β₂-Glycoprotein I Is a Cofactor for t-PA-Mediated Plasminogen Activation.

Regulation of the conversion of plasminogen to plasmin by tissue-type plasminogen activator (t-PA) is critical in the control of fibrin deposition. While several plasminogen activators have been described, soluble plasma cofactors that stimulate fibrinolysis have not been characterized. Here, we report that the abundant plasma glycoprotein, β₂-glycoprotein I (β₂GPI), stimulates t-PA - dependent plasminogen activation both in the fluid phase and within a fibrin gel. Moreover, depletion of β₂GPI from plasma reduced the lysis of fibrin thrombi, and exogenous β₂GPI enhanced the activity of t-PA in a rat arteriovenous shunt thrombosis model. β₂GPI bound t-PA with high affinity (K_d ∼ 20 nM), and caused a 20-fold increase in the catalytic efficiency (k_cat/K_m) of t-PA - mediated conversion of Glu-plasminogen to plasmin, primarily by stimulating t-PA amidolytic activity. Structure-function analysis revealed that the region within β₂GPI responsible for stimulating t-PA activity is at least partially contained within β₂GPI domain V. Finally, stimulation of t-PA - mediated plasminogen activity by β₂GPI was inhibited by monoclonal anti-β₂GPI antibodies, as well as by anti-β₂GPI antibodies from patients with antiphospholipid syndrome (APS). These findings suggest that β₂GPI may be an endogenous regulator of fibrinolysis. Impairment of β₂GPI-stimulated fibrinolysis by anti-β₂GPI antibodies may contribute to the development of thrombosis in patients with APS.