Preliminary experience with oral thrombopoietin-receptor agonists, primarily hetrombopag, in pediatric immune thrombocytopenia: a pilot single-center retrospective report

Introduction

Immune thrombocytopenia (ITP) in children is an immune-mediated bleeding disorder characterized by both accelerated platelet destruction and suppressed platelet production, with an estimated incidence of 1.6–5.3 per 100,000 person-years (1,2). ITP is categorized as primary or secondary based on other medical conditions present at diagnosis. It can be further subcategorized as newly diagnosed (0–3 months), persistent (>3–12 months), or chronic (>12 months) according to disease duration (3).

Most children with ITP do not require therapy and may experience spontaneous resolution. For those who need treatment, first-line therapies such as corticosteroids and intravenous immunoglobulin (IVIG) remain standard options. For children with persistent/chronic ITP who fail first-line therapy, contemporary guidance [the American Society of Hematology (ASH) 2019 and the 2019 International Consensus Report] supports individualized second-line choices—primarily thrombopoietin receptor agonists (TPO-RAs) and rituximab—with a preference for avoiding splenectomy in the pediatric population whenever possible (4,5).

In practice, the choice depends on bleeding phenotype, duration of ITP, family preferences, access to medications, and local experience. Although TPO-RAs are generally considered non-immunosuppressive and convenient, barriers such as drug availability, monitoring requirements, and cost may influence uptake in real-world settings.

TPO-RAs are non-immunosuppressive agents that stimulate thrombopoiesis by activating the thrombopoietin receptor and downstream signaling pathways, thereby promoting megakaryocyte proliferation and platelet production (6). Romiplostim and eltrombopag have pediatric evidence from randomized trials and real-world cohorts, and avatrombopag data in children have also recently emerged (7-9). In China, hetrombopag (an oral small-molecule TPO-RA) was approved for adult ITP in 2021 (10) and has entered routine practice; however, pediatric evidence is still limited and prospective data are emerging, including an ongoing pediatric randomized trial (NCT04737850) (11). Therefore, our aim was to provide preliminary real-world data to address critical gaps in the pediatric use of hetrombopag—specifically regarding its safety profile, dosage titration patterns, and clinical effectiveness in a non-trial setting—supplementing the current scarcity of evidence for this newer agent compared to established TPO-RAs like eltrombopag.

In this brief research report, we retrospectively reviewed children with ITP treated with oral TPO-RAs at our center to describe platelet trajectories, bleeding outcomes, and safety in routine practice. Given the single-center design, small sample size, heterogeneity of disease duration (ranging from newly diagnosed to chronic), and the predominance of hetrombopag exposure, the analysis is intended to be descriptive; furthermore, the retrospective reliance on medical records for bleeding and safety outcomes introduces potential reporting and observation bias. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0151/rc).

Methods

Patients

The overall workflow of this study is illustrated in Figure S1. Eighteen children with ITP treated in the Department of Hematology at Qingdao Women and Children’s Hospital between January 2023 and June 2024 were included in this study. These children had not achieved remission after first-line treatments such as glucocorticoids and immunoglobulin and were subsequently treated with oral TPO-RAs (eltrombopag, hetrombopag, or avatrombopag; including one child who received avatrombopag). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was approved by the Ethics Committee of Qingdao Women and Children’s Hospital (2025.01.16; No. QFELL-YJ-2025-31). Informed consent was not required due to the retrospective nature of this record-based study.

Inclusion criteria: (I) age: 1–18 years; (II) peripheral blood platelet count ≤30×10⁹/L, or >30×10⁹/L with abnormal bleeding; (III) ineffective response or failed to retain long-term response after first-line therapies (standard glucocorticoid and IVIGs therapy).

Exclusion criteria: (I) congenital thrombocytopenia or other known causes of secondary thrombocytopenia; (II) malignancy; (III) severe liver or kidney dysfunction; (IV) severe immune deficiency or systemic autoimmune disease requiring ongoing immunosuppression; (V) severe acute viral infection at the time of TPO-RA initiation; and (VI) incomplete clinical records that precluded assessment of key outcomes. Concomitant medications (including agents affecting platelet function or coagulation) were recorded; their use was not an automatic exclusion criterion if clinically indicated, but was considered during safety interpretation.

