Review

. 2025 Nov 18;3(1):100129.

doi: 10.1016/j.bvth.2025.100129. eCollection 2026 Feb.

Inflammatory cytokines, inflammasomes, and neutrophil extracellular traps in primary immune thrombocytopenia pathogenesis

Alessandro Lucchesi¹, Maria Belen Rodriguez², Matias Cordoba², Johnny Zhou³, Otto Lam³, Divya Pushkarna³, Lora Benoit³, Drew Provan⁴

Affiliations

¹ Oncology and Hematology, IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori," Meldola, Italy.
² Rare Blood Disorders, Sanofi, Cambridge, MA.
³ Evidinno Outcomes Research Inc, Vancouver, BC, Canada.
⁴ Hematology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.

PMID: 41630798
PMCID: PMC12861000
DOI: 10.1016/j.bvth.2025.100129

Review

Inflammatory cytokines, inflammasomes, and neutrophil extracellular traps in primary immune thrombocytopenia pathogenesis

Alessandro Lucchesi et al. Blood Vessel Thromb Hemost. 2025.

. 2025 Nov 18;3(1):100129.

doi: 10.1016/j.bvth.2025.100129. eCollection 2026 Feb.

Authors

Alessandro Lucchesi¹, Maria Belen Rodriguez², Matias Cordoba², Johnny Zhou³, Otto Lam³, Divya Pushkarna³, Lora Benoit³, Drew Provan⁴

Affiliations

¹ Oncology and Hematology, IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori," Meldola, Italy.
² Rare Blood Disorders, Sanofi, Cambridge, MA.
³ Evidinno Outcomes Research Inc, Vancouver, BC, Canada.
⁴ Hematology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.

PMID: 41630798
PMCID: PMC12861000
DOI: 10.1016/j.bvth.2025.100129

Abstract

Primary immune thrombocytopenia (ITP) is a disorder characterized by enhanced platelet clearance and impaired production due to immune dysregulation. Central to its pathogenesis are platelet autoantibodies, T-cell-mediated processes, and altered cytokine profiles, which exacerbate clearance and hinder production. These mechanisms mirror other immune-mediated diseases and contribute to symptoms such as fatigue and thromboembolism. Despite extensive research, the inflammatory role in ITP remains unclear, with variability across studies underscoring the need for further investigation to optimize therapies. This study aims to summarize the evidence on inflammatory cytokines, inflammasomes, and neutrophil extracellular traps (NET) in adult primary ITP. A systematic literature review was conducted using Embase and MEDLINE (search date 9 January 2024), covering publications from the past decade. Observational studies and clinical trials reporting inflammatory markers were included (79 studies). Most studies were case-control (69.7%) and conducted in China (77.2%). Activation of multiple immune and inflammatory pathways was observed. T helper 17 (Th17; n = 21) and T follicular helper cells (n = 4) demonstrated involvement, with Th17-derived interleukin-17 (IL-17) contributing prominently to the inflammatory milieu. NLRP3 inflammasome hyperactivity/increased expression (n = 6 studies) emerged as a significant pathway, and strongly associated markers (IL-18 [n = 4]) were elevated. Additionally, NET and neutrophil activation promoted inflammation and thrombosis (n = 2). In conclusion, immune dysregulation from Th17 cell pathways and NLRP3 inflammasome strongly contribute to inflammation in adults with primary ITP, with IL-18 and IL-17 linked to disease activity/progression. The findings suggest a need for novel therapies to target immune dysregulation and clarify their roles in ITP.

© 2026 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

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Conflict of interest statement

Conflict-of-interest disclosure: A.L. reports honoraria from Amgen, Novartis, Grifols, Sobi, Sanofi, Incyte, Pfizer, and Bristol Myers Squibb; and consultancy for Sobi, Sanofi, Novartis, Amgen, Grifols, Protagonist, MorphoSys, AOP, and GSK. D. Provan reports research support from Amgen and Novartis; honoraria from Amgen, Novartis, Sobi, UCB, and Argenx; and consultancy for UCB, MedImmune, Ono Pharmaceuticals, Sobi, Argenx, Takeda, Dexcel Pharma, Climb Bio, Chugai, and Candid Therapeutics. M.B.R. and M.C. report employment with Sanofi. O.L., J.Z., and D. Pushkarna report employment and L.B. reports a contractual relationship with Evidinno Outcomes Research Inc, which was commissioned by Sanofi to conduct this study.

Figures

**Figure 1.**
**PRISMA flow diagram.** MA, meta-analysis; SLR, systematic literature review.

**Figure 2.**
**Overview of key inflammatory pathways.** Studies reported on IFN-γ (35 studies),^,^,^,, , ^,^,^,^,^,^,^,^,^,^,^,^,^,^,^,, , , , ^,^,^,^,^,^,^,^,, , Th17 cells (21),^,^,^,, , , ^,, , , , ^,^,^,^,^,^,^,^,^,^,^,^,^,^,^,^,^,^,^,^,^, TNF-α (16),^,^,^,^,^,^,^,^,^,^,^,^,^,, , Th1 cells (14),, , ^,^,^,, , ^,^,^,^,^,^,^, complement components (7),^,^,^,^, NLRP3 inflammasome (6),, , , ^,^, nuclear factor κβ (NF-κB; 3),^,^, NETosis (2),^, Th22 cells (2),^, T follicular helper (Tfh; 4) cells,^,^,^, and Th9 cells (1). Interleukins included IL-1 (7 studies),^,^,^,^,^, IL-2 (13),^,^,^,^,^,^,^,^,^,^,^, IL-6 (n11),^,^,^,^,^,^,^,^,^,^,^, IL-9 (2),^, IL-17 (21),^,^,^,, , , ^,, , , , ^,^,^,^,^,^,^,^,^,^,^,^,^,^,^,^,^,^,^,^,^, IL-18 (4),^,^,^, IL-21 (6),^,^,^,^,^, IL-22 (3),^,^, IL-23 (8),^,^,^,^,^,^,^, and IL-27 (3).^,^,

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References

1. Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019;3(23):3829–3866. - PMC - PubMed
1. Lev P, Goette N, Marta R. Pathophysiological mechanisms leading to low platelet count in immune thrombocytopenia. J Immunol Sci. 2020;4(2):1–7.
1. Li Q, Marcoux G, Hu Y, et al. Autoimmune effector mechanisms associated with a defective immunosuppressive axis in immune thrombocytopenia (ITP) Autoimmun Rev. 2024;23(12) - PubMed
1. Audia S, Mahévas M, Nivet M, Ouandji S, Ciudad M, Bonnotte B. Immune thrombocytopenia: recent advances in pathogenesis and treatments. Hemasphere. 2021;5(6):e574. - PMC - PubMed
1. Zufferey A, Kapur R, Semple JW. Pathogenesis and therapeutic mechanisms in immune thrombocytopenia (ITP) J Clin Med. 2017;6(2):16.

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Inflammatory cytokines, inflammasomes, and neutrophil extracellular traps in primary immune thrombocytopenia pathogenesis

Affiliations

Inflammatory cytokines, inflammasomes, and neutrophil extracellular traps in primary immune thrombocytopenia pathogenesis

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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