Skip to main content

Advertisement

Log in

Autoimmune-mediated thrombocytopenia after allogeneic hematopoietic stem cell transplantation: significance of detecting reticulated platelets and glycoprotein-specific platelet autoantibodies

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Autoimmune hematological disorders are rare complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Diagnosis of immune thrombocytopenia (ITP) is challenging, especially after allo-HSCT, because various complications such as graft-versus-host disease, disease relapse, viral infection, thrombotic microangiopathy, and drug side effects can also cause thrombocytopenia. Assessment of reticulated platelets (RP) and plasma thrombopoietin (TPO) levels may be useful to distinguish between ITP and hypoplastic thrombocytopenia. ITP is generally characterized by an increased percentage of RP, and a normal or slightly increased plasma TPO level. We now report three cases of thrombocytopenia after allo-HSCT. RP% was elevated in these patients, as it is in primary ITP. However, in contrast to primary ITP, plasma TPO levels were high in two of three patients. Anti-αIIbβ3 and anti-GPIb/IX-specific direct IgG antibodies were detected as well, suggesting occurrence of immune-mediated platelet destruction in addition to bone marrow suppression in two patients. All three patients were successfully treated with corticosteroids and/or thrombopoietin receptor agonists (TPO-RAs). These results suggest that increased RP% and detection of glycoprotein-specific platelet autoantibodies are useful for the diagnosis of ITP after HSCT.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Faraci M, Zecca M, Pillon M, Rovelli A, Menconi MC, Ripaldi M, et al. Autoimmune hematological diseases after allogeneic hematopoietic stem cell transplantation in children: an Italian multicenter experience. Biol Blood Marrow Transplant. 2014;20:272–8.

    Article  Google Scholar 

  2. Daikeler T, Labopin M, Ruggeri A, Crotta A, Abinun M, Hussein AA, et al. New autoimmune diseases after cord blood transplantation: a retrospective study of EUROCORD and the Autoimmune Disease Working Party of the European Group for Blood and Marrow Transplantation. Blood. 2013;121:1059–64.

    Article  CAS  Google Scholar 

  3. Holbro A, Abinun M, Daikeler T. Management of autoimmune diseases after haematopoietic stem cell transplantation. Br J Haematol. 2012;157:281–90.

    Article  CAS  Google Scholar 

  4. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346:995–1008.

    Article  Google Scholar 

  5. McMillan R. The pathogenesis of chronic immune thrombocytopenic purpura. Semin Hematol. 2007;44:S3–11.

    Article  CAS  Google Scholar 

  6. Kashiwagi H, Tomiyama Y. Pathophysiology and management of primary immune thrombocytopenia. Int J Hematol. 2013;98:24–33.

    Article  CAS  Google Scholar 

  7. Yuan C, Boyd AM, Nelson J, Patel RD, Varela JC, Goldstein SC, et al. Eltrombopag for treating thrombocytopenia after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2019;25:1320–4.

    Article  CAS  Google Scholar 

  8. Kurata Y, Hayashi S, Kiyoi T, Kosugi S, Kashiwagi H, Honda S, et al. Diagnostic value of tests for reticulated platelets, plasma glycocalicin, and thrombopoietin levels for discriminating between hyperdestructive and hypoplastic thrombocytopenia. Am J Clin Pathol. 2001;115:656–64.

    Article  CAS  Google Scholar 

  9. Porcelijn L, Folman CC, Bossers B, Huiskes E, Overbeeke MA, von dem Schoot CE, et al. The diagnostic value of thrombopoietin level measurements in thrombocytopenia. Thromb Haemost. 1998;79:1101–5.

    Article  CAS  Google Scholar 

  10. Sakakura M, Wada H, Abe Y, Nishioka J, Tomatsu H, Hamaguchi Y, et al. Usefulness of measurement of reticulated platelets for diagnosis of idiopathic thrombocytopenic purpura. Clin Appl Thromb Hemost. 2005;11:253–61.

