beta 2 glycoprotein I-function in health and disease

Beta-2 glycoprotein I (beta(2)GPI) is the principal target of autoantibodies in the anti phospholipid syndrome (APS). It is abundant in human plasma and shares high homology between different mammalian species. Although the exact physiological function of beta(2)GPI 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. beta(2)GPI is involved in the coagulation pathway, exerting both procoagulant and anticoagulant activities. Plasma from beta(2)GPI-deficient mice exhibits impaired thrombin generation in vitro. Recently, it has been demonstrated that beta(2)GPI 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 beta(2)GPI abolishes its inhibition of FXI activation and results in reduced ability of the cleaved 2GPI 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 beta(2)GPI may attenuate the contact activation pathway by inhibiting activation of FXI by thrombin. Moreover, because 2GPI 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. (c) 2004 Published by Elsevier Ltd.