Little is known about the physiological role of beta-2-glycoprotein I (β2GPI) despite it being the major auto-antigen in the antiphospholipid syndrome. A systematic study of the role of β2GPI in thrombus formation in vivo has not been performed to date. Herein, we report that β2GPI deficient (-/-) mice have enhanced thrombus formation compared to wild type (WT) mice in a laser-induced arteriole and venule model of thrombosis. Furthermore, neutrophil accumulation and elastase activity was enhanced in thrombi of β2GPI -/- compared with WT mice. The antithrombotic function of β2GPI is dependent on its fifth domain (domain V); intravenous administration of the β2GPI domain deletion mutant lacking domain V (human recombinant domain I-IV) had no effect on platelet and fibrin thrombus size in β2GPI -/- or WT mice. On the contrary, intravenous administration of human recombinant domain V significantly inhibited platelet and fibrin thrombus size in both β2GPI -/- mice and WT mice. These findings reveal a major role for β2GPI as a natural anticoagulant and implicate domain V of β2GPI as a potential antithrombotic therapy.
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