Immune complications and their management in inherited and acquired bleeding disorders

Abstract

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.

Graphical abstract

Figure 1.

Clinical immunotherapies and alternative approaches to eliminate or circumvent antibodies against coagulation factors formed in patients with bleeding disorders. These concepts are illustrated using inhibitor formation in the treatment of hemophilia as an example. Alternative strategies include [1] immune tolerance induction (ITI) by frequent IV administration of antigen; [2] transient immune suppression therapy (IST); and [3] restoration of hemostasis using nonfactor therapeutics, thus avoiding the use of the target antigen. Center: Inhibitory antibodies are produced by B cells upon their T helper cell-dependent activation. T follicular helper cells promote the organization of germinal centers and the production of antibodies. B cells may differentiate into memory B cells (B_M) or plasma cells (PCs), which produce antibodies long-term. Ultimately, inhibitors prevent blood clot formation by reducing/eliminating the activation of factor X. This reaction is a critical component of the coagulation cascade and normally occurs through the cooperation of activated FVIII (FVIIIa) and factor IX (FIXa). Left: Although little is known about the mechanisms by which ITI reverses inhibitor production upon frequent IV factor administration, evidence supports that high antigen doses can directly inhibit B_M. IST may use small molecule drugs such as cyclophosphamide, a DNA alkylating agent that eliminates proliferating cells such as activated B and T cells. Rituximab (anti-CD20 antibody) depletes mature B cells (but not B_M or PCs). Regulatory T cells (Tregs) are able to suppress inhibitor formation. Therefore, experimental approaches use inhibition of the mTOR pathway with rapamycin/sirolimus (which aids in deletion of effector T cells, suppresses germinal center formation, and promotes Treg induction); oral antigen administration or hepatic gene transfer to induce Tregs, or Treg cell therapy, among other approaches. Right: Alternatively, nonfactor therapies bypass the effect of inhibitors by using a bispecific antibody that partially mimics the function of FVIII but is not recognized by FVIII inhibitors (a treatment that, however, only applies to HA) or promotes coagulation by elimination/neutralization of critical components of anticoagulant pathways (such as AT or TFPI) through small interfering RNA or monoclonal antibody therapy. AT, antithrombin III; TFPI, tissue factor pathway inhibitor.

Figure 2.

Overall strategy for IST for acquired HA. Proposed therapies are based on prognostic risk factors (FVIII clotting activity and inhibitor titers in Bethesda Units, BU). The response could be assessed as a complete response or significant and sustained improvement on the FVIII:C and/or reduction of inhibitor titers at the end of 3 to 4 weeks. In the case of failure in achieving these outcomes, the therapeutic intervention should proceed with the subsequent regimen.

Figure 3.

Potential cellular immunotherapies to suppress inhibitor formation in factor replacement therapy for hemophilia based on the engineering of T cells that have emerged from preclinical studies. In preclinical studies, T cells were gene-modified ex vivo by viral gene transfer, expanded, and subsequently transplanted to suppress inhibitor formation. These approaches seek to generate antigen-specific Tregs, as shown in several proof-of-principle studies on FVIII. Examples include redirection of antigen-specificity by transduction of CD4⁺FoxP3⁺ Tregs with FVIII-specific chimeric antigen receptor or T-cell receptor fusion construct (TRuC), which avoids major histocompatibility complex restrictions (top left); or with FVIII-specific TCR (top right). B-cell antigen receptors (BARs) use a portion of FVIII so that gene-modified CD4⁺FoxP3⁺ Tregs suppress FVIII-specific B cells (which express B-cell receptors for FVIII; bottom right). Alternatively, the introduction of a BAR to CD8⁺ T cells enables these cytolytic cells to eliminate FVIII-specific B cells (bottom right). Finally, expanded FVIII-specific effector CD4⁺ T cells can be reprogrammed to become Tregs by FoxP3 gene transfer (bottom left).