Beta 2 glycoprotein I--function in health and disease.

Beta-2 glycoprotein I (beta2GPI) is the principal target of autoantibodies in the antiphospholipid syndrome (APS). It is abundant in human plasma and shares high homology between different mammalian species. Although the exact physiological function of beta2GPI has not been fully elucidated, several interactions have been described with other proteins and with negatively charged surfaces, such as anionic phospholipids, dextran and heparin. beta2GPI is involved in the coagulation pathway, exerting both procoagulant and anticoagulant activities. Plasma from beta2GPI-deficient mice exhibits impaired thrombin generation in vitro. Recently, it has been demonstrated that beta2GPI binds factor (F) XI in vitro at concentrations lower than those of the protein in human plasma, and this binding inhibits FXI activation to FXIa by thrombin and FXIIa. Proteolytic cleavage of the fifth domain of beta2GPI abolishes its inhibition of FXI activation and results in reduced ability of the cleaved beta2GPI to bind phospholipids. It retains its ability to bind FXI. In vivo activation of FXI by thrombin is thought to be an important mechanism by which coagulation is accelerated via components of the contact activation pathway. Thus beta2GPI may attenuate the contact activation pathway by inhibiting activation of FXI by thrombin. Moreover, because beta2GPI is the dominant autoantigen in patients with APS, dysregulation of this pathway by autoantibodies may be an important mechanism for thrombosis in patients with APS.