IC 50 values for ibrutinib and acalabrutinib were four- to fivefold lower than the drug plasma concentrations in patients treated for B-cell malignancies. The concentrations that inhibit 50% (IC 50) of FcγRIIA cross-linking–induced platelet aggregation were for the irreversible BTKi's ibrutinib 0.08 µM, zanubrutinib 0.11 µM, acalabrutinib 0.38 µM, tirabrutinib 0.42 µM, evobrutinib 1.13 µM, and for the reversible BTKi fenebrutinib 0.011 µM. We found that all BTKi’s blocked platelet activation in blood after FcγRIIA stimulation by antibody-mediated cross-linking (inducing platelet aggregation and secretion) or anti-CD9 antibody (inducing platelet aggregation only). We explored the potential to prevent FcγRIIA-induced platelet activation by BTK inhibitors (BTKi’s) approved (ibrutinib, acalabrutinib) or in clinical trials (zanubrutinib and tirabrutinib ) for B-cell malignancies, or in trials for autoimmune diseases (evobrutinib, fenebrutinib ). Downstream FcγRIIA Bruton tyrosine kinase (BTK) is activated however, its role in Fc receptor–induced platelet activation is unknown. Activation of the platelet Fc-receptor CD32a (FcγRIIA) is an early and crucial step in the pathogenesis of heparin-induced thrombocytopenia type II (HIT) that has not been therapeutically targeted.