Inhibitors in hemophilia: Mechanisms, prevalence, diagnosis, and eradication

INTRODUCTION — One of the most challenging aspects of hemophilia management is the care of a patient who develops an inhibitor (an antibody directed against infused factor that inhibits the function of the factor). Individuals who develop inhibitors can often no longer use standard factor replacement to treat bleeding or to provide prophylaxis against bleeding.

This topic discusses the mechanisms and risk factors for inhibitor development and the routine management of individuals with inhibitors, including immune tolerance induction (ITI) to eradicate inhibitors and alternative types of prophylaxis.

Separate topic reviews discuss the treatment of bleeding in individuals with inhibitors as well as other aspects of hemophilia care and acquired coagulation factor inhibitors (autoantibodies).

●Treatment of bleeding and surgical planning – (See "Treatment of bleeding and perioperative management in hemophilia A and B", section on 'Inhibitors'.)

●Diagnosis of hemophilia – (See "Clinical manifestations and diagnosis of hemophilia".)

●General hemophilia management – (See "Hemophilia A and B: Routine management including prophylaxis" and "Chronic complications and age-related comorbidities in people with hemophilia".)

●Acquired factor inhibitors – (See "Acquired hemophilia A (and other acquired coagulation factor inhibitors)".)

TERMINOLOGY AND DEFINITIONS

●Hemophilia – The hemophilias are bleeding disorders caused by deficiency of clotting factors:

•Deficiency of factor VIII (factor 8) – Hemophilia A

•Deficiency of factor IX (factor 9) – Hemophilia B

Hemophilia A and B severity is classified according to the level of circulating factor activity, which correlates with bleeding risk and the risk of inhibitor development. Mild disease is defined as a factor activity level above 5 and below 40 percent; moderate disease is a factor activity level between 1 and ≤5 percent; and severe disease is a factor activity level <1 percent [1]. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Definitions'.)

Hemophilia C refers to factor XI (factor 11) deficiency, but the phenotypic disease severity, type of bleeding manifestations, and management differ from hemophilia A and B. (See "Factor XI (eleven) deficiency".)

Acquired hemophilia refers to development of a clotting factor deficiency that was not present at birth. Typically, this occurs when an autoantibody is produced against an endogenous factor. Acquired hemophilia A (acquired inhibitor against endogenous factor VIII) is the most common. (See "Acquired hemophilia A (and other acquired coagulation factor inhibitors)".)

●Treatment – Previously untreated patients (PUPs) are those who have not received infusions of replacement factor. Previously treated patients (PTPs) are those who have been exposed to replacement factor.

Minimally treated patients are those with ≤3 exposure days.

●Exposure days – Exposure days refers to the number of days on which the individual was exposed to exogenous factor. As an example, an individual treated with factor infusions on Monday, Wednesday, and Friday for two weeks has six exposure days. An individual treated with two infusions of factor on Monday has one exposure day. The number of exposure days correlates with the risk of inhibitor development, but it is not necessarily a good surrogate for treatment intensity, as discussed below. (See 'Therapy considerations' below.)

●Inhibitors – An inhibitor is a neutralizing antibody that interferes with the function of the factor against which it is directed. In hemophilia A and B, inhibitors are alloantibodies directed against infused factor. Not all antibodies to factor act as inhibitors. Non-neutralizing antibodies directed against coagulation factors may be seen in individuals with hemophilia and in the general population [2-4].

•Titer – Inhibitor titers are quantified using the Bethesda assay. This is a clot-based assay in which serial dilutions of patient plasma are incubated with pooled normal plasma and residual clotting activity is measured. In many cases, the Nijmegen modification is used. If exogenous factor VIII has been administered, heat treatment is sometimes used to remove any exogenous factor VIII and more accurately determine the patient's true inhibitor titer. Individuals receiving emicizumab cannot have an inhibitor titer determined using a clot-based assay. A chromogenic bovine reagent-based Bethesda assay (CBA) is used for individuals receiving emicizumab.

The titer is the reciprocal of the dilution of patient plasma that results in 50 percent factor activity, expressed as Bethesda units (BU) or Nijmegen-Bethesda units (NBU). The titer may also be expressed in BU/mL. The greater the dilution required to titrate out the inhibitor, the higher the inhibitor titer.

•High-responding versus low-responding inhibitor – An inhibitor titer of ≥5 BU at any time is considered a high-responding inhibitor, and a persistent titer <5 BU despite repeated factor VIII or IX exposure is considered a low-responding inhibitor [5,6]. Low-responding inhibitors do not rise to ≥5 BU with repeated exposure to factor. A patient whose titer is ≥5 BU has a greater likelihood of increase upon re-exposure to factor.

•Transient inhibitors – Inhibitors that disappear spontaneously (that decrease below the definition threshold within six months of initial documentation despite continuing exposure to factor without immune tolerance induction) are referred to as transient inhibitors [1].

●Immune tolerance induction – Immune tolerance induction (ITI, also called immune tolerance therapy [ITT] or inhibitor eradication) is the primary method used to eliminate or control inhibitors. It involves administration of frequent, regularly scheduled doses of the deficient factor to reset (tolerize) the individual's immune system and reduce or ablate production of the antibody. The immunologic principles are somewhat similar to immunotherapy for allergic disease, although there are significant differences in the clinical manifestations of the immune response. (See "Allergen immunotherapy for allergic disease: Therapeutic mechanisms" and 'Immune tolerance induction' below.)

