In:
Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 404-404
Abstract:
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 (Kd ∼ 20 nM), and caused a 20-fold increase in the catalytic efficiency (kcat/Km) 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.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V110.11.404.404
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2007
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
Permalink
