FUNCTIONAL-EFFECTS OF ANTICARDIOLIPIN ANTIBODIES

The 'lupus anticoagulant' phenomenon is the best documented functional effect of antiphospholipid (aPL) antibodies, occurring either by inhi bition of the prothrombinase and/or Factor X activation reactions, Und erstanding the mechanism by which aPL antibodies inhibit phospholipid dependent coagulation reactions may yield important clues about their 'thrombogenic effects' in vivo. We conducted a series of studies to de termine the specificity, diversity, and mechanism by which aPL antibod ies inhibit phospholipid dependent reactions. Results showed that puri fied immunoglobulins with lupus anticoagulant, and anti-cardiolipin ac tivities were absorbed by negatively charged phospholipids and both ac tivities were recovered from the phospholipid-antibody precipitate. Pu rified aPL antibodies inhibited the prothrombinase reaction in a plasm a free system in which beta(2)-glycoprotein 1 (beta(2)-GP1) was absent . Affinity purified aPL antibodies had 25-50 times the inhibitory acti vity of immunoglobulin preparations. The phospholipid binding proteins , beta(2)-GP1 and placental anticoagulant protein I (PAP I), independe ntly inhibited the prothrombinase reaction, and when these proteins we re combined with aPL, inhibition of the prothrombinase reaction was ad ditive. Antibodies of syphilis had no inhibitory effect, partially acc ounted for by lack of specificity for phosphotidylserine (PS). Althoug h aPL antibodies inhibited the protein C activation reaction, there wa s no correlation of these activities with inhibition of the prothrombi nase reaction. Together, these results show that aPL exert their effec ts by interaction with negatively charged phospholipids, in particular phosphotidylserine, but lack of correlation between inhibition of the prothrombinase and protein C activation reactions, suggests that the nature of the coagulation protein is also important.