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.