PATHOGENESIS

Mechanisms of formation and action — Inhibitors form when the immune system recognizes the infused factor as foreign and generates neutralizing antibodies. Predisposing and provoking factors are enumerated below. (See 'Predisposing influences' below.)

Inhibitors are high-affinity antibodies (primarily immunoglobulin G [IgG]) directed against the factor protein [3]. They are often polyclonal (produced by separate B cell clones with many distinct antibody specificities that recognize distinct epitopes). In contrast, inhibitors in individuals with acquired hemophilia are often monoclonal (derived from a single B cell clone). In one study, approximately 80 percent of individuals with hemophilia A who developed inhibitors had at least two or more independent antibody specificities against factor VIII [7].

Emerging data suggest that IgG subtype signatures may impact inhibitor development [8-11].

In hemophilia A, most antibodies are directed against the A2 and/or C2 domains of the protein (figure 1). Mechanisms include the following:

●Interference with factor VIII binding to phospholipids or von Willebrand factor (VWF) via binding to the C2 domain [7,12-18]

●Interference with factor VIII binding to factor IX or blocking of the intrinsic ten-ase activity of the factor VIIIa-factor IXa complex [19,20]

●Increased clearance of factor VIII via direct proteolysis [21,22]

The domain structure of the factor VIII and factor IX molecules and functional regions of the proteins are discussed separately. (See "Biology and normal function of factor VIII and factor IX".)

Predisposing influences — Influences that contribute to inhibitor development are complex, multifactorial, and incompletely understood [5].

They are likely to involve:

●Characteristics of the patient (see 'Patient characteristics' below):

•Causative genetic mutations (pathogenic variants)

•Severity of hemophilia

•Variation in other regulatory genes

●Hemophilia treatment (see 'Therapy considerations' below):

•Use of replacement factor versus emicizumab (for hemophilia A)

•Age at first exposure

•Product used

•Intensity of dosing

•Use of prophylaxis versus on-demand treatment

●The environment (see 'External/environmental factors' below):

•Surgery

•Trauma

•Other danger signals

Sometimes these elements may be difficult to tier in importance because most of the available data come from observational studies that may be subject to a variety of interrelated and confounding factors. As examples:

●Different populations in different parts of the world may have different pathogenic variants in the F8 or F9 genes and immune response genes and may be treated using different products at different intensities, starting at different ages.

●Individuals with more severe disease are likely to have more exposure days earlier in their disease course and are at higher risk for inhibitor development generally.

●Individuals in certain populations may co-inherit certain factor mutations and certain mutations affecting the immune response

Risk factors for inhibitor development in hemophilia A have been studied extensively compared with hemophilia B because hemophilia A is more common and the incidence of inhibitors is higher. Further, hemophilia B is often associated with point mutations, which are less commonly associated with inhibitor development, rather than deletions, insertions, inversions, and frame shift mutations. The extent to which the information on predisposing factors can be generalized to hemophilia B is not known and may differ substantially. Research continues to define the best predictors of inhibitor development in both hemophilia A and B, as well as methods to decrease or prevent formation.

Patient characteristics — Inhibitors are much more common in hemophilia A than in hemophilia B. (See 'Epidemiology' below.)

Beyond this, there are several established patient characteristics that increase inhibitor risk. These include genetic factors related to the specific factor mutation and those related to immune response genes. Race and ethnicity also play a role, but their mechanisms are not well-elucidated.

●Factor gene variant – The specific variant in the relevant factor gene (F8 or F9) determines disease severity, and more severe disease is associated with greater inhibitor risk. This is likely because lower levels (or absence) of endogenous factor will make it less likely that the individual's immune system was tolerized to the antigen during development and more likely that the infused product is recognized by the recipient's immune system as foreign. There may also be factor antigen circulating in some individuals with absent factor activity, and these individuals may be more likely to be tolerized to that factor.

Thus, large deletions and nonsense mutations (creation of an internal stop codon) in the F8 gene are much more likely to be associated with inhibitors compared with small deletions, insertions, or missense mutations (creation of an amino acid change) [5,23-27]. The intron 22 gene inversion, present in 40 to 45 percent of individuals with severe hemophilia A, carries an intermediate risk [26,28]. (See "Genetics of hemophilia A and B", section on 'F8 gene (hemophilia A)'.)

•In a meta-analysis of studies that examined F8 genotype and inhibitor risk in 5383 individuals with hemophilia A using intron 22 inversions as the control group, the odds ratios (ORs) for inhibitor development with large deletions, nonsense mutations, small deletions/insertions, and missense mutations were 3.6, 1.4, 0.5, and 0.3, respectively [28].

•In an analysis of 586 participants who had data entered in the Haemophilia A Mutation, Search, Test and Resource Site (HAMSTeRS registry), the frequencies of inhibitors were as follows [29]:

-Large (>200 bp) deletions – 38 percent

-Nonsense mutations – 36 percent

-Inversions – 20 percent

-Small (≤86 bp) deletions – 14 percent

-Missense mutations – 7 percent

Other studies have identified specific high-risk F8 variants in individuals with mild to moderate hemophilia A such as the C2 domain Trp2229Cys mutation and the Arg593Cys mutation [30,31].

