Autoantibodies to phospholipid-binding plasma proteins: a new view of lupus anticoagulants and other "antiphospholipid" autoantibodies.

L UPUS ANTICOAGULANTS, and “antiphospholipid” autoantibodies in general, are of considerable clinical importance because of their strong association with thrombosis, recurrent fetal loss, and thrombocytopenia, ie, the “antiphospholipid” antibody syndrome.’ This review focuses on recent evidence that “antiphospholipid” autoantibodies are not directed against anionic phospholipids, as has previously been thought, but are part of a larger group of autoantibodies against certain phospholipid-binding plasma proteins. At present, the most common and best characterized antigenic targets are &glycoprotein I (P2GPI)’-* and prothr~mbin.~”~ Other phospholipid-binding proteins, particularly protein C and protein S,” may be important targets as well. Autoantibodies with these specificities differ from acquired coagulation factor inhibitors in that they preferentially bind antigens that are immobilized on anionic phospholipid membranes or certain synthetic surfaces. In most instances, antibody binding to the antigens in the fluid-phase is weak or nondetectable. Thus, such autoantibodies usually do not decrease plasma antigen levels. Although direct evidence for a pathophysiologic role of “antiphospholipid” autoantibodies is lacking, it is hypothesized that autoantibodies to phospholipid-binding proteins contribute directly to a thrombotic diathesis by interfering with hemostatic reactions that occur on anionic phospholipid membranes in vivo. Interestingly, the effect of autoantibodies on target antigen function may vary. For example, certain antibodies to P2GPI enhance its activity,””’ whereas antibodies to phospholipid-bound activated protein C are inhibitory.” Taken together, these new observations explain much of the confusion regarding the laboratory tests used to detect “ antiphospholipid” antibodies and are providing key insights into the pathophysiology of the “antiphospholipid” antibody syndrome.