Comparison of variably specific Bruton tyrosine kinase inhibitors on platelet aggregation mediated by Fcγ receptor (FcγR) IIa, glycoprotein VI, and platelet endothelial aggregation receptor (PEAR) 1: implications for Bruton tyrosine kinase inhibitors as antithrombotic therapy.

BACKGROUND

Bruton tyrosine kinase (BTK) inhibitors (BTKi) have been proposed as therapy for thrombosis driven by immune complex activation of platelets via FcγRIIa. Since patients who lack BTK (X-linked agammaglobulinemia [XLA]) do not have excessive bleeding, highly specific BTKi may be antithrombotic without increasing the risk of hemorrhage. Our knowledge of the full range of effects of BTKi on platelet function is incomplete, in particular, the role of BTKi on signaling via platelet endothelial aggregation receptor (PEAR) 1, a receptor linked to thrombotic cardiovascular disease.

OBJECTIVES

This study assessed the role of BTK in platelet aggregation initiated through Fcγ receptor (FcγR)IIa, glycoprotein (GP)VI, PEAR1, and other receptors.

METHODS

Platelets of control and patients with XLA were treated with BTKi of varying specificity and analyzed by light transmission aggregometry and immunoblotting.

RESULTS

Both nonspecific and highly specific BTKi profoundly inhibited platelet aggregation mediated by FcγRIIa, PEAR1, and GPVI, but not protease-activated receptor 1, the thromboxane receptor, α2β1, or GPIb/von Willebrand factor. Inhibition of phosphorylation of BTK Y223 correlated with inhibition of aggregation. Platelets of 4 patients with XLA had markedly reduced or no responses to activation via GPVI and FcγRIIa.

CONCLUSION

BTK plays important roles in signaling via FcγRIIa, GPVI, and PEAR1, but clinical studies are required to assess the optimal BTKi for inhibiting thrombotic disorders mediated via these receptors.