Enhancement of protein S anticoagulant function by beta(2)-glycoprotein I,a major target antigen of antiphospholipid antibodies: beta(2)-glycoprotein I interferes with binding of protein S to its plasma inhibitor, C4b-binding protein

Thrombosis in the antiphospholipid syndrome has been associated with acquir ed deficiency of the anticoagulant protein S. We sought evidence that beta( 2)-glycoprotein I, a major target antigen for antiphospholipid antibodies, is involved in regulation of protein S activity. Incubation of purified pro tein S or plasma with beta(2)-glycoprotein I reversed functional modulation of protein S by its plasma inhibitor, the C4b-binding protein. In a plasma -free ELISA, beta(2)-glycoprotein I prevented the binding of protein S and C4b-binding protein when preincubated with immobilized protein S but not wh en similarly preincubated with C46-binding protein. beta(2)-glycoprotein I in fluid phase interfered with precipitation of protein S by sepharose-boun d C4b-binding protein. Effects of beta(2)-glycoprotein I on protein S funct ion were inhibited by one of four monoclonal anti-beta(2)-glycoprotein I an tibodies. These data suggest that beta(2)-glycoprotein I helps maintain ade quate plasma levels of circulating free, active protein S. Antiphospholipid (anti-beta(2)-plycoprotein I) antibodies might cause sporadic thrombosis, at least in part, by impairing this novel regulatory mechanism.