Institute for Prevention of Cardiovascular Diseases and.
Department of Transfusion Medicine, Cell Therapeutics and Hemostaseology, Ludwig-Maximilians University, Munich, Germany.
Blood Adv. 2019 Dec 10;3(23):4021-4033. doi: 10.1182/bloodadvances.2019000617.
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% (IC50) 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. 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 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.
血小板 Fc 受体 CD32a（FcγRIIA）的激活是肝素诱导的血小板减少症 II 型（HIT）发病机制中的早期和关键步骤，目前尚未得到治疗靶向。下游 FcγRIIA Bruton 酪氨酸激酶（BTK）被激活；然而，其在 Fc 受体诱导的血小板激活中的作用尚不清楚。我们探索了通过 BTK 抑制剂（BTKi）预防 FcγRIIA 诱导的血小板激活的潜力，这些抑制剂已获得批准（依鲁替尼、阿卡替尼）或正在临床试验中（zanubrutinib [BGB-3111]和 tirabrutinib [ONO/GS-4059]）用于治疗 B 细胞恶性肿瘤，或在临床试验中用于治疗自身免疫性疾病（evobrutinib、fenebrutinib [GDC-0853]）。我们发现，所有 BTKi 在 FcγRIIA 被抗体介导的交联（诱导血小板聚集和分泌）或抗 CD9 抗体（仅诱导血小板聚集）刺激后，均可阻止血液中的血小板激活。抑制 50%（IC50）FcγRIIA 交联诱导的血小板聚集的浓度分别为不可逆 BTKi 依鲁替尼 0.08 µM、zanubrutinib 0.11 µM、阿卡替尼 0.38 µM、tirabrutinib 0.42 µM、evobrutinib 1.13 µM 和可逆 BTKi fenebrutinib 0.011 µM。依鲁替尼和阿卡替尼的 IC50 值比接受 B 细胞恶性肿瘤治疗的患者的药物血浆浓度低四到五倍。BTKi 还抑制 FcγRIIA 交联后三磷酸腺苷分泌、P-选择素表达和血小板-中性粒细胞复合物形成。此外，BTKi 还阻断了由 HIT 患者血清刺激的供体血液中的血小板聚集。单次口服依鲁替尼（280mg）即可快速和持续抑制血小板 FcγRIIA 激活。二磷酸腺苷、花生四烯酸或血栓素受体激活肽诱导的血小板聚集不受抑制。因此，不可逆和可逆 BTKi 可有效抑制血液中 FcγRIIA 诱导的血小板激活。这一新的原理值得在 HIT 患者中进行测试。
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