ANTIPHOSPHOLIPID ANTIBODY - FUNCTIONAL SPECIFICITY FOR INHIBITION OF PROTHROMBIN ACTIVATION BY THE PROTHROMBINASE COMPLEX

The antiphospholipid syndrome (APS) is associated with production of a utoantibodies with lupus anticoagulant (LA) activity. These antibodies cause prolongation of in vitro clotting tests by inhibition of the co nversion of prothrombin to thrombin in the presence of anionic phospho lipid (PL). The extent to which this inhibition reflects antibody bind ing to, or functional inhibition of, phospholipids alone, prothrombin alone, or a prothrombin-phospholipid complex is pertinent to our under standing of the pathophysiology of this syndrome. Immunoglobulin fract ions (IgG) from 18 patients with LA activity were tested for inhibitor y activity against prothrombin activation by either factor Xa, in a pu rified prothrombinase system, or by purified fractions of snake venoms (E. carinatus, E. multisquamatus) which cleave prothrombin at the sam e initial site as the prothrombinase complex but do not require anioni c phospholipid as a cofactor. Parallel testing of the same IgG samples for prothrombin binding by immunoassay was performed. Although all Ig G samples inhibited the prothrombinase reaction, only three exhibited any inhibition of venom protease prothrombin activation in either the presence or absence of PL. Only one sample exhibited prothrombin bindi ng by Western blot. These results suggest that lupus anticoagulant ant ibodies are heterogenous and that many if not most, of the autoantibod y populations responsible for LA activity impair prothrombin activatio n by interaction either with phospholipid alone or with a restricted r ange of prothrombin-phospholipid epitopes expressed by prothrombin onl y as part of the intact prothrombin-prothrombinase complex.