Nicked β2-glycoprotein I: A marker of cerebral infarct and a novel role in the negative feedback pathway of extrinsic fibrinolysis

Shinsuke Yasuda, Tatsuya Atsumi, Masahiro Ieko, Eiji Matsuura, Kazuko Kobayashi, Junko Inagaki, Hisao Kato, Hideyuki Tanaka, Minoru Yamakado, Minoru Akino, Hisatoshi Saitou, Yoshiharu Amasaki, Satoshi Jodo, Olga Amengual, Takao Koike

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Abstract

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.

Original languageEnglish
Pages (from-to)3766-3772
Number of pages7
JournalBlood
Volume103
Issue number10
DOIs
Publication statusPublished - May 15 2004
Externally publishedYes

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ASJC Scopus subject areas

  • Hematology

Cite this

Yasuda, S., Atsumi, T., Ieko, M., Matsuura, E., Kobayashi, K., Inagaki, J., Kato, H., Tanaka, H., Yamakado, M., Akino, M., Saitou, H., Amasaki, Y., Jodo, S., Amengual, O., & Koike, T. (2004). Nicked β2-glycoprotein I: A marker of cerebral infarct and a novel role in the negative feedback pathway of extrinsic fibrinolysis. Blood, 103(10), 3766-3772. https://doi.org/10.1182/blood-2003-08-2712