The Paradox of the Lupus Anticoagulant: History and Perspectives

Abstract

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 "lupus anticoagulant (LA)" 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, β2-glycoprotein I (β2GPI). The presence of β2GPI-dependent LA represents a well-recognized risk factor for venous and arterial thromboembolism, as well as pregnancy loss and morbidity. β2GPI-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.

Synthesis of Phospholipid-Protein Conjugates as New Antigens for Autoimmune Antibodies

“…Dilution 1:100 was found to be optimal for testing, whereas linear range was optimal for synthetic conjugates (Supporting Information, Figure S4). In agreement with previous reports, we found IgG Abs to be the most relevant for a-PL detection [27,28,29] (Table 1; Supporting Information, Table S1). Among other antigens, PE-PT and PE-β2GPI bound target Abs with highest signal to noise ratio compared to healthy controls.…”

Novel Phospholipid-Protein Conjugates Allow Improved Detection of Antibodies in Patients with Autoimmune Diseases

“…Separate application of biologically complementary phospholipids and plasma proteins lead to low clinical relevance of detected autoantibodies [ 30 – 32 ]. Moreover, chemical heterogeneity of typically applied antigens extracted from natural sources, their low stability and therefore poor reproducibility of the available assays might contribute to current disagreement between tests [ 13 ]. In this study our main goal was to specifically detect clinically important autoantibodies using novel, reliable reagents.…”

“…Cross-reactivity of autoantibodies is another obstacle to their utilization as biomarkers for autoimmune conditions [ 9 ]. Low specificity results in low reliability of tests and limits their usefulness in diagnostics and understanding autoimmune diseases [ 9 , 12 , 13 ]. In particular, cross-reactivity with nucleic acids and other proteins has been reported [ 9 , 12 ].…”