Treatment plan

Therapeutic management was standardized according to the “Chinese Expert Consensus on the Clinical Application Management of Thrombopoietic Drugs (2023 edition)”, with individualized adjustments based on clinician judgment. Hetrombopag was initiated at 5 mg/day (titrated up to 40 mg/day) once daily after meals. Similarly, eltrombopag was initiated at 25 mg/day (titrated between 12.5–75 mg/day) and avatrombopag at 20 mg/day, following established pediatric dosing guidelines to ensure consistency. Concomitant and rescue therapies—including corticosteroids, IVIG, and single-donor platelet transfusions—were administered when clinically indicated, and antifibrinolytic agents were utilized for significant mucosal or organ-bleeding risks. Adverse reactions were managed with symptomatic treatments tailored to the child’s condition.

Follow-up and observation indicators

The blood routine and adverse drug reactions were systematically recorded, with the final follow-up conducted on June 30, 2024. During the initial phase, weekly blood routine reviews were performed, transitioning to every 2–4 weeks once dosage stabilized. Adhering to the consensus protocol, treatment was discontinued if no response (NR) occurred at maximum dosage within 2–4 weeks or if platelet counts exceeded 400×10⁹/L; therapy was resumed if counts subsequently dropped below 150×10⁹/L.

The time to response for each individual was recorded, defined as the time to achieve overall response (OR) or complete response (CR) after initiating oral TPO-RA therapy. Bleeding severity was assessed using the Buchanan & Adix pediatric ITP bleeding scale (overall grade 0–4) based on history and physical examination at baseline and follow-up visits (12). Grades were defined as: grade 0, no bleeding; grade 1, mild skin findings without mucosal bleeding; grade 2, more extensive skin findings without mucosal bleeding; grade 3, clinically significant mucosal bleeding affecting daily life; and grade 4, severe bleeding with a clinically relevant hemoglobin drop and/or suspected internal bleeding. Bleeding grades were extracted from the clinical records; no centralized adjudication was performed.

Safety outcomes were assessed by reviewing clinical notes and laboratory/auxiliary examinations during follow-up. Adverse events (AEs) were recorded as any new or worsening clinical symptom, laboratory abnormality, or test abnormality documented by the treating physician after TPO-RA initiation. Because this was a retrospective study, adverse-event grading and causality assessment were not centralized; events are therefore reported descriptively based on available documentation.

The clinical efficacy of TPO-RA treatment was evaluated through platelet counts recorded at baseline (initial visit) and after 1–3 weeks and 1–4 months of therapy, alongside bleeding grade improvements.

Statistical analysis

SPSS 26.0 software was used for data analysis. Continuous variables were summarized as median (P25, P75) or mean ± standard deviation (SD) as appropriate. Because platelet counts were skewed and the sample size was small, with incomplete follow-up at some time points, paired comparisons between baseline and prespecified time points (week 1, month 1, month 3, and month 6) were performed using the Wilcoxon signed-rank test on complete cases. Holm-adjusted P values were reported to address multiplicity, and a paired t-test was used as a sensitivity analysis where distributions did not deviate substantially from normality. Changes in bleeding grades (Buchanan & Adix 0–4) were evaluated using the Wilcoxon signed-rank test at the individual level and the Chi-squared test for group-level distributions. Missing data were handled using complete-case analyses without imputation. Normality of continuous variables was assessed (Shapiro-Wilk test and visual inspection).

Exploratory analyses of potential factors associated with treatment response were performed using Chi-squared or Fisher’s exact tests as appropriate (age, sex, disease duration, infection status, baseline bleeding grade, and antibody status). Given the small sample size, these analyses were considered hypothesis-generating and not powered to exclude clinically meaningful effects.

Results

General information

A total of 18 children with ITP were treated and followed up in the Department of Hematology, Qingdao Women and Children’s Hospital between January 2023 and June 2024. The cohort included 11 males (61.1%) and 7 females (38.9%), aged 1–14 years. According to international criteria, 3 patients (16.7%) had newly diagnosed ITP, 4 (22.2%) had persistent ITP, and 11 (61.1%) had chronic ITP. All patients had previously received corticosteroids, and 7 (38.9%) had received IVIG. Fifteen patients received hetrombopag, 2 received eltrombopag, and 1 received avatrombopag. Baseline characteristics are summarized in Table 1. One patient discontinued hetrombopag and switched to oral corticosteroids during follow-up.

