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

## TL;DR

This study shows that cancer drugs targeting VEGF and VEGFR can cause a dangerous blood disorder called TMA, with different drugs causing it in different ways and timelines.

## Contribution

First comprehensive risk assessment and mechanistic validation of TMA caused by VEGF/VEGFR inhibitors in cancer therapy.

## Key findings

- VEGFR inhibitors cause rapid endothelial damage through complement activation, while VEGF inhibitors trigger delayed TMA via suppressed VEGF signaling.
- Bevacizumab, Sunitinib, Ramucirumab, and Aflibercept significantly increase TMA risks, with Bevacizumab showing the highest risk.
- Pan-cancer analysis identified platelet aggregation and complement activation as key drivers of TMA.

## Abstract

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 (p < 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.

This study investigates the risk of thrombotic microangiopathy (TMA) induced by vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) inhibitors in cancer therapy. Using data from the FDA Adverse Event Reporting System (FAERS), the WHO Global Database for Adverse Drug Reactions (Vigibase), and The Cancer Genome Atlas (TCGA), along with clinical analysis of 1,698 patients and animal experiments, it reveals that VEGFR inhibitors cause rapid endothelial damage through complement activation, while VEGF inhibitors trigger delayed TMA via suppressed VEGF signaling. The analysis of TCGA pan‐cancer transcriptomic data identified critical pathways involved, such as platelet activation and complement cascade, contributing to TMA development. Animal model studies further confirmed these findings, with hematoxylin and eosin (HE) staining of kidney tissues showing significant endothelial damage, thrombus formation, and mesangial cell proliferation, reinforcing the biological mechanisms. This comprehensive approach underscores the need for regular monitoring of renal function and platelet counts in patients receiving VEGF/VEGFR inhibitors to mitigate TMA risks.

First comprehensive risk assessment linking vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) inhibitors (e.g., Bevacizumab, Sunitinib) to thrombotic microangiopathy (TMA) in cancer therapy using the FDA Adverse Event Reporting System (FAERS) and the WHO Global Database for Adverse Drug Reactions (Vigibase) databases.Mechanistic validation via animal models: VEGFR inhibitors induce acute endothelial damage via complement activation, while VEGF inhibitors trigger delayed TMA through VEGF signaling suppression.Clinical relevance was confirmed by biochemical data from 1698 patients, showing posttreatment platelet decline (p < 0.001) and hemolysis markers elevation.Pan‐cancer pathway analysis identifies platelet aggregation and complement activation as key drivers of TMA, informing targeted monitoring and therapeutic strategies.Practical recommendations: Regular monitoring of renal function and platelet counts for early TMA detection in patients receiving antiangiogenic therapies.

First comprehensive risk assessment linking vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) inhibitors (e.g., Bevacizumab, Sunitinib) to thrombotic microangiopathy (TMA) in cancer therapy using the FDA Adverse Event Reporting System (FAERS) and the WHO Global Database for Adverse Drug Reactions (Vigibase) databases.

Mechanistic validation via animal models: VEGFR inhibitors induce acute endothelial damage via complement activation, while VEGF inhibitors trigger delayed TMA through VEGF signaling suppression.

Clinical relevance was confirmed by biochemical data from 1698 patients, showing posttreatment platelet decline (p < 0.001) and hemolysis markers elevation.

Pan‐cancer pathway analysis identifies platelet aggregation and complement activation as key drivers of TMA, informing targeted monitoring and therapeutic strategies.

Practical recommendations: Regular monitoring of renal function and platelet counts for early TMA detection in patients receiving antiangiogenic therapies.