Bevacizumab immune complexes activate platelets and induce thrombosis in FCGR2A transgenic mice.
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 FcgammaRIIa (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 FcgammaRIIa activation.


RESULTS
We found that Bev immune complexes (IC) activate platelets via FcgammaRIIa, and therefore attempted to reproduce this finding in vivo using FcgammaRIIa (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 FcgammaRIIa receptor, and that this provides a better explanation for the thrombotic events observed in vivo.
Meyer
T
T
Center for Thrombosis Research, Florida Hospital, Orlando, FL, USA. todd.meyer@flhosp.org
Robles-Carrillo
L
L
Robson
T
T
Langer
F
F
Desai
H
H
Davila
M
M
Amaya
M
M
Francis
J L
JL
Amirkhosravi
A
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized; D000936:Antigen-Antibody Complex / Q000009:adverse effects*; D000068258:Bevacizumab; D006493:Heparin / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D015539:Platelet Activation / Q000187:drug effects*; D017452:Receptors, IgG / Q000235:genetics / Q000502:physiology*; D013927:Thrombosis / Q000139:chemically induced*; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000936:Antigen-Antibody Complex; C080568:Fc gamma receptor IIA; D017452:Receptors, IgG; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D006493:Heparin