As noted below, there are several normal F8 polymorphisms that do not cause hemophilia and may be distributed differently in individuals of different races; these may contribute to different rates of inhibitor development (eg, due to minor antigenic differences between endogenous factor VIII and the factor VIII protein sequence in the replacement product) [32]. (See 'Replacement product' below.)

Data are much more limited for hemophilia B, but they confirm a greater frequency of inhibitors in those with severe disease [33]. In a sequencing study, complete F9 gene deletions conferred a higher risk than truncating mutations, partial deletions, or missense mutations [34].

●Immune response genes – Development of inhibitors is an immune phenomenon, and some data have suggested that genes involved in the immune response to foreign proteins may contribute to inhibitor development [5]. As an example, the Hemophilia Inhibitor Genetics Study (HIGS) evaluated genes involved in immune regulation among 104 sibling pairs with hemophilia A who were discordant in inhibitor status [35]. As siblings, these individuals had the same F8 mutation. Analysis of single nucleotide polymorphisms (SNPs) demonstrated variations in 13 immune response/immune modifier genes that correlated with inhibitor development. Other studies have implicated specific genes including those that encode human leukocyte antigen (HLA) class II antigens, interleukins, tumor necrosis factor (TNF)-alpha, and/or cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) [36-41].

A prospective study in previously untreated patients with hemophilia A found different classes of immune responses during the first 50 exposure days, some of which correlated more strongly with inhibitor development (eg, development of IgG3 against factor VIII) [42].

●Other genetic contributions – There may be other as yet undefined genetic factors that influence inhibitor development. This possibility is suggested by case-control studies that have found increased rates of inhibitors in individuals with a family history of inhibitors [24,30,43].

●Race and ethnicity – Individuals with African ancestry or Hispanic ethnicity have a higher rate of inhibitor development compared with White people. A study from the Centers for Disease Control (CDC) in the United States that reported on the prevalence of inhibitors among 5651 people with hemophilia A found the following prevalence of inhibitors in different races/ethnicities [44]:

•Black people – 27 percent

•Hispanic people – 25 percent

•Non-Hispanic White people – 16 percent

Other studies have reported significantly higher inhibitor prevalences in Black people and people from Asian countries with hemophilia. As an example, a study involving 460 families in the Malmo international brother study (388 families with hemophilia A and 72 families with hemophilia B) reported inhibitors in 56 percent of Black people and 27 percent of White people [45]. The incidence of inhibitors in this study was as high as 50 percent in individuals with Asian, Indian, or Hispanic ancestry. In hemophilia B, a review from a large United States database (3800 patients) found that the OR for inhibitor development was 2.8 for Black people (95% CI 1.4-5.5) and 1.7 for individuals with Hispanic ethnicity (95% CI 0.7-3.7) [33]. A report from the Japan Hemophilia Inhibitor Study identified inhibitors in 32 percent of people with severe hemophilia A, 7 percent with moderate hemophilia A, 2 percent with mild hemophilia A, and 15 percent with severe hemophilia B [46].

Race or ethnicity may be a surrogate for biologic differences that affect the immune response and/or for differences in medical care.

Another connection between race and inhibitor development may involve mismatch between the amino acid sequence of the factor present in the replacement product and the endogenous factor in the recipient that could make the recipient's immune system more likely to recognize the replacement factor as foreign and generate an immune response. In a study that sequenced the F8 gene in 78 Black people with hemophilia A who had developed inhibitors, the people with inhibitors were more likely to have endogenous factor VIII amino acid sequences that differed from the amino acid sequence in the recombinant factor VIII replacement products that were available at the time [32]. (See 'Replacement product' below.)

●Age – Age-associated changes in immune function may also affect inhibitor development. However, in children, age-related changes are complicated by age-related increases in the number of exposure days, making it challenging to distinguish between endogenous immune responses and effects of factor exposure. The risk changes beyond the age of 60 years due to loss of immune surveillance [47]. (See "Immune function in older adults".)

The correlation between age at which prophylaxis is initiated and risk of inhibitor development is complex, as discussed below. (See 'Therapy considerations' below.)

Many of these studies are affected by different frequency of inhibitor testing, making cross-study comparisons difficult.

Therapy considerations — Therapy-related factors that may influence inhibitor development in susceptible individuals include the source, purity, and formulation of the replacement product (eg, plasma-derived versus recombinant, full-length versus modified factor sequence, presence of von Willebrand factor [VWF] or other proteins) and the intensity of treatment (eg, dose, number of exposure days) [5].

In hemophilia A, the use of emicizumab may delay the emergence of an inhibitor by reducing exposure to exogenous factor VIII. Emicizumab is not a factor VIII product and does not contain similar epitopes. However, in high risk or susceptible individuals, the incidence of inhibitor emergence is not yet established when emicizumab is started early in life; at this time, it is unknown if the incidence of inhibitor development is less, the same or increased over time when exposure to factor VIII is delayed. The development of a method in infants and very young children to use emicizumab for bleed prevention and controlled factor VIII exposure to decrease the incidence of emergence of inhibitors are not established and require prospective study.

For individuals treated with replacement factor, the age at which factor replacement is initiated and switching products do not appear to have a major role in inhibitor development; however, the age does tend to correlate with number of exposure days, which does affect inhibitor risk. (See 'Intensity of therapy (dose, schedule, number of exposure days)' below and 'External/environmental factors' below.)

