β2-Glycoprotein I (β2-GPI) is proteolytically cleaved by plasmin in domain V (nicked β2-GPI), being unable to bind to phospholipids. This cleavage may occur in vivo and elevated plasma levels of nicked β2-GPI were detected in patients with massive plasmin generation and fibrinolysis turnover. In this study, we report higher prevalence of elevated ratio of nicked β 2-GPI against total β2-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 β2-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 β 2-GPI binds to Glu-plasminogen with KD of 0.37 × 10-6 M, presumably mediatad by the interaction between the fifth domain of nicked β2-GPI and the fifth kringle domain of Glu-plasminogen. Nicked β2-GPI also suppressed plasmin generation up to 70% in the presence of tissue plasminogen activator, plasminogen, and fibrin. Intact β2-GPI lacks these properties. These data suggest that β2-GPI/plasmin-nicked β 2-GPI controls extrinsic fibrinolysis via a negative feedback pathway loop.
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