β2-Glycoprotein I binds factor XI and inhibits its activation by thrombin and factor XIIa: Loss of inhibition by clipped β2-glycoprotein I

Activation of factor XI (FXI) by thrombin in vivo plays a role in coagulation by providing an important positive feedback mechanism for additional thrombin generation. FXI is activated in vitro by thrombin, or FXIIa in the presence of dextran sulfate. In this report, we investigated the effect of β2-glycoprotein I (β2GPI) on the activation of FXI. β2GPI bound FXI in vitro and inhibited its activation to FXIa by thrombin and FXIIa. The affinity of the interaction between β2GPI and FXI was equivalent to the interaction between FXI and high molecular weight kininogen. Inhibition of FXI activation occurred with lower concentrations of β2GPI than found in human plasma. Proteolytic clipping of β2GPI by plasmin abolished its inhibition of FXI activation. The results suggest a mechanism of regulation whereby physiological concentrations of β2GPI may attenuate thrombin generation in vivo by inhibition of FXI activation. Plasmin cleavage of β2GPI provides a negative feedback that counteracts its inhibition of FXI activation.