Replacement product — There are a number of factor concentrates, including plasma-derived of various purities as well as recombinant products that contain various genetic sequences and/or sequence or other modifications to prolong half-life, and that are made with a number of different cell culture systems and purification protocols. Some plasma-derived products also contain VWF. At this time, it is not possible to identify a "best" factor replacement product that has all the optimal attributes for each patient. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Available products'.)

As each of the replacement products has become available at different times, and practices have varied over time and place, comparison with historical controls is especially difficult. There is only a single large randomized trial comparing different products (the SIPPET trial), and no trial has compared all available products with each other.

The 2016 Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) trial remains the only prospective randomized trial comparing replacement products. SIPPET randomly assigned 264 children under the age of six years with severe hemophilia A (factor VIII <1 percent) and no or minimal previous factor therapy to receive a recombinant factor VIII product or a plasma-derived factor VIII product containing VWF, and followed them for up to 50 exposure days or three years after randomization, whichever came first [48]. Importantly, the treatment regimen (prophylaxis versus on-demand) was at the discretion of the treating clinician, and long-acting products were not included. The primary outcome was development of any inhibitor with a titer of at least 0.4 Bethesda units (BU) using a centrally performed assay (Nijmegen method). Secondary outcomes included development of high titer inhibitors (≥5 BU). The majority of patients were enrolled from India, Egypt, and Iran, with smaller numbers from the United States, Italy, and other countries.

The peak timing of inhibitor development in SIPPET participants was during the first 15 exposure days. Inhibitors developed in a higher percentage of the those treated with the recombinant factor product (47 of 126 individuals who received recombinant factor VIII [37 percent] versus 29 of 125 individuals who received plasma-derived factor VIII with VWF [23 percent]; hazard ratio [HR] for recombinant products 1.87) [48]. The results remained essentially the same when analyzed after removing data on second-generation products, which previously had been suggested to have an increased risk of inhibitor development. High titer inhibitors were also more frequent in the recombinant factor VIII arm (24 versus 16 percent).

There were two deaths, both in the plasma-derived factor VIII with VWF arm (one from bleeding and one motor vehicle accident) and nine episodes of severe bleeding (six in the recombinant factor VIII arm and five in the plasma-derived factor VIII with VWF arm). The rate of prophylaxis (rather than on-demand therapy) was slightly higher in the recombinant factor VIII arm (55 versus 51 percent).

There has been great interest in determining the generalizability and clinical application of the SIPPET results, as noted by the study's authors [49]. A more challenging question is whether the results can be generalized to other recombinant factor products (eg, third-generation or extended half-life products, versus the specific first-, second-, and third-generation recombinant products used in the trial) [50]. The following conclusions seem reasonable:

●For all patients, the choice of product is complex and must balance a number of benefits, risks, and burdens. For those who require treatment with a factor replacement product for prophylaxis or treatment of bleeding, we individualize the choice of product based on the patient's circumstances and needs, following an open discussion with the patient regarding data on specific products and patient values and preferences.

●All inhibitors in the SIPPET trial occurred before 39 exposure days, and all high titer inhibitors occurred before 34 exposure days. Thus, for individuals with hemophilia A who are receiving a recombinant factor VIII product, who have not developed an inhibitor, and who are past the high-risk exposure period, switching to a VWF-containing plasma-derived product is not indicated for reducing inhibitor risk.

●Analysis of each specific recombinant product used in the trial did not alter the initial findings [49]. However, the trial did not include some of the recombinant products that have subsequently become available, which appear to have an inhibitor rate that may approach that seen with factor VIII plus VWF-containing products. Thus, the decision to avoid exposure to recombinant products during the early phases of treatment requires a discussion between the family and provider.

The Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation (NHF) in the United States and the European Medicines Agency have not advocated a change to plasma-derived products based on the results of the SIPPET trial [51-53]. (See 'Society guideline links' below.)

The mechanism of increased risk of inhibitors with certain recombinant products is unknown. The plasma-derived products studied in the SIPPET trial contained VWF and other plasma proteins and are likely to differ in post-translational modifications from the recombinant products used in the trial, which were manufactured from non-human cell lines. It is possible that VWF may mask epitopes on the infused plasma-derived factor VIII or may protect factor VIII from endocytosis by antigen-presenting cells [54]. However, not all plasma-derived products contain VWF, and some recombinant products are made in human cell lines; the impact of these differences on inhibitor development is unknown.

Further trials using the newer-generation recombinant products made in human cell lines and those with extended half-lives are being conducted. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Factor VIII products for hemophilia A' and "Hemophilia A and B: Routine management including prophylaxis", section on 'Products for hemophilia B'.)

Prior to the SIPPET trial, information on inhibitor development with recombinant products was obtained in the 2013 Research Of Determinants of INhibitor development among previously untreated patients with haemophilia (RODIN) study, which prospectively evaluated 574 children with severe hemophilia A [55]. Inhibitors developed in 32 percent (high titer inhibitors in 22 percent). The risk of inhibitor formation was higher with second-generation full-length recombinant products compared with third-generation recombinant products (adjusted HR 1.60; 95% CI 1.08-2.37); however, the implications of this finding were less clear due to lack of randomization and small numbers of patients.

While observational studies may show lower numbers of inhibitors with different products, this should not be interpreted to demonstrate a causal effect, as confounding factors (differences in patient groups, choice of product, and others) may have affected the results [56-59].

