Association of thrombopoietin-related drugs with thromboembolic events: Mendelian randomization and a real-world study

Abstract

Background: Studies have shown conflicting results when using thrombopoietin-related drugs (TPORD) for thromboembolic events (TEEs). Our study aimed to explore the correlation between TPORDs and TEEs. Method: Drug-targeted Mendelian randomization (MR) and multivariate MR (MVMR) analysis were used to explore the causal relationship between TPORDs and TEEs such as venous thromboembolism (VTE), deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI) and ischemic stroke (STR). At the same time, a real-world study was conducted by extracting adverse events (AEs) from the FDA Adverse Event Reporting System database included in AERSMine to further validate our findings. Outcome: In drug-target MR, TPORDs were associated with VTE (OR = 1.193, 95% confidence interval (CI): 1.001–1.423, p = 0.049], DVT (OR = 1.321, 95% CI: 1.027–1.700, p = 0.030), MI (OR = 1.216, 95% CI: 1.010–1.464, p = 0.039), STR (OR = 1.224, 95% CI: 1.021–1.468, p = 0.029). VTE/DVT/STR remained stable in MVMR (VTE: OR = 1.3, 95% CI: 1.187–1.422, p < 0.001; DVT: OR = 1.465,95% CI:1.285–1.671, p < 0.001; STR: OR = 1.119, 95% CI: 1.018–1.229, p = 0.019) and real-world studies [lower bound of proportional reporting ratio (ROR) greater than 1]. The significance of myocardial infarction disappeared in MVMR (OR = 0.996, 95% CI: 0.894–1.109, p = 0.942) and in real-world studies (lower ROR lower than 1). There was no evidence of a causal relationship between TPORD and PE (OR = 1.244, 95% CI: 0.969-1.597, p = 0.087), but it generated a signal from a real-world study (lower bound of ROR greater than 1). Conclusion: This study suggests that TPORDs may be associated with an increased risk of TEEs, particularly AEs leading to VTE/DVT/STR. In addition, the relationship between TPORDs and PE/MI is debatable and requires more research.