β2-glycoprotein I, anti-β2-glycoprotein 1, and fibrinolysis

beta 2-glycoproteind (beta(2)GPI) is a phospholipid-binding plasma protein that consists of five homologous domains. Domain V is distinguished from others by bearing a positively charged lysine cluster and hydrophobic extra C-terminal loop. beta(2)GPI has been known as a natural anticoagulant regulator. beta(2)GPI exerts anticoagulant activity by inhibition of phospholipid-dependent coagulation reactions such as prothrombinase, tenase, and factor XII activation. It also binds factor XI and inhibits its activation. On the other hand, beta(2)GPI inhibits anticoagulant activity of activated protein C. According to the data from knockout mice, beta(2)GPI may contribute to thrombin generation in vivo. Phospholipid-bound beta(2)GPI is one of the major target antigens for anti phospholipid antibodies present in patients with anti phospholipid syndrome (APS). Binding of pathogenic anti-beta(2)GPI antibodies increases the affinity of beta(2)GPI to the cell surface and disrupts the coagulation/fibrinolysis balance on the cell surface. These pathogenic antibodies activate endothelial cells via signal transduction events in the presence of beta(2)GPI. Impaired fibrinolysis has been reported in patients with APS. Using a newly developed chromogenic assay, we demonstrated lower activity of intrinsic fibrinolysis in euglobulin fractions from APS patients. Addition of monoclonal anti-beta(2)GPI antibodies with beta(2)GPI also decreased fibrinolytic activity in this assay system. beta(2)GPI is proteotytically cleaved by plasmin in domain V (nicked beta(2)GPI) and becomes unable to bind to phospholipids, reducing antigenicity against antiphospholipid antibodies. This cleavage occurs in patients with increased fibrinolysis turnover. Nicked beta(2)GPI binds to plasminogen and suppresses plasmin generation in the presence of fibrin, plasminogen, and tissue plasminogen activator (tPA). Thus, nicked beta(2)GPI plays a role in the extrinsic fibrinolysis via a negative feedback pathway loop. (c) 2004 Elsevier Ltd. All rights reserved.