Intensity of therapy (dose, schedule, number of exposure days) — The dose and schedule at which the factor product is administered is reflected in the number of exposure days (each exposure day is a day on which the patient received one or more factor infusions) (see 'Terminology and definitions' above), which is a strong predictor of inhibitor development.

●Hemophilia A – The majority of inhibitors typically develop during the first 20 exposure days, as illustrated in the following studies:

•Severe disease – In the SIPPET trial (randomized trial of recombinant versus plasma-derived factor VIII in 264 children with severe hemophilia A), all inhibitors developed before exposure day 39, and 90 percent occurred before exposure day 20; for high titer inhibitors, all occurred before exposure day 34 and 90 percent before exposure day 16 [60].

In the FranceCoag cohort (395 children with severe hemophilia A), the median number of exposure days at inhibitor detection was 14, and the greatest percentage of inhibitors developed before exposure day 25 [57].

•Mild to moderate disease – In the INSIGHT study, inhibitor development was assessed in 1112 people with mild to moderate hemophilia A (factor VIII levels 2 to 40 units/dL) who were treated with factor VIII, 59 of whom developed inhibitors [61]. Of these, 41 (69 percent) developed an inhibitor before 50 exposure days, 17 (29 percent) developed an inhibitor between 50 and 100 exposure days, and one developed an inhibitor after 100 exposure days. The cumulative risk of inhibitor development was calculated as 5 percent at 28 exposure days, 7 percent at 50 exposure days, and 13 percent at 100 exposure days.

●Hemophilia B – There are fewer data to use in determining the correlation between the number of exposure days and inhibitor development in individuals with hemophilia B. In a review of the 88 patients in the international hemophilia B database, those who developed inhibitors did so at a median of 11 exposure days [62].

However, dose intensity is not simply the number of exposure days. As an example, dosing twice daily for three consecutive days after a serious bleed is more intense than dosing once every other day for three days of prophylaxis, yet both are counted as three exposure days. Thus, dose intensity may constitute a separate consideration over and above the number of exposure days. Dose intensity may be a surrogate for other factors that may affect the immune response, such as the degree of tissue injury. (See 'Patient characteristics' above and 'External/environmental factors' below.)

If an individual requires factor administration for surgery or to treat bleeding, factor should not be withheld to reduce the risk of inhibitor development. Data are conflicting regarding whether the risk of inhibitors changes with continuous infusion versus intermittent dosing. Some studies have suggested that continuous infusion increases inhibitor rate and others have suggested the opposite [63,64]. Thus, we do not favor or disfavor continuous infusion; we use the therapy that is deemed optimal for hemostasis for the specific patient. (See "Treatment of bleeding and perioperative management in hemophilia A and B".)

Age at which factor prophylaxis is initiated — The age at which factor replacement is initiated is challenging to separate from the severity of disease. Starting prophylaxis early may reduce inhibitor development, especially if there is ongoing exposure without danger signals such as repeated exposures in the absence of surgery, trauma, or spontaneous bleeding. However, this must be balanced with the burdens of routine intravenous therapy in a young infant or child. This paradigm has begun to change with the introduction of emicizumab for hemophilia A. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Age of initiation and dosing schedule'.)

Although not addressed in a randomized trial, the effect of age at first treatment seems to be a marker for other risk factors rather than an independent risk factor for inhibitor development. Two studies demonstrated that age at first treatment did not correlate with inhibitor development after adjustment for other factors:

●In a case-control study involving 108 children with hemophilia A, there was a trend towards greater likelihood of inhibitor development when factor was started at a younger age (<11 months versus ≥11 months), but this trend was no longer present after adjusting for genetic factors [24].

●In the Concerted Action on Neutralizing Antibodies in severe hemophilia A (CANAL) study, which retrospectively investigated 366 patients with hemophilia A, the rate of inhibitor development appeared to correlate with age at first replacement therapy, but the effect disappeared after adjustment for treatment intensity [25].

Switching factor products — There are multiple studies that address the role of switching factor products in inhibitor development; none of these support an increased risk of inhibitor development due to switching products in previously treated patients with >50 exposure days [65-67]. As an example, in an observational study in which all patients with hemophilia A in Ireland (113 individuals) were switched from one recombinant factor VIII product to another, only one developed a new inhibitor; this was a one-year-old boy who had only received three doses of the previous product and was therefore at high risk for inhibitor development [68].

If antibodies form in multiply-exposed patients who have been changed to a new product, it is reasonable to investigate product-related factors [65,69,70]. In this case, consideration should be given to the use of the prior product if the patient has had many exposure days in the past, although change to the prior product may not always result in inhibitor disappearance.

External/environmental factors — Some studies have suggested that the degree of injury or tissue damage present at the time of factor infusion may contribute to the immune response to the factor (ie, the "danger theory") [5,71]. This is consistent with data in other (non-hemophilic) disease states that suggests the presence of damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) may engender an increased immune response [72]. (See "An overview of the innate immune system", section on 'Microbial detection through pattern recognition'.)

More severe injury is likely to accompany major bleeding and/or surgery. Investigators in the RODIN study used the dose of factor VIII as a surrogate for more severe injury and analyzed the rate of inhibitor development relative to the factor VIII dose intensity in a subset of previously unexposed children given factor VIII [73]. High-intensity factor treatment was associated with an increased risk of inhibitor development (adjusted HR 2.0; 95% CI 1.3-3.0), while prophylactic therapy was associated with a lower risk (adjusted HR 0.61; 95% CI 0.35-1.1).

