Disorders of coagulation, resulting in serious risks for bleeding, may be caused by autoantibody formation or by mutations in genes encoding coagulation factors. In the latter case, antidrug antibodies (ADAs) may form against the clotting factor protein drugs used in replacement therapy, as is well documented in the treatment of the X-linked disease hemophilia. Such neutralizing antibodies against factors VIII or IX substantially complicate treatment. Autoantibody formation against factor VIII leads to acquired hemophilia. Although rare, antibody formation may occur in the treatment of other clotting factor deficiencies (eg, against von Willebrand factor [VWF]). The main strategies that have emerged to address these immune responses include (1) clinical immune tolerance induction (ITI) protocols; (2) immune suppression therapies (ISTs); and (3) the development of drugs that can improve hemostasis while bypassing the antibodies against coagulation factors altogether (some of these nonfactor therapies/NFTs are antibody-based, but they are distinct from traditional immunotherapy as they do not target the immune system). Choice of immune or alternative therapy and criteria for selection of a specific regimen for inherited and autoimmune bleeding disorders are explained. ITI serves as an important proof of principle that antigen-specific immune tolerance can be achieved in humans through repeated antigen administration, even in the absence of immune suppression. Finally, novel immunotherapy approaches that are still in the preclinical phase, such as cellular (for instance, regulatory T cell [Treg]) immunotherapies, gene therapy, and oral antigen administration, are discussed.

中文翻译：

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遗传性和获得性出血性疾病的免疫并发症及其治疗。

导致严重出血风险的凝血障碍可能是由自身抗体形成或编码凝血因子的基因突变引起的。在后一种情况下，可能会针对替代疗法中使用的凝血因子蛋白药物形成抗药物抗体 (ADA)，这在 X 连锁疾病血友病的治疗中已有充分记录。这种针对因子VIII或IX的中和抗体使治疗显着复杂化。针对因子 VIII 的自身抗体形成会导致获得性血友病。尽管罕见，但在治疗其他凝血因子缺陷（例如针对血管性血友病因子 [VWF]）时可能会出现抗体形成。解决这些免疫反应的主要策略包括（1）临床免疫耐受诱导（ITI）方案；(2) 免疫抑制疗法（IST）；(3) 开发可以改善止血的药物，同时完全绕过抗凝血因子的抗体（其中一些非因子疗法/NFT 是基于抗体的，但它们与传统的免疫疗法不同，因为它们不针对免疫系统）。解释了免疫或替代疗法的选择以及遗传性和自身免疫性出血性疾病特定治疗方案的选择标准。ITI 是一个重要的原理证明，表明即使在没有免疫抑制的情况下，通过重复施用抗原也可以在人类中实现抗原特异性免疫耐受。最后，讨论了仍处于临床前阶段的新型免疫治疗方法，例如细胞（例如调节性 T 细胞 [Treg]）免疫疗法、基因疗法和口服抗原给药。