Evaluation of clinical and laboratory features of antiphospholipid syndrome: a retrospective study of 637 patients

We retrospectively analysed the data of 1519 antiphospholipid antibody (APLA) positive patients between 1986 and 1999. Among them 637 were considered to have antiphospholipid syndrome (APS) based on the 1999 preliminary classification criteria, while 704 patients had no clinical signs of the syndrome. Our aim was to compare the autoantibody profile and clinical characteristics of primary and secondary APS, moreover to evaluate the associations between different APLA and specific symptoms attributable to APS. In our results, the APLA profiles for primary and SLE-associated secondary APS were similar. Among the evaluated clinical symptoms, cerebrovascular thrombosis was found to be more frequent in the SLE-associated, than in the primary APS group (P = 0.04). We identified important differences in the clinical profile of patient populations with various types of APLA. Venous thrombosis occurred more frequently in subjects withlupus anticoagulant (LA), than in those with IgG or IgM type ACLA (P < 0.0001), while coronary, carotid and peripheral artery thrombosis occurred more often in subjects with IgG or IgM ACLA (P < 0.0001). These findings may support the role of antibodies to cardiolipin or its cofactor, beta2glycoprotein I (beta2-GPI) in the initiation and progression of atherosclerosis. Cerebrovascular thrombosis was detected in larger proportion of LA or IgG ACLA-positive patients compared with to IgM ACLA-positive subjects, while the occurrence of foetal loss was similar in all three groups.     

CAPS Registry

Patients with catastrophic antiphospholipid syndrome (APS) have in common: a) clinical evidence of multiple organ involvement developing over a very short period of time; b) histopathological evidence of multiple small vessel occlusions, and c) laboratory confirmation of the presence of antiphospholipid antibodies (aPL), usually in high titre. Although patients with catastrophic APS represent less than 1% of all patients with APS, they are usually in a life-threatening situation. The rarity of this syndrome makes it extraordinarily difficult to study in any systematic way. In order to correlate all the published case reports as well as newly diagnosed cases from all over the world, an international registry of patients with catastrophic APS (CAPS Registry) was created in 2000 by the European Forum on aPL. Currently, it documents the clinical, laboratory and therapeutic data of more than 400 patients and can be consulted through Internet at www.med.ub.es/MIMMUN/FORUM/CAPS.HTM. The analysis of this registry has allowed the characterization of the clinical and laboratory features of the catastrophic APS as well as the establishment of preliminary criteria for its classification and guidelines for its management.     

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.     

Antiphospholipid antibiodies: a critical review of the literature

PURPOSE OF REVIEW: The antiphospholipid antibody syndrome is defined by the presence of antiphospholipid antibodies in patients with recurrent venous or arterial thromboembolism or pregnancy morbidity. Antithrombotic therapies are the mainstay of treatment to reduce the risk of recurrent thromboembolism that characterizes this condition. RECENT FINDINGS: Limitations in the laboratory testing for antiphospholipid antibodies and changes in the diagnostic criteria for antiphospholipid antibody syndrome are important to recognize as they will affect the type of patients enrolled in the clinical trials evaluating antiphospholipid antibody syndrome therapies. In this review, we discuss the laboratory testing and diagnostic criteria for antiphospholipid antibody syndrome, and examine the evidence supporting the optimal antithrombotic management of patients with antiphospholipid antibodies. Studies addressing the management of patients with antiphospholipid antibodies and venous thromboembolism, and antiphospholipid antibodies and ischemic stroke, will be critically reviewed. SUMMARY: Clinical trials and observational studies have evaluated the optimal type, intensity and duration of anticoagulant therapy in patients with antiphospholipid antibodies. Critical evaluation of these studies is required to assess the generalizability of the results and how these results may be applicable to individual patients.     

Antiphospholipid antibodies--we are not quite there yet

The diagnosis of antiphospholipid syndrome is predominantly made in the laboratory and depends on the persistent presence of antiphospholipid antibodies in individuals with thrombosis or pregnancy morbidity. Correct diagnosis of the syndrome is imperative to prevent unnecessary long secondary thromboprophylaxis. Three antiphospholipid antibody subtypes are included in the classification criteria of the antiphospholipid syndrome: lupus anticoagulants, anticardiolipin antibodies and anti-β2-glycoprotein I antibodies. Only lupus anticoagulants are undisputedly associated with thrombosis, which is why the serological criteria of the antiphospholipid syndrome are under debate. All of the assays used to detect antiphospholipid antibodies are in need of better standardization, although progress has been made in the detection of lupus anticoagulants. The inconsistent association between both anticardiolipin and anti-β2-glycoprotein I antibodies and thrombosis is a cause for alarm. We are in need of better assays to detect those individuals at risk for thrombosis and population-based prospective studies to provide us with accurate risk assessments.     

