Primary immune thrombocytopenia (ITP) in children is an autoimmune disorder characterized by isolated thrombocytopenia (platelet count <100×10⁹/L) and an increased propensity for bleeding (1). The pathophysiology of ITP involves antibody-mediated platelet destruction and impaired megakaryopoiesis, leading to a heterogeneous clinical spectrum ranging from asymptomatic thrombocytopenia to life-threatening intracranial hemorrhage (2). While the majority of pediatric ITP cases follow a self-limiting course, approximately 20%-30% of patients progress to persistent or chronic disease, necessitating prolonged therapeutic intervention (3). Conventional therapies, including corticosteroids, intravenous immunoglobulin (IVIg), and anti-D immunoglobulin, demonstrate rapid platelet count elevation; however, their efficacy is suboptimal, with response rates of 50%-70%, and long-term use is associated with significant adverse effects such as infections and osteoporosis (4). Splenectomy and immunosuppressive agents (e.g., rituximab) are limited by procedural risks and immunosuppression-related complications, respectively (5).

In recent years, thrombopoietin receptor agonists (TPO-RAs) have emerged as a cornerstone in the management of thrombocytopenia across various etiologies, offering effective reduction in bleeding risk, decreased reliance on platelet transfusions, and avoidance of transfusion-related adverse events (6). TPO-RAs encompass recombinant human thrombopoietin (rhTPO) and TPO-RAs, which exert their effects by binding to the thrombopoietin (TPO) receptor, thereby stimulating megakaryocyte proliferation, differentiation, and maturation to enhance platelet production (7, 8). The two most widely utilized TPO-RAs in clinical practice are romiplostim and eltrombopag (9, 10). Eltrombopag, the only oral TPO-RA approved by the U.S. Food and Drug Administration (FDA) for pediatric use (≥1 year), has demonstrated robust efficacy in multiple randomized controlled trials (11). Romiplostim, a subcutaneous peptibody, has also shown favorable response rates in children with chronic ITP (12). rhTPO, characterized by its rapid onset of action (1–2 weeks), is particularly advantageous in managing acute bleeding episodes in pediatric patients (13).

Despite their widespread use, direct comparative data on the efficacy and safety of rhTPO, romiplostim, and eltrombopag in pediatric ITP remain scarce. Existing evidence is predominantly derived from single-agent clinical trials or retrospective analyses with limited sample sizes and short follow-up durations, precluding a comprehensive assessment of long-term outcomes and risks. This gap in evidence underscores the critical need for well-designed comparative studies that can directly evaluate the relative benefits and adverse effect profiles of these agents in pediatric populations. Such analyses would not only guide optimal treatment selection but also inform individualized risk-benefit discussions, especially in cases where long-term therapy may be required. In the absence of head-to-head trials, meta-analyses and indirect comparisons offer a valuable interim approach to synthesizing existing data and identifying meaningful trends that warrant further investigation. Therefore, this study aims to conduct a systematic review and network meta-analysis to compare the efficacy and safety profiles of rhTPO, romiplostim, and eltrombopag in pediatric ITP, thereby providing evidence-based insights to inform clinical decision-making.

The therapeutic paradigm for pediatric primary ITP has evolved significantly with the introduction of TPO-RAs. This study represents the first systematic review and network meta-analysis to comprehensively evaluate the comparative efficacy and safety of three TPO-RAs—romiplostim, rhTPO, and eltrombopag—in pediatric ITP. The findings reveal that romiplostim demonstrates superior efficacy, as evidenced by its high overall response rate (OR = 17.57) and SUCRA value (0.96), while rhTPO exhibits the most favorable safety profile (SUCRA = 0.78). Eltrombopag, in contrast, offers a balanced profile between efficacy and safety, providing clinicians with critical insights for individualized therapeutic decision-making in pediatric ITP.

Romiplostim, a long-acting peptide-based TPO-RA, achieves its therapeutic effects through sustained stimulation of megakaryocyte proliferation via subcutaneous administration. Its efficacy advantage is likely attributable to its unique pharmacokinetic properties, including a prolonged half-life of approximately 50 hours, which significantly exceeds that of eltrombopag (21–35 hours) and rhTPO (3–4 hours) (21, 22). This extended half-life may enhance its ability to maintain stable platelet counts over time. Although the forest plot from the meta-analysis suggests an elevated odds ratio for adverse events associated with romiplostim (OR = 3.79), the confidence interval crosses the line of null effect, indicating that this finding is not statistically significant. Despite this, the observed trend, coupled with the biological rationale linking prolonged megakaryocyte stimulation to the development of bone marrow fibrosis, justifies the clinical concern. This aligns with findings from Li et al. (23), who reported fibrotic complications in the context of romiplostim use. Therefore, while the data do not yet definitively confirm an increased risk, they underscore the need for ongoing monitoring and further high-quality studies to better delineate the long-term safety profile of romiplostim, particularly in relation to marrow pathology.

