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  • Basic Science Article
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Can T-cell and B-cell excision circles predict development of inhibitors in pediatric hemophilia A?

Pediatric Research volume 93, pages 1546–1550 (2023)Cite this article

Abstract

Background

Hemophilia A (HA) therapy requires intravenous replacement infusions of factor (F) VIII concentrate. Inhibitors are high-affinity immunoglobulin G that are directed against FVIII and thereby render replacement therapy ineffective. This complication has significant prognostic implications. We aimed to examine the immune system involvement in inhibitor formation specifically T-cell excision circles (TRECs) and B-cell excision circles (KRECs), markers of new T and B cells, respectively, and examine them as surrogate markers for inhibitor formation.

Methods

Blood samples were collected from 35 children with severe HA. Children were divided into two groups: with FVIII inhibitors and without FVIII inhibitors. TRECs and KRECs were measured in peripheral blood.

Results

A total of 11 patients with inhibitors and 24 without were evaluated. Children with inhibitors had higher levels of TRECs however not statistically significant (p = 0.085). CjKREC levels were higher in the inhibitor patients (p = 0.003). Moreover, the sj/cjKREC ratio was lower in the inhibitor patients (p = 0.015).

Conclusions

Our findings may add to the notion that inhibitor formation is attributed to humoral immunity due to peripheral B-cell expansion and loss of peripheral tolerance. Improved knowledge regarding the involvement of the immune system in the formation of FVIII inhibitors will enable better therapy tailoring in the era of non-replacement therapies.

Impact

  • The etiology of FVIII inhibitor formation is multifactorial, in which the immune system plays a pivotal role.

  • Our findings may add to the notion that inhibitor formation is attributed to humoral immunity due to peripheral B-cell expansion and production of antibodies against FVIII.

  • Improved knowledge regarding the involvement of the immune system in the development of FVIII inhibitors will enable the identification of patients prone to inhibitor development and better therapy tailoring in the new era of non-replacement therapies.

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Fig. 1: TREC levels in hemophilia A patients with and without inhibitors.
Fig. 2: TREC levels in three hemophilia A patients with inhibitors before and after inhibitor formation.
Fig. 3: KREC levels in hemophilia A patients with and without inhibitors.
Fig. 4: KREC levels in three hemophilia A patients prior to and after inhibitor formation.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

This manuscript is dedicated to honor the memory of our dear collaborator and friend, Prof. Valder Arruda.

Funding

This study was supported by a research grant from Novo Nordisk.

Author information

Author notes

  1. These authors contributed equally: Raz Somech, Gili Kenet.

Authors and Affiliations

  1. National Hemophilia Center, Sheba Medical Center, Tel Hashomer, Israel

    Sarina Levy-Mendelovich, Einat Avishai, Rima Dardik, Asaaf Arie Barg & Gili Kenet

  2. Amalia Biron Research Institute of Thrombosis and Hemostasis, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Sarina Levy-Mendelovich, Einat Avishai, Rima Dardik, Asaaf Arie Barg & Gili Kenet

  3. The Sheba Talpiot Medical Leadership Program, Tel Hashomer, Israel

    Sarina Levy-Mendelovich

  4. Pediatric Department A and the Immunology Service, Jeffrey Modell Foundation canter, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center affiliated with Sackler school of medicine, Tel Aviv University, Tel Hashomer, Israel

    Atar Lev & Raz Somech

  5. Department of Pathophysiology, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia

    Ivan Budnik

Authors
  1. Sarina Levy-Mendelovich
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Contributions

S.L.-M., G.K., R.S., A.L., and I.B. made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data. E.A., R.D., and A.A.B. contributed to drafting the article or revising it critically for important intellectual content. All authors approved the final version of the manuscript to be published.

Corresponding author

Correspondence to Sarina Levy-Mendelovich.

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Competing interests

S.L.-M. received a grant and research support from Pfizer and Novo Nordisk. G.K. received a grant and research support from Alnylam, Bayer, BPL, Opko Biologics, Pfizer, Shire, and honoraria for consultancy/lectures from Alnylam, Bayer, CSL, Opko Biologics, Pfizer, Takeda, and ROCHE. Other authors have no relevant conflict of interest.

Ethics approval and consent to participate

Children’s parents gave informed consent for their child’s participation in the study. The study was approved by the Ethics Committee of Sheba Medical Center.

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Levy-Mendelovich, S., Lev, A., Avishai, E. et al. Can T-cell and B-cell excision circles predict development of inhibitors in pediatric hemophilia A?. Pediatr Res 93, 1546–1550 (2023). https://doi.org/10.1038/s41390-022-02268-5

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