Clinical utility of laboratory tests used to identify antiphospholipid antibodies and to diagnose the antiphospholipid syndrome

The antiphospholipid syndrome (APS) is defined by thrombotic and/or obstetric events together with the presence of antiphospholipid antibodies in plasma of patients. The original laboratory criteria of APS included lupus anticoagulants (LA) and/or IgG/IgM anticardiolipin antibodies (aCL). They were recently updated with the addition of IgG/IgM anti-beta2 glycoprotein I antibodies (anti-beta2GPI), a better definition of "medium to high antibody titer," and the extension to 12 weeks of the "persistence in time." The revised criteria represent an improvement; however, the potential overdiagnosis of APS remains possible, thus putting patients at risk of overtreatment. To reduce this possibility, proposals have been made to implement strict guidelines for the performance of the LA assay, to exclude aCL measurements in their current application from the criteria, and to limit the measurement of anti-beta2GPI to the G isotype. This should also help in simplifying the laboratory workup of patients being investigated for APS.     

Relapsing catastrophic antiphospholipid syndrome: report of three cases

BACKGROUND: The catastrophic variant of the antiphospholipid syndrome (CAPS), also now known as Asherson's syndrome, is defined as a potential life-threatening variant of the antiphospholipid syndrome, which is characterized by multiple small-vessel thrombosis that can lead to multiorgan failure. Relapses in patients with the CAPS are very uncommon. OBJECTIVE: To describe the clinical and laboratory features of patients with relapsing episodes of CAPS. METHODS: Three patients with relapsing CAPS are presented with their clinical and laboratory features. RESULTS: Seven episodes of CAPS that occurred in the 3 patients reported were analyzed. The median time between the episodes of CAPS was 12.5 months (range, 2.5-48). Precipitating factors were identified in 2 episodes only (Legionella respiratory tract infection and periodontal infection). The most significant manifestations of the episodes were renal involvement (5 episodes), central nervous system and cardiac involvement (4 episodes), and pulmonary and hepatic involvement (3 episodes each). Interestingly, laboratory features of definite microangiopathic hemolytic anemia (MHA) were present in 5 of 7 episodes of relapsing CAPS. The remaining episodes presented with thrombocytopenia, schistocytes, and anemia but data concerning hemolysis and Coombs tests were not reported. Rituximab was used in 2 episodes. CONCLUSIONS: Relapses occur very infrequently in patients with the CAPS. The presence of MHA is common in these patients, suggesting that an association between MHA and relapses of CAPS could be present and that a "continuum" between various MHAs might exist, as recently suggested.     

The overlap of Sjögren's syndrome with other systemic autoimmune diseases

OBJECTIVE: To analyze the main diagnostic problems caused by the overlap between Sj?gren's syndrome (SS) and other systemic autoimmune diseases (SAD). METHODS: We performed a MEDLINE search for articles published between January 1966 and December 2005 that specifically analyzed the overlap between SS and other SAD. We identified a list of diagnostic problems in patients with primary SS who had features considered typical of other SAD. RESULTS: Clinically, the main diagnostic problems occur in SS patients presenting with arthritis, Raynaud phenomenon, cutaneous features (subacute cutaneous lupus erythematosus, purpura, livedo reticularis, erythema nodosum), interstitial pulmonary disease, and cytopenias (leukopenia, thrombocytopenia). Immunologically, antiphospholipid antibodies (aPL) and antineutrophil cytoplasmic antibodies (ANCA) are the most frequent atypical autoantibodies found in primary SS, with a prevalence ranging between 10 and 20%. However, coexisting antiphospholipid syndrome or systemic vasculitis is only detected in around 10% of SS patients with aPL or ANCA. Anti-DNA and anticentromere antibodies have a prevalence of 5 to 10%, but are more closely related to clinical and/or laboratory data suggestive of associated systemic lupus erythematosus and limited systemic sclerosis, respectively, leading to the fulfillment of classification criteria for these diseases in more than 25% of cases. CONCLUSION: The wide variety of clinical and immunological manifestations of patients with primary SS often overlap with other SAD, making the differentiation between primary SS, SS associated with SAD, and SS-like presentations of some other SAD difficult. This overlap suggests that the current classification criteria are useful in differentiating between autoimmune and non-autoimmune processes but fail to clearly differentiate among SAD.     

