Off-target drug effects on platelet function: Protecting an Achilles heel of drug development

The development of new drugs is often limited or even halted by their side effects on platelet number or function. This review introduces the signalling pathways and the role of various platelet receptors, such as GPIIb/IIIa, GPIb-IX-V, GPVI and P-selectin. The large scope of platelet function tests are described, including aggregometry, flow cytometry, VerifyNow, adhesion and in vivo thrombosis and haemostasis assays. Several important examples of drugs that have off-target effects influencing platelet function are discussed, including GPIIb/IIIa inhibitors, oligonucleotides, BH3 mimetics and Bruton tyrosine kinase inhibitors. Finally, challenges for future drug development with regards to platelet function are outlined, including the conclusion that no single assay can fully predict drug effects and thus a combination of platelet function tests is often required to assess platelet function in the context of newly developed therapeutics.