Relationship between thromboembolic events and thrombopoietin receptor agonists: a pharmacovigilance analysis of the FDA Adverse Event Reporting System and the Japanese Adverse Drug Event Report

Abstract

Objective: Thrombopoietin receptor agonists (TPO-RAs) are widely used in thrombocytopenia, yet their association with thromboembolic events (TEEs) remains concerning. This study aimed to assess the real-world TEE risk associated with TPO-RAs.

Design: Retrospective pharmacovigilance analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) databases.

Setting: Both FAERS and JADER were searched from January 2004 to March 2025.

Main outcome measures: Disproportionality analyses were performed using reporting OR (ROR), proportional reporting ratio (PRR), informational component (IC) and empirical Bayesian geometric mean (EBGM) to identify potential safety signals.

Results: 4005 TEE from FAERS and 569 from JADER were analysed. Venous TEE showed higher prevalence and signal intensity (FAERS: n=1489, ROR 4.19, PRR 4.14, EBGM05 3.94, IC025 0.37; JADER: n=269, ROR 15.95, PRR 14.27, EBGM05 12.56, IC025 2.14). Lusutrombopag had the strongest TEE signal (FAERS: n=7, ROR 8.80, PRR 7.77, EBGM05 4.00, IC025 1.25; JADER: n=41, ROR 38.02, PRR 16.94, EBGM05 11.45, IC025 2.38). FAERS identified 49 positive signals, while JADER identified 30, with 20 signals overlapping. Subgroup analysis indicated males had higher arterial TEE risk with TPO-RAs, while females had higher venous TEE risk in both FAERS and JADER. In FAERS, elderly (≥60 years) showed elevated arterial TEE risk with TPO-RAs and romiplostim, while non-elderly had higher venous TEE risk with avatrombopag and eltrombopag.

Conclusions: The study provided real-world evidence of TEE associated with TPO-RAs, highlighting a strong link despite variations in signal values and regional reporting practices. Findings underscore ongoing clinical safety surveillance for TPO-RAs.

Keywords: Adverse events; CLINICAL PHARMACOLOGY; Thromboembolism.

Figure 1. Selection process of TEE reports associated with TPO-RAs in FAERS and JADER Databases. Note: N represents the number of patients, and AE represents the number of AE reports. AE, adverse event; FAERS, The Food and Drug Administration Adverse Event Reporting System; JADER, The Japanese Adverse Drug Event Report; PS, primary suspect; TEE, thromboembolic events; TPO-RAs, thrombopoietin receptor agonists.

Figure 2. The distribution of the top 20 reported PTs in FAERS and JADER databases. FAERS, The Food and Drug Administration Adverse Event Reporting System; JADER, The Japanese Adverse Drug Event Report; PT, preferred term; SOC, system organ class.

Figure 3. Signal detection at the PT level. The top 20 positive signals (ranked by case number) associated with TPO-RAs at the PT level in FAERS (A) and JADER (B) databases. Venn diagram showing the overlap of 49 positive signals in FAERS and 30 positive signals in JADER (C). EBGM05, the lower 90 two-sided CI of empirical Bayesian geometric mean; FAERS, The Food and Drug Administration Adverse Event Reporting System; IC025, the lower limit of the 95 two-sided CI of the information component; JADER, The Japanese Adverse Drug Event Report; PRR, proportional reporting ratio; PT, preferred term; ROR, reporting OR; TPO-RAs, thrombopoietin receptor agonists.

Figure 4. Gender and age subgroup analyses in TPO-RAs related to TEE from FAERS and JADER databases. Orange indicates ROR values greater than 1, and females/elderly (≥ 60 years) are more likely to have adverse reactions. Green indicates ROR values less than 1, and males/non-elderly (<60 years) are more likely to have adverse reactions. Grey indicates ROR values that could not be calculated. FAERS, The Food and Drug Administration Adverse Event Reporting System; JADER, The Japanese Adverse Drug Event Report; NA, not applicable; ROR, reporting OR; TEE, thromboembolic events; TPO-RAs, thrombopoietin receptor agonists.