Authors

Discussion

Thrombocytopenia (TP) is one of the side effects that can be observed in pre-clinical or clinical assessment of potential new medicines. Reduced platelet number could reflect the effects of agents or their metabolites on platelet production, platelet function, causing enhanced consumption due to in vivo activation, or on the rate of platelet destruction/removal.

Several in vitro assays can be performed to assess the possible effects of compounds on platelet activation or aggregation. These assays can be performed in a 96-well plate format, offering a higher throughout mode compared to the traditional platelet testing.

The possible effects of the agents on platelet viability can also, in part, be addressed in vitro by a range of assays: measurement of phosphatidylserine (PS) exposure, metabolic activity (MTS assay) or by using viability dyes by flow cytometry.

Several pro-apoptotic agents in development for oncology indications have been shown to induce thrombocytopenia. We have confirmed the effects on platelet viability in line with selectivity of their mechanism of action: a BH3-mimetic ABT-737 inhibiting BCL-2, BCL-XL and BCL-W and a more selective BCL-2 inhibitor ABT-199 (Venetoclax). The effects were also dependent on the test conditions: platelets in plasma versus isolated platelets treated with the compounds at room temperature and at 37°C. Our data suggest that when assessing the potential effects of new agents on platelet viability, the results should be interpreted with caution and in the context of the study design, preferably such studies need to include one or several reference compounds. 

The characteristics of the observed TP, e.g. extent, frequency of occurrence, rate of recovery of the platelet count, in combination with the results of in vitro assessment of the agents can be helpful in elucidating the mechanism of action and assessing the risk of their direct ef