Linking preclinical models to clinical realities: VEGF/VEGFR inhibitors and thrombotic microangiopathy in cancer therapy

This study examines the link between vascular endothelial growth factor inhibitors (VEGFi) and VEGF receptor inhibitors (VEGFRi) used in treating malignant tumors and the incidence of thrombotic microangiopathy (TMA). Understanding TMA's clinical features and mechanisms is essential for its management due to its severe impacts. This study analyzed data from the FDA's Adverse Event Reporting System (FAERS) and WHO's global pharmacovigilance database (Vigibase) to assess the risk of TMA associated with VEGF and VEGFR inhibitors. We also examined TMA and thrombotic thrombocytopenic purpura (TTP) risks using patient biochemical data from a local hospital and explored underlying biological mechanisms through animal models and pan-cancer analysis. Our study confirms that VEGFi and VEGFRi elevate the risk of TMA. Notably, Bevacizumab, Sunitinib, Ramucirumab, and Aflibercept significantly increase TMA risks, with Bevacizumab showing the highest risk (reporting odds ratio 4.96 [4.08-6.03] in Vigibase and 2.33 [1.84-2.94] in FAERS). Biochemical analysis from 1698 patients indicated impaired kidney function and hemolytic events, confirming that VEGFi and VEGFRi significantly increase the risk of TMA/TTP in clinical use (<i>p</i> < 0.001). Animal studies highlighted that Semaxanib causes more severe endothelial damage and thrombus formation than Bevacizumab, further validating that VEGFi typically induces TMA later than VEGFRi. Transcriptomic analysis and pan-cancer pathway insights identified critical pathways involving reduced VEGF signaling, abnormal complement activation, and excessive platelet aggregation leading to thrombosis. The results underscore the enhanced risk of TMA posed by these inhibitors, particularly noting the timelines and mechanisms through which different inhibitors trigger TMA, and recommend regular monitoring of biochemical markers for early risk assessment and management.