The family history of patients with primary or secondary antiphospholipid syndrome (APS)

OBJECTIVE: To evaluate familial history for evidence of antiphospholipid syndrome (APS) and autoimmune disease in rheumatology department patients with primary or secondary APS. METHODS: We retrospectively studied patients with APS and systemic lupus erythematosus (SLE) managed at the Rheumatology Department of the Bichat University Hospital, Paris, between 1987 and 1996. Data were collected by chart review and by a 1997 standardized telephone interview. RESULTS: We identified 108 patients with APS managed during the ten-year study period. According to classical classification criteria, 39 patients had primary antiphospholipid syndrome (PAPS) and 69 secondary antiphospholipid syndrome (SAPS). Family history data were obtained for 29 (74%) and 55 (80%) PAPS and SAPS patients. respectively (78% of the 108 patients). Twelve PAPS (41% and 19 SAPS (35%) patients had one or more relatives with evidence of at least one clinical feature of APS such as thrombosis or recurrent fetal loss; of these patients, seven in the PAPS (24%) and 11 in the SAPS (20%) group had two or more relatives with evidence of a clinical feature of APS. Three PAPS (10%) and 14 SAPS (25%) patients had one or more family members with an autoimmune disease. CONCLUSION: A positive family history for autoimmune disease and/or antiphospholipid syndrome is common in patients with PAPS or SAPS. This finding supports a genetic contribution to APS. The percentage of a positive family history for autoimmune disease tend to be higher in patients with SAPS than in those with PAPS.     

Antiprothrombin antibody testing: detection and clinical utility

Anticardiolipin antibody (aCL), anti-beta2 glycoprotein I antibodies, and lupus anticoagulant (LA) are the only laboratory tests considered within the revised criteria for the classification of the antiphospholipid syndrome (APS). Recently, antibodies against phosphatidylserine-prothrombin complex (aPS/PT) have been detected, and these antibodies, rather than antibodies against prothrombin alone, are closely associated with APS and LA. The sensitivity and specificity of aPS/PT for the diagnosis of APS were assessed in a population of patients with a variety of autoimmune disorders. aCL and aPS/PT have similar diagnostic value for APS, therefore aPS/PT should be further explored, not only for research purposes but also as a candidate for one of the laboratory criteria for the classification of the APS.     

The antiphospholipid syndrome: prevalence among patients with stroke and transient ischemic attacks

PURPOSE: The prevalence of the antiphospholipid syndrome was determined prospectively in patients presenting with stroke and transient ischemic attacks. An attempt was made to define a subset of stroke patients at risk for this syndrome on the basis of their clinical features. PATIENTS AND METHODS: Fifty-one consecutive patients with stroke and transient ischemic attacks were assessed. Tests used for the laboratory diagnosis of the antiphospholipid syndrome included four phospholipid-dependent coagulation tests for detection of the lupus anticoagulant, and two enzyme-linked immunosorbent assays for antibodies to phospholipid. RESULTS: Three of 51 patients (6%, 95% confidence intervals 0% to 12.0%) had a lupus anticoagulant and the clinical features of the antiphospholipid syndrome. Seven patients had clinical features suggestive of the syndrome but negative laboratory tests. Those patients who were clinically unlikely to have this syndrome also had negative laboratory tests. CONCLUSION: In a series of 51 unselected patients presenting with stroke and transient ischemic attacks, three had the antiphospholipid syndrome. The clinical features of this syndrome are helpful in identifying this group of patients. The role of the lupus anticoagulant in the pathogenesis of stroke remains to be defined.     

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.     

Clinical significance of different antiphospholipid antibodies in the WAPS (warfarin in the antiphospholipid syndrome) study

To assess the clinical significance of lupus anticoagulants (LAs) and antiphospholipid antibodies (aPLs) toward thrombosis and abortions, we measured them in 112 patients whose samples were available at enrollment in the warfarin in the antiphospholipid syndrome (WAPS) study. Enzyme-linked immunosorbent assay (ELISA) and coagulation test values in the highest and lowest tertiles were compared. When considered separately, IgG antibodies to beta2-glycoprotein I (abeta2GPI) and prothrombin (aPT) were associated with anamnestic arterial and venous thrombosis, respectively, and those to annexin AV (aAnAV) with abortions. IgM antibodies to protein S and the lupus ratio of the dilute prothrombin time were associated with prospective thrombosis. No other association for IgM antibodies was seen. LA-positive patients who carried abeta2GPI antibodies were at risk of anamnestic arterial and total thrombosis and aPT antibodies to that of anamnestic venous and total thrombosis. LA-positive patients who carried IgG abeta2GPI and aAnAV antibodies were at risk for both anamnestic abortion and prospective thrombosis. Overall, these data support the inclusion of abeta2GPI antibodies in and suggest the removal of anticardiolipin antibodies from the laboratory criteria of the antiphospholipid syndrome. They also suggest that the measurement of aPT and aAnAV antibodies is useful in some selected situations and that there is little role for IgM antibody detection.     

