Abstract Number: PB1806
Meeting: ISTH 2020 Congress
Background: Vinorelbine is a vinca alkaloid used to treat non-small-cell-lung carcinoma and metastatic breast cancer. Side effects include neutropenia and thrombocytopenia causing immunosuppression and a risk of bleeding events. A virtual-high throughput screen (vHTS) identified vinorelbine as a ligand for FcγRIIa.
Aims: As FcγRIIa is expressed on both platelets and neutrophils we investigated the possibility that vinorelbine-mediated thrombocytopenia and neutropenia may be FcγRIIa-mediated.
Methods: vHTS was performed using 3D pharmacophore matching in silico using Molecular Operating Environment (CCG, Montreal). Platelet adhesion assays, aggregometry, loss of single platelet, as well as ATP secretion assays were performed to characterise its effects on platelets. We further tested the effect on TNFα secretion in differentiated U937 cells stimulated with IgG.
Results: Vinorelbine inhibited platelet adhesion to IgG (IC50 of 11µM), as well as heat-agglutinated IgG (HAIg)-induced platelet aggregation (vinorelbine: 7% ± 6%; vehicle control 65% ±10%; P< 0.05). This inhibition was selective as no inhibition was seen for ADP-induced aggregation (ADP, 68% ± 9%; ADP + vinorelbine 71% ± 11%, NS). When added to PRP, vinorelbine induced platelet aggregation (29 ± 3.8%) associated with a 24% reduction in single platelets and an increase in ATP release (34% ± 7.8%; P< 0.01). Vinorelbine also inhibited IgG-induced TNFα secretion in U937 cells (90% ± 6% inhibition).
Conclusions: The ability of vinorelbine to inhibit both platelet adhesion to IgG and HAIgG-induced platelet aggregation confirms the vHTS result that vinorelbine is a ligand for FcγRIIa. Its ability to induce platelet activation suggests that it has agonist activity on FcγRIIa. This FcγRIIa agonist activity may explain the loss of both platelets and neutrophils in patients and suggests that the use of an FcγRIIa antagonist such as intravenous IgG may ameliorate this adverse effect.
To cite this abstract in AMA style:Au Yong JK, Parpia Y, Golla K, Ni Gabhann J, Arkins L, Cox D, Brennan M. A Potential Role for the FcγRIIa in Vinorelbine Induced Thrombocytopenia and Neutropenia [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/a-potential-role-for-the-fc%ce%b3riia-in-vinorelbine-induced-thrombocytopenia-and-neutropenia/. Accessed August 15, 2022.
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