von Hundelshausen Philipp, Siess Wolfgang, Duan Rundan, Bohnert Tonika, Hopkins Brian T, Weber Christian
Institute for Cardiovascular Prevention, University Hospital LMU Munich, Ludwig-Maximilians-Universität, Munich, Germany (P.v.H., W.S., R.D., C.W.).
German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany (P.v.H., W.S., C.W.).
Circulation. 2026 Feb 10;153(6):435-456. doi: 10.1161/CIRCULATIONAHA.125.076186. Epub 2026 Feb 9.
Btk (Bruton's tyrosine kinase), a Tec-family kinase initially recognized for its role in B-cell signaling, has emerged as a critical player in thrombosis and cardiovascular disease. Beyond the established therapeutic effects of Btk inhibitors in B-cell malignancies, its expression in platelets, macrophages, and neutrophils implicates Btk in platelet activation, atherothrombosis, and innate immunity. This state-of-the-art review synthesizes the current understanding of Btk's mechanistic contributions to thrombosis and cardiovascular disease, evaluates the evolution of Btk inhibitors (BTKi), and explores their therapeutic potential. Patients with X-linked agammaglobulinemia who lack Btk do not have a bleeding diathesis, indicating that platelet-selective Btk inhibition would be a safe antithrombotic strategy. In platelets, Btk mediates immunoreceptor tyrosine-based activation motif-dependent and -independent signaling, driving atherothrombosis, venous thrombosis, and immunothrombosis without affecting hemostatic platelet functions. In myeloid cells, Btk amplifies inflammation via NLRP3 inflammasome activation and neutrophil extracellular trap formation, linking it to thromboinflammation and atherosclerosis. First-generation BTKi such as ibrutinib demonstrate antithrombotic efficacy but are limited by off-target effects, including bleeding and atrial fibrillation. Second- and third-generation inhibitors (eg, acalabrutinib, zanubrutinib, and pirtobrutinib) show enhanced selectivity, reducing cardiovascular toxicity in patients with B-cell malignancies. Highly selective BTKi (fenebrutinib and remibrutinib) do not show bleeding in clinical trials of various autoimmune disorders, and covalent selective BTKi applied at low dosage are expected to selectively inhibit Btk in platelets without bleeding side effects. Preclinical data and early observations from compassionate use in patients with atypical autoimmune thrombosis highlight the potential of BTKi as selective antithrombotic agents beyond traditional therapies. This review conceptualizes and underscores Btk's pivotal role at immune-thrombosis interfaces in atherothrombosis, advocating for precision medicine approaches and innovative platforms to unlock its full therapeutic potential in cardiovascular disease management.
布鲁顿酪氨酸激酶（Btk）是一种最初因其在B细胞信号传导中的作用而被认可的Tec家族激酶，现已成为血栓形成和心血管疾病中的关键因子。除了Btk抑制剂在B细胞恶性肿瘤中已确立的治疗效果外，其在血小板、巨噬细胞和中性粒细胞中的表达表明Btk参与了血小板活化、动脉粥样硬化血栓形成和固有免疫。这篇前沿综述综合了目前对Btk在血栓形成和心血管疾病中机制作用的理解，评估了Btk抑制剂（BTKi）的发展，并探讨了它们的治疗潜力。患有X连锁无丙种球蛋白血症且缺乏Btk的患者没有出血倾向，这表明血小板选择性Btk抑制将是一种安全的抗血栓策略。在血小板中，Btk介导基于免疫受体酪氨酸的活化基序依赖性和非依赖性信号传导，驱动动脉粥样硬化血栓形成、静脉血栓形成和免疫血栓形成，而不影响血小板的止血功能。在髓样细胞中，Btk通过NLRP3炎性小体激活和中性粒细胞胞外陷阱形成放大炎症，将其与血栓炎症和动脉粥样硬化联系起来。第一代BTKi，如伊布替尼，显示出抗血栓疗效，但受到脱靶效应的限制，包括出血和心房颤动。第二代和第三代抑制剂（如阿卡替尼、泽布替尼和派托布替尼）表现出更高的选择性，降低了B细胞恶性肿瘤患者的心血管毒性。高选择性BTKi（非奈布替尼和瑞米布替尼）在各种自身免疫性疾病的临床试验中未显示出血现象，低剂量应用的共价选择性BTKi有望在不产生出血副作用的情况下选择性抑制血小板中的Btk。临床前数据以及对非典型自身免疫性血栓形成患者同情用药的早期观察结果凸显了BTKi作为超越传统疗法的选择性抗血栓药物的潜力。这篇综述概念化并强调了Btk在动脉粥样硬化血栓形成的免疫血栓界面中的关键作用，倡导采用精准医学方法和创新平台来释放其在心血管疾病管理中的全部治疗潜力。
