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      Oral Bruton tyrosine kinase inhibitors block activation of the platelet Fc receptor CD32a (FcγRIIA): a new option in HIT?

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          Key Points

          • Six different BTKi’s blocked platelet activation in blood after FcγRIIA stimulation by cross-linking, anti-CD9 antibodies, or HIT serum.

          • Established oral irreversible and novel reversible BTKi’s may offer a new option to treat HIT.

          Abstract

          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. Downstream FcγRIIA Bruton tyrosine kinase (BTK) is activated; however, its role in Fc receptor–induced platelet activation is unknown. We explored the potential to prevent FcγRIIA-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 FcγRIIA stimulation by antibody-mediated cross-linking (inducing platelet aggregation and secretion) or anti-CD9 antibody (inducing platelet aggregation only). 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. 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 BTKi’s also suppressed adenosine triphosphate secretion, P-selectin expression, and platelet-neutrophil complex formation after FcγRIIA 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 FcγRIIA activation. Platelet aggregation by adenosine 5′-diphosphate, arachidonic acid, or thrombin receptor-activating peptide was not inhibited. Thus, irreversible and reversible BTKi’s potently inhibit platelet activation by FcγRIIA in blood. This new rationale deserves testing in patients with HIT.

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          Author and article information

          Journal
          Blood Adv
          Blood Adv
          bloodoa
          Blood Adv
          Blood Advances
          Blood Advances
          American Society of Hematology (Washington, DC )
          2473-9529
          2473-9537
          10 December 2019
          6 December 2019
          6 December 2019
          : 3
          : 23
          : 4021-4033
          Affiliations
          [1 ]Institute for Prevention of Cardiovascular Diseases and
          [2 ]Department of Transfusion Medicine, Cell Therapeutics and Hemostaseology, Ludwig-Maximilians University, Munich, Germany;
          [3 ]German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany; and
          [4 ]Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
          Author information
          https://orcid.org/0000-0003-4610-8714
          https://orcid.org/0000-0001-7474-9370
          Article
          PMC6963242 PMC6963242 6963242 2019/ADV2019000617
          10.1182/bloodadvances.2019000617
          6963242
          31809536
          dbbaea4d-41e6-4053-92d7-a9aa58bed627
          © 2019 by The American Society of Hematology
          History
          : 24 June 2019
          : 28 October 2019
          Page count
          Pages: 13
          Categories
          29
          Thrombosis and Hemostasis
          Custom metadata
          free

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