    Article  Google Scholar 

  11. Kosugi S, Kurata Y, Tomiyama Y, Tahara T, Kato T, Tadokoro S, et al. Circulating thrombopoietin level in chronic immune thrombocytopenic purpura. Br J Haematol. 1996;93:704–6.

    Article  CAS  Google Scholar 

  12. Emmons RV, Reid DM, Cohen RL, Meng G, Young NS, Dunbar CE, et al. Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Blood. 1996;87:4068–71.

    Article  CAS  Google Scholar 

  13. Kiyomizu K, Kashiwagi H, Nakazawa T, Tadokoro S, Honda S, Kanakura Y, et al. Recognition of highly restricted regions in the β-propeller domain of αIIb by platelet-associated anti-αIIbβ3 autoantibodies in primary immune thrombocytopenia. Blood. 2012;120:1499–509.

    Article  CAS  Google Scholar 

  14. Li J, van der Wal DE, Zhu G, Xu M, Yougbare I, Ma L, et al. Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia. Nat Commun. 2015;6:7737.

    Article  CAS  Google Scholar 

  15. Vrbensky JR, Moore JE, Arnold DM, Smith JW, Kelton JG, Nazy I. The sensitivity and specificity of platelet autoantibody testing in immune thrombocytopenia: a systematic review and meta-analysis of a diagnostic test. J Thromb Haemost. 2019;17:787–94.

    Article  Google Scholar 

  16. Kosugi S, Tomiyama Y, Shiraga M, Kashiwagi H, Nakao H, Kanayama Y, et al. Cyclic thrombocytopenia associated with IgM anti-GPIIb-IIIa autoantibodies. Br J Haematol. 1994;88:809–15.

    Article  CAS  Google Scholar 

  17. Roux E, Dumont-Girard F, Starobinski M, Siegrist CA, Helg C, Chapuis B, et al. Recovery of immune reactivity after T-cell-depleted bone marrow transplantation depends on thymic activity. Blood. 2000;96:2299–303.

    Article  CAS  Google Scholar 

  18. Matsumoto R, Ito K, Hosono N, Matsuda Y, Tai K, Sakamaki I, et al. Acute myeloid leukemia developing secondary immune thrombocytopenia after umbilical cord blood transplantation. Rinsho Ketsueki. 2017;58:433–7.

    PubMed  Google Scholar 

  19. Sugiyama D, Nishikawa H, Maeda Y, Nishioka M, Tanemura A, Katayama I, et al. Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. Proc Natl Acad Sci USA. 2013;110:17945–50.

    Article  CAS  Google Scholar 

  20. Kurose K, Ohue Y, Wada H, Iida S, Ishida T, Kojima T, et al. Phase Ia study of FoxP3+ CD4 Treg depletion by infusion of a humanized anti-CCR4 antibody, KW-0761, in cancer patients. Clin Cancer Res. 2015;21:4327–36.

    Article  CAS  Google Scholar 

  21. Nomura S, Matsuzaki T, Ozaki Y, Yamaoka M, Yoshimura C, Katsura K, et al. Clinical significance of HLA-DRB1*0410 in Japanese patients with idiopathic thrombocytopenic purpura. Blood. 1998;91:3616–22.

    Article  CAS  Google Scholar 

  22. Kuwana M, Kaburaki J, Pandey JP, Murata M, Kawakami Y, Inoko H, et al. HLA class II alleles in Japanese patients with immune thrombocytopenic purpura. Associations with anti-platelet glycoprotein autoantibodies and responses to splenectomy. Tissue Antigens. 2000;56:337–43.

    Article  CAS  Google Scholar 

  23. Kuwana M, Kurata Y, Fujimura K, Fujisawa K, Wada H, Nagasawa T, et al. Preliminary laboratory based diagnostic criteria for immune thrombocytopenic purpura: evaluation by multi-center prospective study. J Thromb Haemost. 2006;4:1936–43.

