BEta(2)-glycoprotein I (beta(2)-GPI) is proteolytically cleaved by plasmin in domain V (nicked beta(2)-GPI), being unable to bind to phospholipids. This cleavage may occur in vivo and elevated plasma levels of nicked beta(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 beta(2)-GPI against total beta(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 beta(2)-GPI 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 beta(2)-GPI binds to Glu-plasminogen with K(D) of 0.37 x 10(-6) M, presumably mediated by the interaction between the fifth domain of nicked beta(2)-GPI and the fifth kringle domain of Glu-plasminogen. Nicked beta(2)-GPI also suppressed plasmin generation up to 70% in the presence of tissue plasminogen activator, plasminogen, and fibrin. Intact beta(2)-GPI lacks these properties. These data suggest that beta(2)-GPI/plasmin-nicked beta(2)-GPI controls extrinsic fibrinolysis via a negative feedback pathway loop.