How we diagnose the antiphospholipid syndrome

The 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 (beta(2)GPI) antibodies in view of their recent inclusion in the APS classification criteria. The clinical utility of using the beta(2)GPI 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.     

Added value of non-criteria antiphospholipid antibodies for antiphospholipid syndrome: lessons learned from year-long routine measurements

Clinical Rheumatology - The international classification criteria for definite antiphospholipid syndrome (APS) include three laboratory measurements: lupus anticoagulant (LA), IgG and IgM isotypes...     

Coexistence of five autoimmune diseases: diagnostic and therapeutic difficulties

We report the case of coexistence of five autoimmune diseases in a 36-year-old woman, who initially developed psoriasis. Several years later, the patient was diagnosed with a mixed connective tissue disease and primary biliary cirrhosis (PBC). On admission to the Department of Rheumatology and Connective Tissue Diseases, the patient fulfilled classification criteria of an overlap syndrome systemic lupus erythematosus (SLE) with secondary antiphospholipid syndrome/systemic sclerosis (SSc)/Sjogren's syndrome (SS) with coexisting PBC and psoriasis. The SLE symptoms included discoid lupus erythematosus, arthritis, pancytopenia, antinuclear antibodies and anticardiolipin antibodies. Moreover, the patient met the criteria of antiphospholipid syndrome diagnosed based on preterm delivery before week 34, and high values of anticardiolipin antibodies were found at repeated determinations. The SSc symptoms included sclerodactyly, pulmonary fibrosis with pulmonary hypertension and esophageal dysfunction. The SS syndrome involved xerostomia, xerophthalmia, the positive Schirmer's test and presence of anti-SS antibodies. The literature reports overlap syndromes in various combinations; however, the coexistence of five autoimmune diseases is extremely rare.     

A review of the sapporo and revised Sapporo criteria for the classification of antiphospholipid syndrome. Where do the revised sapporo criteria add value?

OBJECTIVE: The preliminary classification criteria for antiphospholipid syndrome (APS), or the Sapporo criteria, are widely used for the inclusion of patients with APS into clinical studies. Revised Sapporo criteria have been proposed as an improved criteria set. Whether these criteria sets fulfill the current standards of measurement science are unknown. The purpose of this study was (1) to evaluate the developmental methodology and measurement properties of the Sapporo and the revised Sapporo criteria for use in clinical trials; and (2) to evaluate if the revised Sapporo criteria provide added value over the Sapporo criteria. METHODS: A computer search for articles describing use of the Sapporo and the revised Sapporo criteria was performed. Item generation, item reduction, sensibility, validity, and reliability of the criteria were evaluated. RESULTS: The Sapporo criteria set has incremental face and content validity over its predecessors. However, through separation of anti-ss2-glycoprotein I antibodies as a sub-item, the specification of a wider time interval between serologic testing, the specification of a time interval between serology and clinical manifestations, and specification of definitions for clinical manifestations and laboratory titer thresholds, the revised Sapporo criteria set has incremental face and content validity over the Sapporo criteria. The complexity of the criteria, diagnostic tests, and immunologic tests limits their feasibility. The reliability of each criterion is unknown. The discriminative capacity of the Sapporo criteria is good, with sensitivity, specificity, and positive and negative predictive values of 0.71, 0.98, 0.95, and 0.88, respectively, compared to patients with systemic lupus erythematosus. The discriminative capacity of the revised Sapporo criteria is unknown. CONCLUSION: The revised Sapporo criteria set has incremental face and content validity compared its predecessors. Reliability testing of each criterion is needed before these criteria can be confidently used in multicenter APS trials. Discriminatory testing of the revised Sapporo criteria is required.     

A vitamin K antagonist rapidly reverses a blue toe syndrome in a patient with lupus anticoagulant and antiprothrombin antibodies

A 30-year old male was admitted to the hospital with extremely painful blueish discoloration of his toes. After clinical and laboratory evaluation the diagnosis of a blue toe syndrome due to primary antiphospholipid syndrome (APS) was made. Complete resolution of the blue toe syndrome occurred within 72 hours following 9 mg phenprocoumon. APS consists of the association of lupus anticoagulant or antiphospholipid antibodies with arterial or venous thrombosis, thrombocytopenia, and spontaneous abortion. The exact pathways leading to thrombosis are still unknown. Our group has previously proposed that membrane-associated immune complexes contribute towards clinical symptoms in the antiphospholipid syndrome. The case presented strengthens that concept.