Advertisement

Reduced β2-GPI is associated with increased platelet aggregation and activation in patients with prolonged isolated thrombocytopenia after allo-HSCT

  • Haixia Fu
  • Jingzhong Zhao
  • Lanping Xu
  • Kaiyan Liu
  • Yu Wang
  • Huan Chen
  • Wei Han
  • Jingzhi Wang
  • Fengrong Wang
  • Xiaojun Huang
  • Xiaohui ZhangEmail author
Research Paper
  • 1 Downloads

Abstract

We aimed to measure platelet function and its relationship with β2-GPI in prolonged isolated thrombocytopenia (PT) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Fifty-six patients with PT and 60 allo-HSCT recipients without PT (non-PT controls) were enrolled. Platelet aggregation and activation, β2-GPI and anti-β2-GPI antibody levels, vWF antigen, and vWF activity were analyzed. The effect of β2-GPI on platelet aggregation was also measured ex vivo. Results showed that ADP-induced platelet aggregation significantly increased (39%±7.5% vs. 23%±8.5%, P=0.032), and the platelet expression of both CD62p (33.6%±11.6% vs. 8.5%±3.5%, P<0.001) and PAC-1 (42.4%±7.6% vs. 6.8%±2.2%, P<0.001) was significantly higher in patients with PT than in those without PT. Significantly lower β2-GPI levels (164.2±12 μg mL−1 vs. 234.2±16 μg mL−1, P<0.001), higher anti-β2-GPI IgG levels (1.78±0.46 U mL−1 vs. 0.94±0.39 U mL−1, P<0.001), and increased vWF activity (133.06%±30.50% vs. 102.17%±25.90%, P<0.001) were observed in patients with PT than in those without PT. Both ADP-induced platelet aggregation (n=116, r2=-0.5042, P<0.001) and vWF activity (n=116, r2=-0.2872, P<0.001) were negatively correlated with β2-GPI levels. In summary, our data suggested that platelet aggregation and activation were significantly higher in patients with PT than in those without PT, which might be associated with reduced β2-GPI levels. The reduced β2-GPI levels might be due to the existence of anti-β2-GPI IgG.

Keywords

β2-GPI hematopoietic stem cell transplantation prolonged isolated thrombocytopenia platelet aggregation platelet activation 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Notes

Acknowledgements

This work was supported by the Key Program of National Natural Science Foundation of China (81730004), National Natural Science Foundation of China (81470343 and 81670116), Beijing Natural Science Foundation (7171013), Beijing Municipal Science and Technology Commission (Z171100001017084) and the National Key Research and Development Program of China (2017YFA0105500, 2017YFA0105503).

Supplementary material

11427_2018_9493_MOESM1_ESM.docx (25 kb)
Supplementary-Fig 1. PT patients had higher ADP plus epinephrine-induced platelet aggregation. The ADP plus epinephrine-induced platelet aggregation were 47.3±3.7% in PT patients (n=10) and 33.7± 2.4% in non-PT patients (n=10) (P=0.007).

