Antiphospholipid Antibodies: Proposed Mechanisms of Action

Abstract

Antiphospholipid antibodies (APA) are a family of immunoglobulins that react with anionic phospholipids, or anionic phospholipids-protein complexes. Recent evidence would support the latter definition. Lupus anticoagulants (LA) inhibit in vitro phospholipid dependent coagulation tests [e.g., activated partial thromboplastin time (APTT), prothrombin time (PT), and dilute Russell viper venom time (dRVVT)]. This inhibition appears to be specific for reagent phospholipids. The addition of freeze-thawed platelets or activated platelets will result in correction of the LA-induced abnormality. Anticardiolipin antibodies (ACA) are related to LA but appear to be distinct. ACA are detected by solid phase assays (ELISA, RIA) and require a plasma cofactor: β₂ Glycoprotein-I (β₂ GPI). ACA and LA activities can be separated in individual patient plasmas by affinity chromatography. In some instances they are of differing isotypes. Preliminary evaluation of β₂ GPI in coagulation assays suggests it may function as a cofactor for LA activity. Recent work also suggests human prothrombin may represent a necessary cofactor for in vitro LA activity. Paradoxically, patients with LA/ACA may sustain thromboembolic events involving both venous and arterial sites. The prothrombotic properties of LA/ ACA have not been satisfactorily characterized. A number of proposals have been reported, including inhibition of prostacyclin (PGI₂) generation by endothelial cells, decreased activity of the protein C system, impaired fibrinolysis, and inhibition of β₂ GPI. Among these various hypotheses, down regulation of the protein C system appears most plausible. Also, LA/ACA may interfere with the phospholipase A₂-phospholipid substrate complex involved in the generation of arachidonic acid from membrane phospholipids.