Inhibitors are a serious treatment complication that can occur when people with hemophilia are exposed to clotting factor concentrates. Some patients may have an immune response to factor concentrates—their immune system may see it as a foreign protein and develop inhibitors (antibodies) against it, which then makes it ineffective for the treatment or prevention of bleeds. The World Federation of Hemophilia (WFH) is proud to announce the release of the 5th edition of Inhibitors in Hemophilia: A Primer, a newly updated resource in the Treatment of Hemophilia (TOH) series. Two expert hematologists, Jenny Goudemand and Manuel Carcao, explain the current understanding of how and why inhibitors form, review the established approaches to managing inhibitors, and look ahead to some potential future developments in the field.
Treatment of inhibitors is one of the biggest challenges in hemophilia care today. TOH 7 Inhibitors in Hemophilia: A Primer (5th edition) is a concise introduction for anyone concerned with inhibitor formation in people with hemophilia. It explains the immune response to factor VIII (FVIII) and factor IX (FIX) concentrates and how inhibitor development is a much more common problem in people with hemophilia A than people with hemophilia B. It describes how inhibitors are detected and diagnosed, and possible risk factors for inhibitor development. The article also discusses the basic principles of inhibitors management and current treatment options:
Inhibitors are most commonly encountered in people with severe hemophilia A (overall 25 to 40% lifetime risk) compared to people with mild/moderate hemophilia A (overall 5 to 15% lifetime risk) and people with hemophilia B (overall 1 to 5% lifetime risk). The article delves into genetic and environmental factors known to influence the risk of inhibitor formation. Several genetic risk factors are well established: genetic mutation, family history of inhibitors, and ethnicity. Environmental risk factors include both treatment-related factors (e.g., dosing regimen, intense exposure) and immune system activation risk factors (e.g., inflammation/infection “danger signals” in the immune response). Although it is known that some patients are at higher risk of inhibitor development due to a combination of various genetic and environmental risk factors, ultimately it is still not known why one patient with a very similar inhibitor risk profile to another patient develops inhibitors, while the other does not.
Next, the article focuses on current strategies for inhibitors management. Bypassing agents are used for the treatment or prevention of bleeds in inhibitor patients. Two types of bypassing agents are available: plasma-derived activated prothrombin complex concentrate (aPCC) and recombinant activated FVIIa (rFVIIa). Both agents are reported to be effective in treating 90% of musculoskeletal bleeds and can be used for both major and minor surgical prophylaxis; there is also increasing evidence to support their use in prophylaxis. However, the bypassing agents are far less effective in treating and preventing bleeds than conventional factor concentrates in patients without inhibitors. Furthermore, bypassing agents are less convenient to use due to their short half-life and the consequent need for frequent infusions (particularly with rFVIIa) or the need for prolonged infusion times (aPCC).
Immune tolerance induction therapy is the only treatment strategy with the potential to eradicate persistent FVIII or FIX inhibitors. ITI involves regular (daily or several times weekly) infusions of variable doses of FVIII or FIX, administered for periods of months to years in an effort to train the immune system to accept FVIII or FIX treatment without producing inhibitors. The article notes that although time-consuming and costly, ITI is effective in 60 to 80% of patients and is considered the standard of care for people with severe hemophilia and persistent inhibitors. Successful ITI enables regular treatment with factor products including prophylaxis, increases quality of life, and, despite a very high short-term cost, reduces the cost of future care. However, due to its high cost and the requirement for access to large quantities of factor concentrate, it is not always possible to undertake ITI in countries with significant resource constraints.
There has been significant progress in the development of non-factor therapies for patients with inhibitors. In Fall 2017, emicizumab was approved for use in hemophilia A patients with inhibitors by the U.S. Food and Drug Administration (FDA) and has since received market authorization in other jurisdictions. In fall 2018, emicizumab received expanded FDA approval for hemophilia A patients without inhibitors. Emicizumab mimics FVIII activity in the coagulation cascade to enable clot formation. Administered subcutaneously once per week in patients with hemophilia A and inhibitors, it has resulted in a significantly reduced (87%) rate of bleeding compared to patients treated with bypassing agents on demand. The article notes that up until now patients with inhibitors have generally experienced more frequent bleeding, including life-threatening bleeds and greater disability than people with hemophilia who do not have inhibitors. With the advent of emicizumab—and as similar treatments are developed—this may no longer be the case in the future.
A number of rebalancing agents which work to rebalance the equilibrium between bleeding and clotting by decreasing anti-coagulants that naturally occur in the blood circulation system (i.e., tissue factor pathway inhibitor, anti-thrombin) are also in various phases of development. The article stresses the need for caution when considering novel agents and non-factor therapies for hemophilia as they carry both known and unknown risks.
Looking forward, the article notes that the field is expected to evolve considerably in the coming years, particularly with the development of extended half-life products, which have the potential to significantly reduce the treatment burden for patients with inhibitors. It is therefore important to stay up to date on the most recent scientific information and regulatory guidance on therapies for hemophilia patients with inhibitors. Visit the WFH eLearning Platform for a wide variety of educational resources about inhibitors, from webcasts of expert presentations at World Congresses to a card game for children!