggesting all domains were relevant. Therefore, more detailed profiling of domain specificity and avidity of anti-β2GPI antibodies may be useful as risk stratification for clinical events. aPS/PT antibodies also represent strong risk factor for thrombosis. Results of multicenter study demonstrated that IgG aPS/PT detection might contribute to a better and more reliable identification of APS patients (10). Due to the heterogeneity of aPL (criteria and non-criteria) the interpretation of aPL results is huge challenge in daily routine practice and should always be related to clinical symptoms and therefore, interaction between the laboratory and clinician is essential. <h3>