Platelet counts increased significantly after treatment

Platelet counts increased following treatment, reflecting primarily the response to hetrombopag given its dominance in the cohort (15/18 patients), although the potential confounding impact of rescue therapies (corticosteroids and IVIG) cannot be fully partitioned. Compared with baseline, platelet counts were significantly higher at week 1 (n=16), month 1 (n=18), month 3 (n=18), and month 6 (n=18), with Wilcoxon signed-rank test yielding Holm-adjusted P values of 0.004, 0.004, 0.004, and 0.005, respectively. Due to variable visit completion (e.g., 16 cases at week 1, 15 at weeks 2–3), analyses at each time point were performed on complete cases without imputation. Two patients who had achieved platelet counts >400 ×10⁹/L temporarily paused treatment but resumed after counts dropped to <150 ×10⁹/L.

Descriptively, median platelet counts increased from 10.5 (4.75–14.75) ×10⁹/L at baseline (n=18) to 36.5 (18.0–108.0) ×10⁹/L at week 1 (n=16), 76.0 (46.0–117.0) ×10⁹/L at month 1 (n=18), 85.0 (44.5–176.0) ×10⁹/L at month 3 (n=18), and 101.0 (74.5–165.25) ×10⁹/L at month 6 (n=18). Platelet trajectories over time are shown in Figure 1.

Figure 1 Platelet trajectories over time. Data are presented as median with IQR. Numbers above each time point indicate the number of available observations (n). IQR, interquartile range.

Individual-level treatment characteristics and outcomes are presented in Table S1, and a descriptive agent-stratified summary of responses and AEs is provided in Table S2.

Bleeding grade showed no statistically significant improvement

Bleeding severity was assessed using the Buchanan and Adix pediatric ITP bleeding score (grades 0–4). Overall, no statistically significant improvement in bleeding grade was observed after treatment (Wilcoxon signed-rank test: Z=−1.915, P=0.056). Baseline bleeding scores were mild in most patients (grade 1 in 8/18; grade 2 in 6/18), and only 2 patients presented with grade 3 bleeding. These findings, alongside a small cohort size and retrospective data collection, limit interpretation. Use of rescue therapies (corticosteroids, IVIG, platelet transfusions) was rare and not included in comparative analysis. Outcomes by agent are presented in Table 2.

Exploratory analysis of influencing factors

Potential influencing factors—including sex, age, ITP duration, infection status, antibody presence, and baseline bleeding tendency—were analyzed for association with response outcomes (CR, OR, NR). No statistically significant associations were detected (all P>0.05), as shown in Table S2. However, given the very small sample size (N=18), these exploratory analyses lack sufficient statistical power to detect meaningful associations, and the results should be viewed strictly as descriptive observations rather than inferential evidence.

Safety

TPO-RA treatment was generally well-tolerated, with abnormal electrocardiogram (ECG) being the most frequent AE (n=5, 27.8%). These findings—primarily sinus arrhythmia and mild QTc prolongation—were clinically asymptomatic, likely reflecting intensive monitoring or reporting bias for minor findings rather than drug-induced cardiotoxicity. Other recorded AEs included elevated liver enzymes (n=3), dyslipidemia (n=2), gastrointestinal symptoms (n=1), abnormal coagulation parameters (n=1), mild facial rash (n=1), and pre-existing severe eczema (n=1). All AEs were grade 1–2 in severity, with no patients discontinued treatment due to AEs. Safety data are summarized in Table 3.

Discussion

This pilot report summarizes a single-center experience dominated by hetrombopag exposure. While the lack of a comparator group and the small, retrospective cohort preclude definitive causal inferences, these findings demonstrate the real-world feasibility of using newer TPO-RAs in children.

Collective evidence from randomized trials and real-world cohorts has established TPO-RAs, particularly romiplostim and eltrombopag, as effective second-line options in pediatric ITP. Reviews have highlighted romiplostim as an important therapeutic option in children, with demonstrated efficacy, acceptable safety, and favorable treatment acceptability, while also emphasizing individualized decision-making and careful monitoring (13-15). In addition, romiplostim has shown encouraging outcomes and safety even in newly diagnosed or persistent pediatric ITP, although larger studies with longer follow-up are still needed (16). Our observation of a rapid median platelet increase—from 10.5×10⁹/L at baseline to 36.5×10⁹/L within the first week—mirrors the response kinetics reported for established TPO-RAs (7-9). This suggests that hetrombopag may provide comparable early efficacy in pediatric patients despite its status as a newer agent with still-maturing high-level evidence.

