Inhibitor development: The last enemy to be defeated in hemophilia A and B
Authors: Francesco Rodeghiero, Giancarlo Castaman
Journal: American Journal of Hematology (2014)

In this issue of the American Journal of Hematology, Soucie et al. present data on a national inhibitor surveillance program in US for patients with hemophilia A and B. This program was developed by the Center for Disease Control in a partnership with the hemophilia treatment community, community-based organizations, industry, and the federal government. Inhibitors were identified as a key public health issue for the hemophilia community. It was noted that appropriate screening may not uniformly be adopted across the country and thus some cases could go unrecognized until clinical evidence suggests testing. As the discovery that blood or plasma transfusion was of some efficacy in the treatment of patients with hemophilia A and B, enormous progress has been made with the introduction by Judith Pool in 1966 of cryoprecipitate (with contains most of plasma factor VIII) and of plasma Cohn fraction IV-1 with its high content of factor IX. These first steps paved the way to the production of factor VIII and IX concentrates (early 1970s) which allowed the administration in small volumes of large amount of the missing proteins. The risk of hemorrhage dramatically decreased, home-treatment and orthopedic surgery became feasible and readily increased, and eventually hemophiliacs enjoyed a much improved quality of life, prolonging significantly their life expectancy 1. However, it soon became apparent that hepatitis B and C (at that time called “non-A non-B” hepatitis) viruses were transmitted with these concentrates produced from massive pool of plasma collected from 1,000 of donors. Even worse from early 1980s the tragedy of Acquired Immune Deficiency Syndrome (AIDS) exploded, causing an epidemic of deaths among the hemophiliacs 2. Starting from mid 1980s, the availability of purer virally inactivated concentrates, together with more accurate donor selections made available by sensitive and specific serological and molecular tests for hepatitis viruses and Human Immunodeficiency Virus (HIV), led to a dramatic safety improvement and no further cases of hepatitis or HIV transmission have been registered during the last 25 years. The genes for factor VIII and factor IX were cloned in 1985 and 1982, respectively, and human recombinant factors were made available at the beginning of 1990s. Following the results of pioneering experience in Sweden 3, the introduction of prophylaxis with these new plasma or recombinant concentrates, along with their larger availability, at least in Western countries, has made the life of the hemophiliacs born in the last 25 years remarkably similar to that of normal people 4. However, this is not entirely the case for those patients who develop inhibitory alloantibodies (inhibitors) against administered factor VIII or IX, which preclude usual treatment with factor VIII/IX and prophylaxis. Apart from the late sequelae associated with chronic hepatitis or HIV infections, the inhibitor risk has emerged as the most important, still unresolved issue in the modern treatment of hemophilia. It is estimated that the incidence of antibody development in subjects with severe (factor less than 1%) or moderately severe (factor 1–5%) hemophilia A is between 20 and 35% 5. A significant percentage is represented by transitory or low titer inhibitors, which usually disappear early by continuing replacement therapy. However, a percentage of patients (around 5–10% of all severe cases, especially children) have long-lasting high titer inhibitors. They usually must undergo immune-tolerance regimens requiring daily administration of very large amounts of FVIII to achieve tolerance, with a success rate around 60–70%, at a significant cost in terms of quality of life and with an extremely high economic burden 6. Among subjects with hemophilia B, inhibitors are much less frequent, affecting only 5% of severe patients. However, the development of factor IX inhibitors can be associated with mild or severe allergic reactions during factor IX administration, thus hampering the adoption of immune-tolerance regimes 6. Inhibitor development occurs at an average age of between 1 and 2 years, and after an average of 9–12 treatments. Inhibitor risk is greatest during the first 50 exposures to factor VIII. Although the risk greatly diminishes after 150 treatment days, a low rate of new inhibitor development has been reported in older patients 5. Recent data in nonsevere hemophilia A suggest that the risk increases throughout the entire life, as in these patients, less frequently treated compared to severe cases, the risk still increases after 50 exposure days 7. It appears that the triggering factors of inhibitor development in severe hemophilia are complex and multifactorial. The type of mutation in the factor VIII/IX gene plays an important role. Large deletions, inversions, and nonsense mutations are associated with the highest risk, probably because the recipient's immune system recognizes the normal factor VIII/IX replacement protein as a foreign molecule 8. However, some missense mutations responsible for mild/moderate hemophilia A are also associated with an increased risk, probably because the amino acid substitution causes major structural rearrangement of the protein, so that the patient's immune system identifies the “normal” exogenously administered factor VIII as nonself 7. Black patients with hemophilia A are twice as likely as white patients to produce inhibitors against replaced factor VIII 9. Family history of inhibitors and intensive replacement treatment, including continuous infusion, especially in particular circumstances (e.g., surgery), have also been considered to carry an increased risk for the development of inhibitors. Major Histocompatibility Complex (MHC) class II alleles and polymorphisms of immune-response genes (IL10, TNF and CTLA4) have been also implied as contributing factors 5. It has been suggested that prophylaxis started at a very early age as well as the presence of von Willebrand Factor (VWF) in concentrates could be protective, but more studies are required to better clarify their role. As a whole, however, there is no definite argument suggesting that the type of concentrate or switching from a concentrate to another represent major risk factors. The results of a large international Survey of Inhibitors in Plasma-Product Exposed Toddlers-Study (SIPPET study) investigating the incidence of inhibitors in previously untreated patients with hemophilia A randomized to plasma-derived or recombinant concentrates are eagerly awaited 10. It is mandatory that every patient with hemophilia A and severe patients with hemophilia B treated with plasma-derived or recombinant factors be surveyed for inhibitors. The treatment of patients who have inhibitors can be very costly and cumbersome and these patients carry a high risk of untreatable bleeding. More appropriate and comprehensive survey programs must be implemented to detect every patient at risk, and avoid unexpected bleeding complications of difficult management. Previously untreated patients must be tested serially and frequently during the first 50 exposure days to concentrates and a strict scrutiny maintained thereafter at least until 150 exposure days are reached. Genetic testing for all hemophilia patients is highly desirable at diagnosis to identify those at a greater risk, also to avoid overtreatment when other therapeutic options are available (e.g., desmopressin for mild hemophilia A) 11. In this context, the US national surveillance program is a timely initiative aiming at a comprehensive evaluation of the epidemiology and of the impact of inhibitor development, which overcomes the limitations of fragmented and not well-standardized local investigations. The centralization of laboratory testing at no charge for patients is a major strength of this program and no doubt will stimulate similar initiatives in other countries. The history of hemophilia is a paradigm of gloomy experiences, but also of outstanding and astonishing progress. We are now on the brink of the second era of hemophilia treatment. Gene therapy has just begun in hemophilia B and new long-acting factor concentrates using pegylation or fusion with albumin or Fc fragment of IgG1 are being introduced in clinical practice and several others are on the way 12, 13. Hopefully, this surveillance program will produce a reliable representation of the inhibitors incidence and associated contributing risk factors (age, exposure time, type of concentrate, etc.) 5 thus making possible to detect any favorable or unfavorable impact of these new promising agents in the context of every day clinical practice.