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Annals of Hematology

, Volume 97, Issue 4, pp 641–654 | Cite as

Diminished expression of β2-GPI is associated with a reduced ability to mitigate complement activation in anti-GPIIb/IIIa-mediated immune thrombocytopenia

  • Xiaolu Zhu
  • Jiamin Zhang
  • Qianming Wang
  • Haixia Fu
  • Yingjun Chang
  • Yuan Kong
  • Meng Lv
  • Lanping Xu
  • Kaiyan Liu
  • Xiaojun Huang
  • Xiaohui ZhangEmail author
Original Article

Abstract

Anti-GPIIb/IIIa-mediated complement activation has been reported to be important in the pathogenesis of immune thrombocytopenia (ITP). However, the role of the complement system and the involved regulatory mechanism remain equivocal. Beta2-glycoprotein I (β2-GPI), known as the main target for antiphospholipid autoantibodies, has been demonstrated as a complement regulator. Here, we investigated the complement-regulatory role of β2-GPI in anti-GPIIb/IIIa-mediated ITP. Plasma complement activation and enhanced complement activation capacity (CAC) were found in ITP patients with anti-GPIIb/IIIa antibodies in vivo and in vitro. Diminished plasma levels of β2-GPI were shown in patients of this group, which was inversely correlated with C5b-9 deposition. C5b-9 generation was inhibited by approximate physiological concentrations of β2-GPI, in a dose-dependent manner. Inhibition of C3a generation by β2-GPI and the existence of β2-GPI/C3 complexes in plasma indicated a regulation on the level of the C3 convertase. Furthermore, β2-GPI down-regulated the phosphorylation levels of c-Jun N-terminal kinase (JNK) and cleavage of BH3 interacting domain death agonist (Bid) and ultimately harbored platelet lysis. Our findings may provide a novel link between diminished plasma levels of β2-GPI and enhanced complement activation, indicating β2-GPI as a potential diagnostic biomarker and therapeutic target in the treatment of anti-GPIIb/IIIa-mediated ITP.

Keywords

Beta2-glycoprotein I (β2-GPI) Complement Immune thrombocytopenia (ITP) JNK Bid 

Notes

Funding information

This work was supported by National Natural Science Foundation of China (No. 81470343 and No. 81670116), Beijing Natural Science Foundation (No. 7171013), and Beijing Municipal Science and Technology Commission (No. Z171100001017084). All these funding are received by Xiao-Hui Zhang.

Compliance with ethical standards

The study was approved by the Peking University People’s Hospital Ethics Committee and the Declaration of Helsinki, and informed consent was obtained from all the participants.

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

277_2017_3215_MOESM1_ESM.eps (130 kb)
Fig. S1 MAPK phosphorylation in anti-GPIIb/IIIa-mediated ITP. a Phosphorylation of ERK, p38MAPK and JNK (p-ERK, p-p38 and p-JNK) in platelets of healthy controls incubated with plasma from healthy controls (lane 1), ITP patients with anti-GPIIb/IIIa antibodies (lane 2) or heat-inactivated plasma of patients (lane 3) with or without GPIIb/IIIa inhibitor SR121566 was determined by Western blotting. b Quantitative analyses of Western blotting of p-ERK, p-JNK and p-p38 (n=4, respectively). *P <.05. **P < .01. ***P < .001. (EPS 130 kb)
277_2017_3215_Fig7_ESM.gif (118 kb)

High resolution image (GIF 117 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Xiaolu Zhu
    • 1
    • 2
    • 3
  • Jiamin Zhang
    • 1
    • 2
    • 3
  • Qianming Wang
    • 1
    • 2
  • Haixia Fu
    • 1
    • 2
  • Yingjun Chang
    • 1
    • 2
    • 3
  • Yuan Kong
    • 1
    • 2
    • 3
  • Meng Lv
    • 1
    • 2
  • Lanping Xu
    • 1
    • 2
    • 3
  • Kaiyan Liu
    • 1
    • 2
    • 3
  • Xiaojun Huang
    • 1
    • 2
    • 3
  • Xiaohui Zhang
    • 1
    • 2
    • 3
    Email author
  1. 1.Peking University People’s HospitalPeking University Institute of HematologyBeijingChina
  2. 2.Beijing Key Laboratory of Hematopoietic Stem Cell TransplantationBeijingChina
  3. 3.Collaborative Innovation Center of HematologyPeking UniversityBeijingChina

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