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

Research output: Contribution to journalArticle

47 Citations (Scopus)

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

Fingerprint

Fibrinolysis
Glycoproteins
Feedback
Fibrinolysin
Plasminogen
Healthy Volunteers
Kringles
Lacunar Stroke
Tissue Plasminogen Activator
Magnetic resonance
Fibrin
Phospholipids
Thrombosis
Stroke
Magnetic Resonance Imaging
Plasmas
Imaging techniques

ASJC Scopus subject areas

  • Hematology

Cite this

Nicked β2-glycoprotein I : A marker of cerebral infarct and a novel role in the negative feedback pathway of extrinsic fibrinolysis. / Yasuda, Shinsuke; Atsumi, Tatsuya; Ieko, Masahiro; Matsuura, Eiji; Kobayashi, Kazuko; Inagaki, Junko; Kato, Hisao; Tanaka, Hideyuki; Yamakado, Minoru; Akino, Minoru; Saitou, Hisatoshi; Amasaki, Yoshiharu; Jodo, Satoshi; Amengual, Olga; Koike, Takao.

In: Blood, Vol. 103, No. 10, 15.05.2004, p. 3766-3772.

Research output: Contribution to journalArticle

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, vol. 103, no. 10, pp. 3766-3772. https://doi.org/10.1182/blood-2003-08-2712
Yasuda, Shinsuke ; Atsumi, Tatsuya ; Ieko, Masahiro ; Matsuura, Eiji ; Kobayashi, Kazuko ; Inagaki, Junko ; Kato, Hisao ; Tanaka, Hideyuki ; Yamakado, Minoru ; Akino, Minoru ; Saitou, Hisatoshi ; Amasaki, Yoshiharu ; Jodo, Satoshi ; Amengual, Olga ; Koike, Takao. / Nicked β2-glycoprotein I : A marker of cerebral infarct and a novel role in the negative feedback pathway of extrinsic fibrinolysis. In: Blood. 2004 ; Vol. 103, No. 10. pp. 3766-3772.
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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.",
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T2 - A marker of cerebral infarct and a novel role in the negative feedback pathway of extrinsic fibrinolysis

AU - Yasuda, Shinsuke

AU - Atsumi, Tatsuya

AU - Ieko, Masahiro

AU - Matsuura, Eiji

AU - Kobayashi, Kazuko

AU - Inagaki, Junko

AU - Kato, Hisao

AU - Tanaka, Hideyuki

AU - Yamakado, Minoru

AU - Akino, Minoru

AU - Saitou, Hisatoshi

AU - Amasaki, Yoshiharu

AU - Jodo, Satoshi

AU - Amengual, Olga

AU - Koike, Takao

PY - 2004/5/15

Y1 - 2004/5/15

N2 - 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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