Beta 2-Glycoprotein I binds factor XI and inhibits its activation by thrombin and factor XIIa: loss of inhibition by clipped beta 2-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 beta(2)-glycoprotein I (beta(2)GPI) on the activation of FXI. beta(2)GPI bound FXI in vitro and inhibited its activation to FXIa by thrombin and FXIIa. The affinity of the interaction between beta(2)GPI and FXI was equivalent to the interaction between FXI and high molecular weight kininogen. Inhibition of FXI activation occurred with lower concentrations of beta(2)GPI than found in human plasma. Proteolytic clipping of beta(2)GPI by plasmin abolished its inhibition of FXI activation. The results suggest a mechanism of regulation whereby physiological concentrations of beta(2)GPI may attenuate thrombin generation in vivo by inhibition of FXI activation. Plasmin cleavage of beta(2)GPI provides a negative feedback that counteracts its inhibition of FXI activation.
Department of Medicine, St. George Hospital, University of New South Wales, Kogarah 2217, Australia.
Tong
T
Shi
G Michael
GM
Iverson
Jian C
JC
Qi
Keith A
KA
Cockerill
Matthew D
MD
Linnik
Pamela
P
Konecny
Steven A
SA
Krilis
D016736:Antiphospholipid Syndrome / Q000378:metabolism; D016264:Dextran Sulfate / Q000378:metabolism; D005172:Factor XI / Q000378:metabolism*; D005174:Factor XII / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism*; D053482:beta 2-Glycoprotein I
D006023:Glycoproteins; D011994:Recombinant Proteins; D053482:beta 2-Glycoprotein I; D005174:Factor XII; D005172:Factor XI; D016264:Dextran Sulfate; D013917:Thrombin