While these findings suggest a potential mechanism, they should not be interpreted to advocate the use of less intensive treatment of severe bleeding. Bleeding is treated with factor infusions or bypassing therapy, as discussed separately. (See "Treatment of bleeding and perioperative management in hemophilia A and B", section on 'Acute therapy for bleeding'.)

Several observational studies have found no correlation between administration of routine vaccinations (eg, influenza vaccine) and inhibitor development [24]. Preclinical studies suggest vaccinations may be associated with a lower risk of inhibitors [74].

Risk score (hemophilia A) — Data from a cohort of consecutive patients with severe hemophilia A in the CANAL study were used to develop a risk score for the development of factor VIII inhibitors based on three risk factors [75]:

●Family history of inhibitors – 2 points

●High-risk gene mutation – 2 points

●Intensive treatment at first bleeding episode – 3 points

In the initial study cohort (332 patients), inhibitor incidences for individuals with risk scores of 0, 2, or ≥3 points were 6, 23, and 57 percent, respectively. Similar incidences were noted in a validation cohort of 64 patients. This score requires that the patient be treated and the genetic change identified, a disadvantage when trying to predict the risk of inhibitor development in individuals who have not been exposed to exogenous factor VIII.

EPIDEMIOLOGY — Inhibitors are more common in hemophilia A than in hemophilia B, with overall prevalence in individuals with severe disease as follows:

●Hemophilia A – Approximately 20 to 30 percent [76-82]

●Hemophilia B – Approximately 1.5 to 3 percent or higher [33,62,77,78,83]

The incidence of inhibitors is highest in individuals with severe disease during the first 50 factor exposure days, although individuals with mild to moderate disease can also develop inhibitors. It has been hypothesized that the presence of some circulating factor IX in most people with hemophilia B may result in a greater likelihood of immune tolerance and may partially explain the lower prevalence of inhibitors [62].

Exposure to emicizumab does not alter the inhibitor rate in factor VIII deficiency, but an indirect effect is possible (reduced inhibitor rates due to fewer exposure days in very young patients); the impact of this shift in prophylactic strategy is under study.

Certain groups such as Black Americans and individuals with Asian, Indian, or Hispanic ancestry, have higher inhibitor rates (up to 50 percent in those with severe hemophilia A and 5 percent of those with severe hemophilia B) [33,84]. (See 'Predisposing influences' above.)

TYPICAL PRESENTATION — Some inhibitors may be clinically silent, especially in hemophilia A, and may not lead to a marked increase in the frequency or severity of bleeding. These inhibitors may be identified when the response to infused factor is inadequate (when factor infusion does not increase factor activity level and/or does not cause bleeding to stop). In a prospective surveillance study in the United States that enrolled 1163 individuals with hemophilia A or B, 23 new factor VIII inhibitors were identified, and of these, 14 (61 percent) were clinically silent [85]. These data underscore the need for ongoing routine inhibitor surveillance in hemophilia. (See 'Routine screening and preoperative testing' below.)

A patient receiving prophylactic factor infusions who develops an inhibitor may experience new breakthrough bleeding or may have poor or delayed resolution of bleeding. Patients with inhibitors may also have altered pharmacokinetics of the replacement factor, which may result in impaired hemostasis and an increased rate of musculoskeletal complications. Over time, inhibitors alter the disease course; affected individuals have poorly controlled joint bleeding and develop target joints, with subsequent increased bleeding in these joints due to acute and chronic synovitis [86]. An inhibitor should be suspected when any bleeding episode is refractory to usual therapy, particularly in patients with severe hemophilia.

Individuals with mild or moderate hemophilia (factor activity between 1 and 40 percent) who develop inhibitors that crossreact with their endogenous factor may be converted to a more severe state, likely through an immunologic phenomenon known as epitope spreading. These inhibitors do not affect baseline factor levels but do impact response to therapy, as they only recognize the infused factor.

High titer inhibitors typically rise at approximately five to seven days after exposure to factor, peak at 7 to 21 days, and may persist for years, even in the absence of re-exposure [87,88].

Individuals who develop inhibitors may have an infusion reaction in response to factor administration, although this is uncommon in hemophilia A. More commonly in hemophilia B, individuals who develop inhibitors may have other manifestations such as allergic-type reactions to factor infusions, typically IgG-mediated, and/or nephrotic syndrome during immune tolerance induction (ITI). (See 'Immune tolerance induction' below.)

SCREENING AND EARLY DIAGNOSIS — Early detection of inhibitors is important, both to be aware of the inhibitor when selecting products to treat bleeding, as well as to facilitate early consideration of inhibitor eradication or switching to a different product for prophylaxis. These decisions are discussed separately. (See "Treatment of bleeding and perioperative management in hemophilia A and B", section on 'Inhibitors' and "Hemophilia A and B: Routine management including prophylaxis", section on 'Overview of decision-making'.)

Routine screening and preoperative testing — Experts generally agree that individuals should be screened periodically for inhibitors and tested for inhibitors prior to surgery and/or if factor infusions do not produce the expected increase in factor levels. Surveillance is a best practice approach because in many cases it is the only way to determine whether an inhibitor has developed. Guidance has been provided by the United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO), which recommends surveillance and testing for inhibitors as follows [47]:

●Hemophilia A – For severe disease, at least every third exposure day or every three months (whichever is sooner) until 20 exposure days have been reached; then every three to six months until 150 exposure days have been reached. For individuals receiving prophylaxis, it may be more practical to measure the trough factor level every three to six months from exposure day 20 until 150 exposure days and only test for an inhibitor if the trough factor level is lower than expected. After exposure day 150, inhibitor testing should continue one to two times per year indefinitely.