The incremental contribution of this pilot series is primarily to document the initial feasibility of hetrombopag in a pediatric setting, as high-level evidence for this specific agent is still maturing compared to romiplostim and eltrombopag. Importantly, prospective evidence for hetrombopag in children is still developing, with an ongoing pediatric trial registered on ClinicalTrials.gov (NCT04737850).

In response to the heterogeneity of exposure and the very small subgroups for non-hetrombopag agents, we avoided class-wide causal language and did not attempt comparative inference across agents. Future multicenter studies with adequate representation of different TPO-RAs should report agent-specific dosing, time-to-response, discontinuation/switching patterns, and standardized safety adjudication.

Recent pediatric studies and reviews have reported real-world use of TPO-RAs, including hetrombopag and avatrombopag, in pediatric ITP (17-21). These reports highlight generally favorable platelet responses but also emphasize the importance of careful monitoring for known or anticipated AEs (e.g., hepatotoxicity, thrombosis, and rebound thrombocytopenia) and the need for standardized outcome definitions.

Given the retrospective nature of our data, bleeding outcomes were assessed using an ordinal pediatric bleeding scale and were not collected at uniform time points for all patients. As a result, the absence of a statistically significant improvement in bleeding grade in our cohort should not be interpreted as evidence that TPO-RAs do not improve bleeding risk; rather, it likely reflects limited power and variable assessment timing; consequently, a clear clinical benefit in terms of bleeding reduction could not be demonstrated in this cohort despite the observed rise in “numbers” (platelet counts).

Bleeding grades were evaluated using the Buchanan & Adix pediatric ITP bleeding scale (overall grade 0–4) (12). At both group and individual levels, we did not detect statistically significant changes in bleeding grade after treatment initiation. In future studies, bleeding assessments should be prospectively standardized (e.g., baseline vs best on-treatment bleeding grade, and documentation of rescue therapy use) to allow more reliable interpretation alongside platelet responses.

Regarding safety, most AEs were mild and laboratory-based. An abnormal ECG was the most frequently documented AE, but detailed ECG findings and formal adjudication were not consistently available in the medical records; therefore, we report these findings descriptively; without a control group or larger sample, it is impossible to determine if these ECG abnormalities or liver enzyme elevations are directly attributable to the medication or represent incidental findings common in this pediatric population.

The exploratory analyses of potential factors associated with response (age, sex, disease duration, infection status, baseline bleeding grade, and antibody status) did not identify statistically significant associations. However, this study is underpowered for such analyses, and the results should be described as ‘no statistically significant associations detected in this small sample’ rather than evidence of no effect.

Finally, ITP and immune-mediated thrombocytopenia can also occur in special pediatric contexts such as post-hematopoietic stem cell transplantation (HSCT). Immune-mediated cytopenias after pediatric HSCT have distinct risk factors and management challenges, and second-/third-line strategies remain heterogeneous (22). Because our cohort reflects primarily primary ITP in a non-transplant setting, our findings may not be generalizable to children with HSCT-related immune-mediated thrombocytopenia.

In summary, within the limitations of a small, retrospective, single-center cohort, oral TPO-RA exposure—predominantly hetrombopag—was associated with improved platelet counts and no unexpected safety signals. These preliminary data are intended to supplement existing literature on newer TPO-RAs like hetrombopag and generate specific hypotheses for larger, adequately powered prospective trials; furthermore, expanding this evidence base in future multicenter studies could support broader international regulatory consideration of hetrombopag and clarify its role as a potentially cost-effective alternative to established agents like eltrombopag.

Conclusions

In conclusion, while limited by its small pilot-scale sample size, oral TPO-RA use (predominantly hetrombopag) in this cohort was associated with increased platelet counts and no new safety concerns, serving as a foundational observation for future large-scale investigations into this specific agent. Critically, the observed increase in platelet counts did not translate into a statistically significant reduction in bleeding risk, and the study’s retrospective nature and small, heterogeneous cohort limit the generalizability of these safety and efficacy observations. As one of the initial real-world reports focusing on pediatric hetrombopag, this study adds a valuable preliminary data point to the international bibliography, highlighting its potential as a viable, oral alternative to established TPO-RAs. Larger, prospective studies are now needed to confirm these findings, facilitate international regulatory evaluations, and better characterize the long-term safety and economic viability of hetrombopag compared to existing therapies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0151/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0151/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0151/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0151/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was approved by the Ethics Committee of Qingdao Women and Children’s Hospital (2025.01.16; No. QFELL-YJ-2025-31). Informed consent was not required due to the retrospective nature of this record-based study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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