Prevalence of different anti-phospholipid antibodies in systemic lupus erythematosus and their relationship with the antiphospholipid syndrome.

The antiphospholipid syndrome is a complex disorder (1 ) that is related to a set of unusual and fascinating antibodies. Recent research is defining these antibodies and their relationship to features of the syndrome. The antiphospholipid syndrome is defined by the association of arterial and/or venous thrombosis, recurrent miscarriages, and anti-phospholipid (aPL) antibodies (1 ). The syndrome may be either idiopathic (primary) or may occur in the setting of an associated disease (secondary), most frequently systemic lupus erythematosus (SLE) or other autoimmune diseases (2, 3). Lupus anticoagulants and anti-cardiolipin antibodies at medium to high titers are laboratory indicators of the condition (4 ). Lupus anticoagulants behave as acquired inhibitors of coagulation and prolong phospholipid-dependent in vitro coagulation tests (5 ), whereas anti-cardiolipin antibodies bind cardiolipin and other anionic phospholipids and are detected in solid-phase immunoassays (6 ). Despite their name, aPL antibodies recognize plasma proteins bound to suitable anionic (not necessarily phospholipid) surfaces rather than anionic phospholipids. Among them, b2glycoprotein I (b2-GPI) (7, 8) and prothrombin (9 ) are the most common and investigated antigenic targets. b2-GPI is required by the majority of autoimmune anti-cardiolipin antibodies to react with cardiolipin in immunoassays (7, 8). Specific subgroups of anti-b2-GPI (10 ) and antiprothrombin (11 ) antibodies are responsible for the lupus anticoagulant activity in phospholipid-dependent coagulation tests. In addition to b2-GPI and prothrombin, (activated) protein C (12 ), protein S (12 ), annexin V (13 ), highand low-molecular weight kininogens (14 ), factor XII (15 ), thrombomodulin (16 ), and tissue-type plasminogen activator (17 ) have been reported to be antigenic targets of aPL antibodies. Because all of these proteins are involved in the initiation and control of blood coagulation, it is conceivable that antibodies that reduce their availability or hamper their function may affect the proand anticoagulant balance. This might represent the pathophysiologic background underlying the increased thrombotic risk of aPL-positive patients. To date, limited and rather inconsistent information is available as to the prevalence and clinical significance of aPL antibodies other than lupus anticoagulants, anti-cardiolipin, anti-b2-GPI, and anti-prothrombin antibodies. There are multiple reasons for this inconsistency. The laboratory methodology used for the detection of aPL antibodies is crucial. Both functional and immunoassays have been used. Enzyme-linked immunoassays are currently the most commonly used methods because they are easily performed, potentially may be automated, and allow the screening of large numbers of samples. Despite their widespread use, standardized assays for detection of the various aPL antibodies are still lacking. For anti-b2GPI and anti-prothrombin antibodies, the mode of presentation of the antigens in immunoassays has long been known to greatly affect their recognition (18 ). In fact, the immune reaction occurs only when g-irradiated polystyrene or high-density polyvinyl chloride plates are used, whereas no binding to proteins immobilized on plain polystyrene plates is observed (9, 11, 19). Under the former conditions, the prevalence of IgG and/or IgM anti-b2-GPI and anti-prothrombin antibodies is ;50% (9, 11, 19). This value is higher when the anionic phospholipid-protein complex represents the antigen (11 ). Two hypotheses have been put forward to explain these findings: