Antiphospholipid syndrome: critical analysis of the diagnostic path

Antiphospholipid syndrome (APS) is diagnosed in the presence of vascular thrombosis or pregnancy morbidity occurring in patients with circulating antiphospholipid antibodies (lupus anticoagulant [LA] and/or IgG/IgM anticardiolipin [aCL] and/or IgG/IgM anti-beta2glycoprotein I [abeta2GPI] antibodies). Each test may identify different autoantibodies; a single test makes the diagnosis possible when positive on two or more occasions at least 12 weeks apart. However, single test positivity may be unrelated to pathogenic antibodies, which are now considered to be a subclass of abeta2GPI antibodies directed against the domain I of this protein. Conversely, all three positive tests identify a single class of abeta2GPI antibodies, thus identifying high-risk patients with APS

The Paradox of the Lupus Anticoagulant: History and Perspectives

A unique coagulation inhibitor prolonging whole-blood clotting time was described more than 50 years ago in two patients with systemic lupus erythematosus (SLE). The immunoglobulin nature of the inhibitor and its interaction with antiphospholipid antibodies was later demonstrated and the term \u201clupus anticoagulant (LA)\u201d was coined to describe this laboratory finding. It soon became apparent that LA was a misnomer as it is often found in plasma from patients with clinical conditions other than SLE and is associated with thromboembolic events that may occur in otherwise healthy individuals. Individuals with LA have circulating autoantibodies that inhibits blood coagulation. These are mostly of IgG or IgM class and mainly directed against a phospholipid (PL)-binding plasma protein, \u3b22-glycoprotein I (\u3b22GPI). The presence of \u3b22GPI-dependent LA represents a well-recognized risk factor for venous and arterial thromboembolism, as well as pregnancy loss and morbidity. \u3b22GPI-dependent LA in the presence of documented previous thromboembolism, or history of pregnancy loss/morbidity, identifies definite anti-PL syndrome. Laboratory diagnosis of LA is thus of particular importance, as it may assign patients with a common event (thrombosis) to a group with a high risk for recurrence, which is a prerequisite for long-term oral antithrombotic treatment

Laboratory Diagnostics of Antiphospholipid Syndrome

Diagnosis of antiphospholipid syndrome (APS) lies in the recognition of antiphospholipid antibodies (aPL). As standardization of tests for the detection of aPL is far from being optimal and reference material is not available, inappropriate diagnoses of APS are not unusual. In the last few years, the concept of triple test positivity has emerged as a useful tool to identify patients with APS. Clinical studies on patients and carriers of triple positivity clearly show that these individuals are at high risk of thromboembolic events and pregnancy loss. Moreover, triple positivity arises from a single (probably pathogenic) antibody directed to domain 1 of \u3b22-glycoprotein I, a protein whose function is still unknown. Studies on homogenous group of patients with single or double positivity are scant, and uncertainties arise on their association with clinical events. Promising but undetermined results come also from the determination of antibodies directed to phosphatidylserine/prothrombin complex. Interpretation of laboratory profile in APS is challenging, and the collaboration between clinical pathologists and clinicians is highly desirable

Efficacy and safety of rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome: Rationale and design of the Trial on Rivaroxaban in AntiPhospholipid Syndrome (TRAPS) trial

Background New oral anticoagulants may simplify long-term therapy in conditions requiring anticoagulation. Rivaroxaban is a direct factor Xa inhibitor that has been extensively studied and is now approved for the prevention and therapy of a number of thromboembolic conditions. Objective and methods This is a multicentre, randomized, open-label, study that will evaluate if Rivaroxaban 20 mg od (or 15 mg od in patients with moderate renal insufficiency) is non-inferior to warfarin (INR target 2.5), for the prevention of thromboembolic events, major bleeding and death in high risk (triple positive) patients with antiphospholipid syndrome. Secondary endpoints will assess the incidence of any individual component of the composite end point. An external adjudication committee will evaluate all suspected outcome events. This will be a unique trial, as it will enrol the biggest homogenous cohort of high risk APS individuals. Conclusion The methods and the study design should be appropriate to achieve study results that are both scientifically valid and relevant to clinical practice. </jats:sec

Correct laboratory approach to APS diagnosis and monitoring

Triple positivity (positive Lupus Anticoagulant, anticardiolipin and anti \u3b22-glycoptrotein I antibodies) identifies the pathogenic autoantibody (anti Domain I of \u3b22-glycoptroteinI) that is present in patients with definite Antiphospholipid Syndrome (APS). This is supported by the fact that a\u3b22GPI antibodies obtained by affinity purification in these patients possess LA activity. Moreover, patients and carriers of this profile carry a much higher risk of thrombosis and pregnancy loss than APS patients with positivity for only one of the tests. Thus, very different risk categories exist among patients with APS as well as among carriers of aPL. Clinical studies and interventional trials should first take these high risk subjects into consideration. Copyright \ua9 2012 Elsevier B.V. All rights reserved

Standardization of lupus anticoagulant. Feasibility study of a calibration model to minimize between-method variability

Results for lupus anticoagulant (LA) are currently expressed as ratio of patient-to-normal clotting times (LA-ratio). Yet, numerical results do vary according to the method used for testing, thus making difficult the between-method comparison of results. We hypothesized that the standardization model currently used for the INR for patients on oral-anticoagulants (OAT) would be of value also for LA standardization. PATIENTS AND METHODS: To test this hypothesis we determined a sensitivity index valid for LA (called LASI) for six LA-detection methods against a common-standard using two sets of calibration-plasmas: (i)normal-plasmas spiked with IgG derived from patients strongly-positive for LA or (ii)plasmas from LA-positive patients. The LASI was then used to convert the LA-ratio into the standardized-LA-ratio (SLA-ratio) according to the equation: SLA-ratio = (LA-ratio)(LASI). RESULTS: We demonstrate that (i)the model is feasible because calibration plots of log-transformed clotting times obtained for the LA-detection methods-vs.-the common-standard gave acceptable LASI values; (ii)the model is effective because between-method variability expressed as coefficient of variation, which was 42.8% with results expressed as LA-ratio, decreased to 7.8% with results expressed as SLA-ratio; (iii)the LASI value calculated with the LA-positive plasmas is more effective in minimizing between-method variability than the LASI value calculated with IgG-spiked plasmas. CONCLUSIONS: A model of LA calibration similar to the INR for patients on OAT is feasible by using plasmas from LA-positive patients instead of patients on OAT. Potential application of the model are:(i)to compare the relative responsiveness of different LA-detection methods,(ii)to minimize differences between their results and (iii)to quantify LA potency

Diagnosis and therapy of antiphospholipid syndrome

Antiphospholipid syndrome (APS) is a clinical condition that has not been well defined yet. Although the clinical component is well established, the laboratory part is a mood issue. According to current guidelines, 3 tests (lupus anticoagulant, anticardiolipin, and anti \u3b22-glycoprotein I antibodies) are officially recommended to assess the presence of antiphospholipid antibodies. According to test positivity, patients are classified into categories in clinical studies. However, it is now clear that classification categories have a different impact on the clinical course of APS. Indeed, patients and healthy carriers with a full positive antibody profile (triple positivity) are those at the highest risk of events. Patients with a single test positivity are those at a lower risk. In this review, on the basis of a laboratory profile, we grade the diagnosis of APS into definite, probable/possible, and uncertain. We also discuss secondary prevention of thrombotic APS, prevention of pregnancy morbidity, and treatment of catastrophic APS. Finally, new tools in laboratory diagnosis and treatment are highlighted