References

  1. Berndt, M., Shen, Y., Dopheide, S., Gardiner, E., and Andrews, R. (2001). The vascular biology of the glycoprotein Ib-IX-V complex. Thromb Haemost 86, 178–188.CrossRefGoogle Scholar
  2. Bielski, M., Yomtovian, R., Lazarus, H.M., and Rosenthal, N. (1998). Prolonged isolated thrombocytopenia after hematopoietic stem cell transplantation: morphologic correlation. Bone Marrow Transplant 22, 1071–1076.CrossRefGoogle Scholar
  3. Canobbio, I., Balduini, C., and Torti, M. (2004). Signalling through the platelet glycoprotein Ib-V–IX complex. Cell Signal 16, 1329–1344.CrossRefGoogle Scholar
  4. de Laat, H.B., Derksen, R.H.W.M., Urbanus, R.T., Roest, M., and de Groot, P.G. (2004). 2-glycoprotein I-dependent lupus anticoagulant highly correlates with thrombosis in the antiphospholipid syndrome. Blood 104, 3598–3602.CrossRefGoogle Scholar
  5. Du, X. (2007). Signaling and regulation of the platelet glycoprotein Ib-IXV complex. Curr Opin Hematol 14, 262–269.CrossRefGoogle Scholar
  6. First, L.R., Smith, B.R., Lipton, J., Nathan, D.G., Parkman, R., and Rappeport, J.M. (1985). Isolated thrombocytopenia after allogeneic bone marrow transplantation: existence of transient and chronic thrombocytopenic syndromes. Blood 65, 368–374.Google Scholar
  7. Fu, Q., Xu, L., Zhang, X., Wang, Y., Chang, Y., Liu, K., and Huang, X. (2018). Platelet transfusion refractoriness after T-cell-replete haploidentical transplantation is associated with inferior clinical outcomes. Sci China Life Sci 61, 569–577.CrossRefGoogle Scholar
  8. Galli, M., Luciani, D., Bertolini, G., and Barbui, T. (2003). Anti-2-glycoprotein I, antiprothrombin antibodies, and the risk of thrombosis in the antiphospholipid syndrome. Blood 102, 2717–2723.CrossRefGoogle Scholar
  9. Huang, X.J., Liu, D.H., Liu, K.Y., Xu, L.P., Chen, H., Han, W., Chen, Y.H., Wang, J.Z., Gao, Z.Y., Zhang, Y.C., et al. (2006). Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant 38, 291–297.CrossRefGoogle Scholar
  10. Huang, X.J., Xu, L.P., Liu, K.Y., Liu, D.H., Wang, Y., Chen, H., Chen, Y. H., Han, W., Wang, J.H., Chen, Y., et al. (2009). Partially matched related donor transplantation can achieve outcomes comparable with unrelated donor transplantation for patients with hematologic malignancies. Clin Cancer Res 15, 4777–4783.CrossRefGoogle Scholar
  11. Hulstein, J.J.J., Lenting, P.J., de Laat, B., Derksen, R.H.W.M., Fijnheer, R., and de Groot, P.G. (2007). 2-Glycoprotein I inhibits von Willebrand factor dependent platelet adhesion and aggregation. Blood 110, 1483–1491.CrossRefGoogle Scholar
  12. Kang, I., Raghavachari, M., Hofmann, C.M., and Marchant, R.E. (2007). Surface-dependent expression in the platelet GPIb binding domain within human von Willebrand factor studied by atomic force microscopy. Thromb Res 119, 731–740.CrossRefGoogle Scholar
  13. Kong, Y., Hu, Y., Zhang, X.H., Wang, Y.Z., Mo, X.D., Zhang, Y.Y., Wang, Y., Han, W., Xu, L.P., Chang, Y.J., et al. (2014). Association between an impaired bone marrow vascular microenvironment and prolonged isolated thrombocytopenia after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 20, 1190–1197.CrossRefGoogle Scholar
  14. Labrador, J., López-Corral, L., Vazquez, L., Sánchez-Guijo, F., Guerrero, C., Sánchez-Barba, M., Lozano, F.S., Alberca, I., Del Cañizo, M.C., Caballero, D., et al. (2015). Incidence and risk factors for life-threatening bleeding after allogeneic stem cell transplant. Br J Haematol 169, 719–725.CrossRefGoogle Scholar
  15. Middelburg, R.A., Carbaat-Ham, J.C., Hesam, H., Ragusi, M.A.A.D., and Zwaginga, J.J. (2016). Platelet function in adult ITP patients can be either increased or decreased, compared to healthy controls, and is associated with bleeding risk. Hematology 21, 549–551.CrossRefGoogle Scholar
  16. Morigi, M., Galbusera, M., Gastoldi, S., Locatelli, M., Buelli, S., Pezzotta, A., Pagani, C., Noris, M., Gobbi, M., Stravalaci, M., et al. (2011). Alternative pathway activation of complement by Shiga toxin promotes exuberant C3a formation that triggers microvascular thrombosis. J Immunol 187, 172–180.CrossRefGoogle Scholar
  17. Nimpf, J., Wurm, H., and Kostner, G.M. (1987). β2-glycoprotein-I (apo-H) inhibits the release reaction of human platelets during ADP-induced aggregation. Atherosclerosis 63, 109–114.CrossRefGoogle Scholar
  18. Ozaki, Y., Asazuma, N., Suzuki-Inoue, K., and Berndt, M.C. (2005). Platelet GPIb-IX-V-dependent signaling. J Thromb Haemost 3, 1745–1751.CrossRefGoogle Scholar