    Article  CAS  Google Scholar 

  24. Sakuragi M, Hayashi S, Maruyama M, Kabutomori O, Kiyokawa T, Nagamine K, et al. Clinical significance of IPF% or RP% measurement in distinguishing primary immune thrombocytopenia from aplastic thrombocytopenic disorders. Int J Hematol. 2015;101:369–75.

    Article  CAS  Google Scholar 

  25. Buttarello M, Mezzapelle G, Freguglia F, Plebani M. Reticulated platelets and immature platelet fraction: clinical applications and method limitations. Int J Lab Hematol. 2020;42:363–70.

    Article  Google Scholar 

  26. Hong KH, Kim HK, Kim JE, Jung JS, Han KS, Cho HI. Prognostic value of immature platelet fraction and plasma thrombopoietin in disseminated intravascular coagulation. Blood Coagul Fibrinolysis. 2009;20:409–14.

    Article  CAS  Google Scholar 

  27. Briggs C, Kunka S, Hart D, Oguni S, Machin SJ. Assessment of an immature platelet fraction (IPF) in peripheral thrombocytopenia. Br J Haematol. 2004;126:93–9.

    Article  Google Scholar 

  28. Fu H, Zhang X, Xu L, Liu K, Huang X. Characterization of thrombopoietin kinetics within 60 days after allogeneic hematopoietic stem cell transplantation and its correlation with megakaryocyte ploidy distribution. Clin Transplant. 2016;30:170–8.

    Article  CAS  Google Scholar 

  29. Nomura S, Ishii K, Inami N, Matsuzaki T, Yamaoka M, Urase F, et al. Antiglycoprotein IIb–IIIa autoantibody in a patient with immune thrombocytopenia after cord blood transplantation. Clin Appl Thromb Hemost. 2009;15:123–4.

    Article  CAS  Google Scholar 

  30. Kashiwagi H, Kuwana M, Hato T, Takafuta T, Fujimura K, Kurata Y, et al. Reference guide for management of adult immune thrombocytopenia in Japan: 2019 Revision. Int J Hematol. 2020;111:329–51.

    Article  Google Scholar 

  31. Narita Y, Uchiyama T, Mizumoto C, Takeoka T, Tomo K, Tsuji M, et al. Successful treatment of post-allogeneic hematopoietic transplant immune thrombocytopenia with eltrombopag. Rinsho Ketsueki. 2018;59:2418–22.

    PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by Grant-in Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan and the Ministry of Health, Labor and Welfare in Japan. Some of co-authors now belong to other institutions as follows; Yasuhiro Shingai: Department of Hematology, Osaka International Cancer Institute, Tomohisa Machida: Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Yukiko Doi: Department of Hematology, Sumitomo Hospital, Tetsuo Maeda: Department of Hematology, Suita Municipal Hospital.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hirokazu Kashiwagi.

Ethics declarations

Conflict of interest

Yoshiaki Tomiyama: lecture fee (Novartis, Kyowa Kirin Co., Ltd.) and consultant fee (Sysmex), Hirokazu Kashiwagi: lecture fee (Novartis).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

12185_2021_3272_MOESM1_ESM.tif

Supplemental figure. Case of thrombocytopenia after allo-HSCT with negative GP-specific platelet autoAbs. A 47-year-old Japanese man with multiple myeloma underwent peripheral blood stem cell transplantation from an HLA-matched related donor. He showed thrombocytopenia (10–20 × 109/L) three months after transplantation. The RP% and plasma TPO levels were 4.8% (reference range; 0.7–6.4%) and 580 pg/mL (< 106 pg/mL), respectively. The cause of thrombocytopenia was unspecified. αIIbβ3- (A) and GPIb/IX- (B) specific direct IgG Abs detection like Fig. 1 is shown (TIF 1358 KB)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Akuta, K., Fukushima, K., Nakata, K. et al. Autoimmune-mediated thrombocytopenia after allogeneic hematopoietic stem cell transplantation: significance of detecting reticulated platelets and glycoprotein-specific platelet autoantibodies. Int J Hematol 115, 322–328 (2022). https://doi.org/10.1007/s12185-021-03272-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-021-03272-x

Keywords

Navigation