Bevacizumab immune complexes activate platelets and induce thrombosis in FCGR2A transgenic mice Article

International Collaboration

cited authors

  • Meyer, T., Robles-Carrillo, L., Robson, T., Langer, F., Desai, H., Davila, M., Amaya, M., Francis, J. L., Amirkhosravi, A.

funding text

  • We thank J. Ma, Florida Hospital, for assistance with histopathological analysis of mouse lung sections. We thank K. Kunihiro and the staff of the Orange County Utilities Water Quality Laboratory (Orlando, FL, USA) for their assistance with fluorescence microscopy. We thank our research assistants P. Elias, J. Meyer, N. Vargas, and V. Venincasa for reagent preparation and laboratory assistance with various experiments. We also thank the oncology physicians and nurses of the Florida Hospital Cancer Instititute, the Florida Hospital Histopathology Laboratory, and the staff of the Florida Hospital Medical Library for their invaluable assistance. This study was supported by grants from the American Heart Association (0655092B) and the Florida Hospital-UCF Gala Endowed Program for Oncologic Research. Generous donations in support of this work were also provided by the Demetree Family, The Fraternal Order of Eagles Aerie 3496, and the Phi Beta Psi Sorority.

abstract

  • Background: Treatment with Bevacizumab has been associated with arterial thromboembolism in colorectal cancer patients. However, the mechanism of this remains poorly understood, and preclinical testing in mice failed to predict thrombosis. Objective: We investigated whether thrombosis might be the result of platelet activation mediated via the Fc gamma RIIa (IgG) receptor - which is not present on mouse platelets - and aimed to identify the functional roles of heparin and platelet surface localization in Bev-induced Fc gamma RIIa activation. Methods and results: We found that Bev immune complexes (IC) activate platelets via Fc gamma RIIa, and therefore attempted to reproduce this finding in vivo using Fc gamma RIIa (hFcR) transgenic mice. Bev IC were shown to be thrombotic in hFcR mice in the presence of heparin. This activity required the heparin-binding domain of Bev's target, vascular endothelial growth factor (VEGF). Heparin promoted Bev IC deposition on to platelets in a mechanism similar to that observed with antibodies from patients with heparin-induced thrombocytopenia. When sub-active amounts of ADP or thrombin were used to prime platelets (simulating hypercoagulability in patients), Bev IC-induced dense granule release was significantly potentiated, and much lower (sub-therapeutic) heparin concentrations were sufficient for Bev IC-induced platelet aggregation. Conclusions: The prevailing rationale for thrombosis in Bev therapy is that VEGF blockade leads to vascular inflammation and clotting. However, we conclude that Bev can induce platelet aggregation, degranulation and thrombosis through complex formation with VEGF and activation of the platelet Fc gamma RIIa receptor, and that this provides a better explanation for the thrombotic events observed in vivo.

Publication Date

  • January 1, 2009

webpage

published in

category

start page

  • 171

end page

  • 181

volume

  • 7

issue

  • 1

WoS Citations

  • 98

WoS References

  • 35