For moderate or mild disease, test annually if exposed to factor as well as after any intensive factor exposure (eg, at least five exposure days) or after any surgery. More intensive surveillance may be appropriate if there is a factor VIII variant with a reported increased risk of inhibitor development. (See 'Patient characteristics' above.)

●Hemophilia B – Be aware of the specific factor IX variant and its inhibitor risk. For severe disease, screen at least every third exposure day or every three months (whichever is sooner) until 20 exposure days have been reached; then every three to six months until 50 exposure days have been reached. After exposure day 50, inhibitor testing is decreased and may not needed unless clinically indicated; no factor IX inhibitors have been reported beyond exposure day 150. Some experts may change the cutoff to exposure day 50, as few factor IX inhibitors emerge beyond 50 exposure days.

A 2015 United States guideline from the International Immune Tolerance Induction Study Investigators and 2015 guidance from the National Hemophilia Foundation (NHF) Medical and Scientific Advisory Council (MASAC) concur with this approach to inhibitor screening [89,90].

These guidelines also note that additional inhibitor testing is appropriate in individuals with hemophilia A or B in selected circumstances such as the following:

●Before elective procedures that may require factor administration

●If the clinical or laboratory response to factor infusion is suboptimal

●If the patient has an infusion reaction or allergic reaction to factor administration

●If the patient has an increase in bleeding manifestations (increased severity or frequency of bleeding)

While not addressed by guidelines, it is also important to monitor inhibitor titers in individuals with hemophilia A with inhibitors who are receiving emicizumab prophylaxis, especially before elective surgery. This is because inhibitor titers in these individuals may decline to undetectable levels, in which case there is a window during which factor infusions can be used to treat or prevent bleeding in emergency situations such as in trauma, severe bleeding, or after a planned surgery in which bleeding was not controlled by standard therapy. Typically, there is an approximately five- to seven-day window before the anamnestic immune response occurs and the inhibitor titer rises. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Emicizumab for hemophilia A'.)

A 2015 expert report from the Centers for Disease Control (CDC) in the United States stated that inhibitors are generally under-reported [91]. In an analysis of 12,851 people with hemophilia in the Universal Data Collection surveillance system, only 39 percent of the data forms indicated that inhibitor testing had been performed (average of 46 percent for those with severe hemophilia).

Inhibitor diagnosis and characterization (titer) — Inhibitors may be detected on routine screening, preoperative testing, or testing for a clinical indication such as inadequate response or allergic reaction to factor infusion, as discussed above. (See 'Routine screening and preoperative testing' above.)

Ideally, inhibitor assays are done after a washout of infused factor, when the individual is at their baseline factor level (eg, at least 48 hours after the last dose of factor VIII or 72 hours after the last dose of factor IX for standard half-life products; longer for extended half-life products) or at the trough before the next factor dose [1,47]. This is because infused factor may mask or quench a low titer inhibitor. Heat treatment may be used to test for the presence of endogenous factor if there is strong suspicion for this quenching phenomenon.

The diagnosis of an inhibitor is made using a Bethesda assay, which both identifies the inhibitor and quantifies it. The assay principle uses serial dilutions of patient plasma incubated at 37ºC with pooled normal plasma and measures factor activity using an activated partial thromboplastin time (aPTT)-based assay [92]. Typically, the Nijmegen modification is used (ie, the Nijmegen-Bethesda assay [NBA]); the NBA is considered the gold standard for inhibitor testing [1]. The Nijmegen modification further standardizes the pH and protein concentrations in the assay, which improves specificity and reliability, especially at low inhibitor titers [93,94].

Importantly, this type of aPTT-based assay cannot be used to diagnose or quantify inhibitors in individuals receiving emicizumab. Emicizumab will normalize the aPTT despite the presence of an inhibitor, making it appear that the inhibitor is absent or of markedly lower titer than it actually is. For individuals receiving emicizumab, inhibitor titer must be measured with a bovine substrate chromogenic assay specific for factor VIIIa activity, similar to testing factor VIII levels on emicizumab. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Emicizumab for hemophilia A' and "Treatment of bleeding and perioperative management in hemophilia A and B", section on 'Patients with hemophilia A receiving emicizumab'.)

The titer of the inhibitor, expressed as Bethesda units (BU), is the reciprocal dilution of patient plasma that results in residual 50 percent factor activity. Thus, an individual with a titer of 20 BU is a much stronger inhibitor than one with a titer of 2 BU.

●A titer of ≥5 BU is considered a high titer inhibitor. Inhibitors that have demonstrated a high titer are considered high-responding inhibitors, even if the titer subsequently declines below 5 BU.

●A titer <5 BU despite repeated exposures to factor is considered a low-responding inhibitor.

An elevated inhibitor titer (typically defined as a level ≥0.6 BU per mL) should be confirmed promptly with a second sample, especially if the first sample was drawn through a heparinized line [1].

