The Concept and Classification of Antiphospholipid/Cofactor Syndromes

Abstract

In 1990, three groups simultaneously reported that putative IgG antibodies to anionic phospholipids were either not directed to phospholipids or at least required β2-grycoprotein-I (β·2-GP-I) for reactivity in vitro. During the same year, our group described a patient with ‘idiopathic’ hemolytic anemia with serum and erythrocyte-bound IgM antibodies to phosphatidylcholine later found to be independent of β2-GP-I for antigen recognition. Lately, the field has been expanded considerably with: (1) the description of other potential antigens such as prothrombin for some lupus anticoagulants, (2) the finding of crossreactivity between some antiphospholipid antibodies (aPL) with thrombomodulin, (3) the presence of serum antibodies to β2-GP-I (anti-β2-GP-I) in patients with SLE and thromboses, (4) the findings that the clinical manifestations of APS in SLE patients associate more strongly with anti-β2-GP-I than with aPL, (5) our finding of a group of SLE patients with the clinical manifestations of APS, with negative serum aPL, but with positive anti-β2-GP-I, (6) the description of a group of patients with the clinical manifestations of APS, without serum aPL, without serological nor clinical evidence of any autoimmune disease, but with IgG anti-β2-GP-I, and (7) the observation that serum anti-phosphatidylethanolamine antibodies detected in some patients with APS require kininogen (alone or complexed with the kininogen-binding protein), prekallikrein and/or factor XI for in vitro reactivity. Thus, there are antibodies that may be considered true aPL; other ‘aPL’ require a protein cofactor for their detection in vitro, at least in the case of β2-GP-I it would appear that their epitope is present on the protein proper not on the phospholipid, hence these are pseudo aPL, and a third group of related anti-cofactor autoantibodies that are directed to the protein in the absence of phospholipid. Clearly, the term ‘antiphospholipid syndrome’ has become obsolete. We propose the term ‘Antiphospholipid/Cofactor Syndromes’ to cull the various syndromes.