Abstract
Activation of the platelet Fc-receptor CD32a (Fc gamma RIIA) is an early and crucial step in the pathogenesis of heparin-induced thrombocytopenia type II (HIT) that has not been therapeutically targeted. Downstream Fc gamma RIIA Bruton tyrosine kinase (BTK) is activated; however, its role in Fc receptor-induced platelet activation is unknown. We explored the potential to prevent Fc gamma RIIA-induced platelet activation by BTK inhibitors (BTKi's) approved (ibrutinib, acalabrutinib) or in clinical trials (zanubrutinib [BGB-3111] and tirabrutinib [ONO/GS-4059]) for B-cell malignancies, or in trials for autoimmune diseases (evobrutinib, fenebrutinib [GDC-0853]). We found that all BTKi's blocked platelet activation in blood after Fc gamma RIIA stimulation by antibody-mediated cross-linking (inducing platelet aggregation and secretion) or anti-CD9 antibody (inducing platelet aggregation only). The concentrations that inhibit 50% (IC50) of Fc gamma RIIA cross-linking-induced platelet aggregation were for the irreversible BTKi's ibrutinib 0.08 mu M, zanubrutinib 0.11 mu M, acalabrutinib 0.38 mu M, tirabrutinib 0.42 mu M, evobrutinib 1.13 mu M, and for the reversible BTKi fenebrutinib 0.011 mu M. IC50 values for ibrutinib and acalabrutinib were four- to fivefold lower than the drug plasma concentrations in patients treated for B-cell malignancies. The BTKi's also suppressed adenosine triphosphate secretion, P-selectin expression, and platelet-neutrophil complex formation after Fc gamma RIIA cross-linking. Moreover, platelet aggregation in donor blood stimulated by sera from HIT patients was blocked by BTKi's. A single oral intake of ibrutinib (280 mg) was sufficient for a rapid and sustained suppression of platelet Fc gamma RIIA activation. Platelet aggregation by adenosine 59-diphosphate, arachidonic acid, or thrombin receptor-activating peptide was not inhibited. Thus, irreversible and reversible BTKi's potently inhibit platelet activation by Fc gamma RIIA in blood. This new rationale deserves testing in patients with HIT.
Original language | English |
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Pages (from-to) | 4021-4033 |
Number of pages | 13 |
Journal | Blood advances |
Volume | 3 |
Issue number | 23 |
DOIs | |
Publication status | Published - 10 Dec 2019 |
Keywords
- MULTIPLE ELECTRODE AGGREGOMETRY
- IBRUTINIB
- PHOSPHORYLATION
- POLYMORPHISM
- AGGREGATION
- THROMBOSIS
- ACID
- GPVI
- TOOL
- BTK