HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Nicked 2-glycoprotein I: a marker of cerebral infarct and a novel role in the negative feedback pathway of extrinsic fibrinolysis

2-Glycoprotein I ( 2-GPI) is proteolytically cleaved by plasmin in domain V (nicked 2-GPI), being unable to bind to phospholipids. This cleavage may occur in vivo and elevated plasma levels of nicked 2-GPI were detected in patients with massive plasmin generation and fibrinolysis turnover. In this study, we report higher prevalence of elevated ratio of nicked 2-GPI against total 2-GPI in patients with ischemic stroke (63%) and healthy subjects with lacunar infarct (27%) when compared to healthy subjects with normal findings on magnetic resonance imaging (8%), suggesting that nicked 2GPI might have a physiologic role beyond that of its parent molecule in patients with thrombosis. Several inhibitors of extrinsic fibrinolysis are known, but a negative feedback regulator has not been yet documented. We demonstrate that nicked 2GPI binds to Glu-plasminogen with KD of 0.37 10 6 M, presumably mediated by the interaction between the fifth domain of nicked 2-GPI and the fifth kringle domain of Glu-plasminogen. Nicked 2GPI also suppressed plasmin generation up to 70% in the presence of tissue plasminogen activator, plasminogen, and fibrin. Intact 2-GPI lacks these properties. These data suggest that 2-GPI/plasmin-nicked 2GPI controls extrinsic fibrinolysis via a negative feedback pathway loop. (Blood. 2004; 103:3766-3772)