Association of anticardiolipin antibodies with vascular injury: possible mechanisms.

Lupus anticoagulant, first observed in 1952 in two patients with systemic lupus erythematosus (SLE), was linked to a phospholipid antigen when positive Wassermann tests for syphilis coincided with the lupus anticoagulant, documenting the lipid nature of the antigen. Bowie and colleagues were the first to unravel the paradoxical prothrombotic tendency of patients with positive lupus anticoagulant. This prothrombotic tendency that often results in microscopic thromboembolism is unique in being detected by positive serological tests. While immunoglobulins of isotypes IgG or IgM may have the lupus anticoagulant eVect, the significance of IgA isotypes is not clear. These antibodies interfere with the in vitro phospholipid dependent coagulation tests. Lupus anticoagulant activity is documented by inability to correct prolonged activated partial thromboplastin time (aPTT) with normal plasma, and the necessity of phospholipid for the inhibition. Lupus anticoagulant belongs to a family of antiphospholipid antibodies (aPL) that also includes reagin and anticardiolipin antibodies (aCL), and the recently recognised antibody to beta-2-glycoprotein I (â2GpI). aCL and lupus anticoagulant are distinct and complementary tests for aPL. In patients with aPL syndrome, 60% will be positive for both lupus anticoagulant and aCL, while either test will be positive in the rest of the patients. Until recently, the most sensitive test for aPL was aCL. This ELISA test determines antibody binding to solid plates coated with cardiolipin or other negatively charged phospholipids. Recently, aPL were shown to be specific for phospholipid-protein complexes, where the protein is identical with being â2GpI, 5 or less often prothrombin, protein C, or protein S. aPL may be either autoimmune or alloimmune. The latter appear transiently after an infection or associated with a lymphoproliferative disorder, and do not usually have clinical implications. The former are persistent and may be primary, as in the aPL syndrome, or secondary to drugs, SLE (where 40% of patients have either lupus anticoagulant or aCL), or other collagen vascular disease. Autoimmune aPL rather than alloimmune, are associated with hypercoagulability. Although in general thrombotic episodes may occur anywhere in the vascular tree, in a single patient the event is either venous or arterial and does not cross react. Clinical manifestations of aPL include venous and arterial thromboembolic phenomena, such as miscarriage, thrombocytopenia, neurological manifestations, deep vein thromboses and pulmonary embolism, or arterial thromboses. Pre-eclampsia has also been reported to be associated with aPL. The syndrome may be either a part of a systemic disorder, classically SLE, or a primary disorder, called the antiphospholipid syndrome. While aPL are in fact a family of antibodies, the incidental finding of positive serology is yet to be determined. However, correlation of incidental aPL with thrombotic episodes has not been documented in large scale surveys. After the discovery of aPL, several mechanisms have been proposed for the pathogenesis of its prothrombotic tendency, such as reduced inhibition of activated factor V, platelet activation, 10 endothelial injury, and direct recognition of phospholipids. However, the probable primary mechanism of aPL hypercoagulablility has recently been elucidated. â2GpI is a 50 kD protein with a natural anticoagulant activity. It inhibits surface mediated activation of prekalikrein and factor XII, activated factor V, and platelet aggregation. â2GpI binds to phospholipid and optimises the reaction in autoimmune diseases but not after infections. aCL activity is dependent on the combination of cardiolipin and â2GpI, with the phospholipid binding protein complex playing the major immunogenic part in the production of aCL specifically and the aPL syndrome in general. 16 Moreover, â2GpI can discriminate between autoimmune aCL and alloimmune aCL, by enhancing the cardiolipin binding in aPL syndrome and inhibiting the cardiolipin binding of post-infectious aCL. These nonpathogenic alloimmune aPL may react with solid phase and fluid phase cardiolipin even in the absence of â2GpI, unlike autoimmune aCL. The prevalence of aCL in arbitrary internal medicine patients is 11%, a rate similar to aCL found in young adults with premature atherosclerosis. However, 26% of a general population of vascular surgery patients are aCL positive. Higher prevalence of aCL may also be found in patients with recurrent vascular insults, such as dialysis patients. In contrast, the proportion of positive aCL in the general population is below 10%. The mechanisms involved in the association between aCL and vascular disease may include one or any combination of endothelial activation, atherogenic, immune, or apoptotic processes in genetically susceptible subjects.