In contrast, rhTPO, a recombinant form of endogenous thrombopoietin, is characterized by rapid onset of action and efficient metabolic clearance, potentially mitigating toxicity related to drug accumulation (24). Eltrombopag, the only oral TPO-RA, demonstrates comparable efficacy to rhTPO and a favorable safety profile, with no significant increase in the risk of hepatotoxicity (OR = 0.68) compared to placebo. Its oral bioavailability and flexible dosing regimen make it particularly suitable for long-term management, especially in younger children or those with needle aversion (25).

These findings are consistent with the American Society of Hematology (ASH) guidelines, which endorse TPO-RAs as the preferred second-line therapy due to their superior response rates (60–80%) compared to alternatives such as rituximab (20–30%) (26). However, the European LeukemiaNet guidelines emphasize the importance of cost-effectiveness, noting that eltrombopag is approximately 40% less expensive than romiplostim, a consideration that is particularly relevant in resource-limited settings. Additionally, Chinese expert consensus underscores the utility of rhTPO in acute settings due to its rapid onset of action (1–2 weeks), making it a preferred choice for managing acute bleeding episodes (27, 28).

The observed differences in efficacy among these agents can be attributed to their distinct mechanisms of action. Romiplostim, an Fc-peptide fusion TPO-RA, binds to the transmembrane domain of the TPO receptor, activating the JAK2/STAT5 signaling pathway to promote megakaryocyte proliferation (21). Its extended half-life is facilitated by Fc-mediated recycling, while subcutaneous administration ensures consistent plasma concentrations (29). Eltrombopag, a small-molecule non-peptide TPO-RA, competitively binds to the extracellular domain of the TPO receptor, activating downstream signaling pathways. However, its oral administration may result in variable plasma concentrations, potentially impacting efficacy stability (30). rhTPO, as a recombinant analog of endogenous thrombopoietin, directly mimics physiological TPO activity, but its short half-life necessitates frequent dosing, which may compromise adherence in chronic ITP management (31).

From a clinical perspective, romiplostim is particularly suited for children with chronic ITP who require rapid and sustained platelet count elevation, especially those refractory to corticosteroids or IVIg. However, its use necessitates vigilant monitoring for bone marrow fibrosis, with bone marrow biopsies recommended at 6- to 12-month intervals. Eltrombopag, owing to its oral administration, is an ideal option for long-term, home-based therapy, particularly in younger children or those with needle phobia (25, 32). rhTPO is preferred in acute settings, such as severe bleeding or perioperative scenarios requiring rapid platelet elevation, though its higher cost (approximately 1.5 times that of eltrombopag) may limit its accessibility in resource-constrained environments (33).

This study is not without limitations. First, the reliance on indirect comparisons, particularly the absence of head-to-head trials comparing romiplostim and eltrombopag, limits the strength of the evidence. Second, the relatively short follow-up duration (median 24 weeks) precludes the assessment of long-term safety outcomes, such as carcinogenicity. Third, the observed heterogeneity may stem from variations in dosing regimens (e.g., romiplostim 2–10 μg/kg) and patient populations, which could influence the results. Future research should prioritize: (1) Conducting multicenter, head-to-head randomized controlled trials comparing eltrombopag and romiplostim; (2) Investigating predictive biomarkers (e.g., TPO receptor gene polymorphisms) to enable precision medicine approaches; (3) Establishing real-world cohorts to evaluate the pharmacoeconomic impact of these therapies.

This study establishes that romiplostim offers the highest efficacy in the treatment of pediatric ITP, though its potential safety risks, particularly the association with bone marrow fibrosis, warrant careful consideration. rhTPO and eltrombopag play pivotal roles in acute-phase management and long-term therapy, respectively. Clinical decision-making should integrate factors such as bleeding risk, treatment adherence, and drug accessibility, while also incorporating individualized biomarkers and long-term safety data. Future research should focus on high-quality head-to-head trials and real-world studies to further refine and optimize therapeutic strategies for pediatric ITP.