  19. Przepiorka, D., Weisdorf, D., Martin, P., Klingemann, H.G., Beatty, P., Hows, J., and Thomas, E.D. (1995). 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant 15, 825–828.Google Scholar
  20. Ruggeri, Z.M. (2003). Von Willebrand factor, platelets and endothelial cell interactions. J Thromb Haemost 1, 1335–1342.CrossRefGoogle Scholar
  21. Shi, T., Giannakopoulos, B., Yan, X., Yu, P., Berndt, M.C., Andrews, R.K., Rivera, J., Iverson, G.M., Cockerill, K.A., Linnik, M.D., et al. (2006). Anti-β2-glycoprotein I antibodies in complex with β2-glycoprotein I can activate platelets in a dysregulated manner via glycoprotein Ib-IXV. Arthritis Rheum 54, 2558–2567.CrossRefGoogle Scholar
  22. Tedesco, F., Pausa, M., Nardon, E., Introna, M., Mantovani, A., and Dobrina, A. (1997). The cytolytically inactive terminal complement complex activates endothelial cells to express adhesion molecules and tissue factor procoagulant activity. J Exp Med 185, 1619–1628.CrossRefGoogle Scholar
  23. van Lier, M., Lee, F., Farndale, R.W., Gorter, G., Verhoef, S., Ohno-Iwashita, Y., Akkerman, J.W.N., and Heijnen, H.F.G. (2005). Adhesive surface determines raft composition in platelets adhered under flow. J Thromb Haemost 3, 2514–2525.CrossRefGoogle Scholar
  24. van Velzen, J.F., Laros-van Gorkom, B.A.P., Pop, G.A.M., and van Heerde, W.L. (2012). Multicolor flow cytometry for evaluation of platelet surface antigens and activation markers. Thromb Res 130, 92–98.CrossRefGoogle Scholar
  25. Wang, Y., Liu, Q.F., Xu, L.P., Liu, K.Y., Zhang, X.H., Ma, X., Fan, Z.P., Wu, D.P., and Huang, X.J. (2015). Haploidentical vs identical-sibling transplant for AML in remission: a multicenter, prospective study. Blood 125, 3956–3962.CrossRefGoogle Scholar
  26. Yamazaki, R., Kuwana, M., Mori, T., Okazaki, Y., Kawakami, Y., Ikeda, Y., and Okamoto, S. (2006). Prolonged thrombocytopenia after allogeneic hematopoietic stem cell transplantation: associations with impaired platelet production and increased platelet turnover. Bone Marrow Transplant 38, 377–384.CrossRefGoogle Scholar
  27. Zhang, X., Fu, H., Xu, L., Liu, D., Wang, J., Liu, K., and Huang, X. (2011). Prolonged thrombocytopenia following allogeneic hematopoietic stem cell transplantation and its association with a reduction in ploidy and an immaturation of megakaryocytes. Biol Blood Marrow Transplant 17, 274–280.CrossRefGoogle Scholar
  28. Zhang, X.H., Wang, G.X., Zhu, H.H., Liu, Y.R., Xu, L.P., Han, W., Chen, H., Chen, Y.H., Wang, F.R., Wang, J.Z., et al. (2015a). Recruitment of CD8+ T cells into bone marrow might explain the suppression of megakaryocyte apoptosis through high expression of CX3CR1+ in prolonged isolated thrombocytopenia after allogeneic hematopoietic stem cell transplantation. Ann Hematol 94, 1689–1698.CrossRefGoogle Scholar
  29. Zhang, X.H., Wang, Q.M., Zhang, J.M., Feng, F.E., Wang, F.R., Chen, H., Zhang, Y.Y., Chen, Y.H., Han, W., Xu, L.P., et al. (2015b). Desialylation is associated with apoptosis and phagocytosis of platelets in patients with prolonged isolated thrombocytopenia after allo-HSCT. J Hematol Oncol 8, 116–131.CrossRefGoogle Scholar
  30. Zhang, X.H., Wang, Q.M., Chen, H., Chen, Y.H., Han, W., Wang, F.R., Wang, J.Z., Zhang, Y.Y., Mo, X.D., Chen, Y., et al. (2016). Clinical characteristics and risk factors of Intracranial hemorrhage in patients following allogeneic hematopoietic stem cell transplantation. Ann Hematol 95, 1637–1643.CrossRefGoogle Scholar
  31. Zhang, W., Gao, F., Lu, D., Sun, N., Yin, X., Jin, M., and Liu, Y. (2016). Anti-β2 glycoprotein I antibodies in complex with β2 glycoprotein I induce platelet activation via two receptors: apolipoprotein E receptor 2′ and glycoprotein I bα. Front Med 10, 76–84.CrossRefGoogle Scholar

Copyright information

© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Haixia Fu
    • 1
    • 2
  • Jingzhong Zhao
    • 3
  • Lanping Xu
    • 1
    • 2
  • Kaiyan Liu
    • 1
    • 2
  • Yu Wang
    • 1
    • 2
  • Huan Chen
    • 1
    • 2
  • Wei Han
    • 1
    • 2
  • Jingzhi Wang
    • 1
    • 2
  • Fengrong Wang
    • 1
    • 2
  • Xiaojun Huang
    • 1
    • 2
  • Xiaohui Zhang
    • 1
    • 2
    Email author
  1. 1.Peking University People’s Hospital, Peking University Institute of HematologyBeijingChina
  2. 2.Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation for the Treatment of Hematological DiseasesBeijingChina
  3. 3.Department of Clinical LaboratoryPeking University People’s HospitalBeijingChina

Personalised recommendations