Sources of test interference in Bethesda assays include other antibodies such as a lupus anticoagulant (LA; an antibody that reacts with phospholipids in the clot-based assay and prolongs the aPTT). If testing reveals an LA, pharmacokinetic studies and serial testing over time may help determine whether a specific factor VIII inhibitor is also present [95]. The dilute Russell viper venom time (dRVVT) and/or IgG factor VIII antibodies may also be useful. Close consultation with the coagulation laboratory is important to ensure that appropriate testing is performed [95]. (See "Diagnosis of antiphospholipid syndrome", section on 'Antiphospholipid antibody testing'.)

Alternative approaches to inhibitor testing and quantification that use immunoassays to detect antibodies to factor are under development but are not in clinical use [96].

Communication of inhibitor status — It is crucial for clinicians caring for people with hemophilia to have current access to the latest information about their inhibitor status. If an individual with an inhibitor has serious bleeding (spontaneous or traumatic) or requires surgery, the details of their inhibitor status will determine pathways for management. Provision of a wallet card (available through a hemophilia treatment center) with accurate information and/or contact information for the individual's primary hemophilia caregiver facilitates provision of this information to people who do not have immediate access to the latest medical record information for the person with hemophilia.

In the United States, development of a new inhibitor should be reported to the US Food and Drug Administration MedWatch adverse event reporting system.

GENERAL PRINCIPLES OF MANAGEMENT

Follow best practices — Strategies for optimal care for individuals at high risk of inhibitor development (and for all individuals with hemophilia) may include one or more of the following [54]:

●Work collaboratively with the local comprehensive Hemophilia Treatment Center (HTC) to register the patient, test according to national standards, and determine the optimal factor replacement product and protocol.

•Global directory from the World Federation of Hemophilia (WFH) – https://wfh.org/find-local-support/#HTCs

•United States directory from the Centers for Disease Control (CDC) – https://www2a.cdc.gov/ncbddd/htcweb/Dir_Report/Dir_Search.asp

●Inform patients of the potential benefits of prophylaxis versus on-demand therapy and the risks and benefits of different factor products. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Overview of decision-making'.)

●Evaluate the possibility of a non-factor prophylaxis products (eg, emicizumab in hemophilia A). (See 'Alternative agents for prophylaxis' below and "Hemophilia A and B: Routine management including prophylaxis", section on 'Emicizumab for hemophilia A'.)

●In individuals with severe hemophilia B, be aware of their specific factor IX variant and its risk of inhibitor development, and ensure that the first 20 infusions of factor IX are administered in a setting with the capability for resuscitation in the event of an anaphylactic reaction, especially in those for whom there is no family history of hemophilia or when the genetic variant has not been identified [47].

Active bleeding and perioperative management — Individuals with high titer inhibitors (typically, ≥5 Bethesda units [BU]) generally require a bypassing agent or alternative product (eg, recombinant porcine factor VIII in hemophilia A) to treat active bleeding or to prevent surgical bleeding. Emicizumab is not used to treat active bleeding. Those with low titer inhibitors (<5 BU) may be treated with higher doses of factor calculated to overcome the inhibitor titer and provide a hemostatic level. These approaches are discussed in detail separately. (See "Treatment of bleeding and perioperative management in hemophilia A and B", section on 'Inhibitors'.)

Alternative agents for prophylaxis — For individuals with hemophilia A, another option for routine prophylaxis is emicizumab, a humanized bispecific monoclonal antibody that substitutes for the function of activated factor VIII in clotting and significantly reduces bleeding rates. This approach will reduce the exposure to factor VIII; however, exposure will need to be monitored and inhibitor titers evaluated to determine if an inhibitor is emerging in an at-risk individual. Details are discussed separately. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Emicizumab for hemophilia A'.)

Inhibitor eradication — Inhibitor eradication using immune tolerance induction (ITI) is appropriate for individuals with high titer inhibitors or high-responding individuals, as well as individuals with low titer inhibitors, as discussed below. (See 'Immune tolerance induction' below.)

IMMUNE TOLERANCE INDUCTION — Immune tolerance induction (ITI) is the principal method for inhibitor eradication [97]. It involves the administration of repeated doses of factor, typically without concurrent immunosuppressive therapy, to tolerize the individual's immune system to the factor and reduce antibody production. If initial ITI is unsuccessful, immunosuppression may be used.

Comprehensive Hemophilia Treatment Centers (HTCs) provide expertise for ITI and should be consulted for the development of any treatment plan in a hemophilic patient with an inhibitor.

Mechanisms by which ITI eliminates inhibitors are not completely understood [98,99].

Indications for ITI — The role of ITI continues to evolve:

●In the early days of ITI, therapy was often delayed until the inhibitor titer declined to <10 BU based on data that ITI would be more successful when the titer was lower at the start of ITI.

●Subsequently, a study reported that when ITI was started promptly after inhibitor detection, overall success rates were not dependent upon titer at start [100]. This strategy was based on the concept that the immune system might be more pliable during the early stages of the immune response, and that earlier intervention might facilitate an earlier resumption of prophylaxis and reduction of bleeding complications.

●With the introduction of emicizumab for prophylaxis and greater knowledge about the safe use of bypassing agents to treat bleeding, ITI concepts and strategies will need to be re-evaluated. In some cases, it may be best for the patient to defer ITI until the optimal circumstances for ITI have been reached for that patient, or perhaps indefinitely. A small series reported successful ITI performed concomitantly with emicizumab administration [101].In some cases, it may be best for the patient to defer ITI until the optimal circumstances for ITI have been reached for that patient; decisions about use of ITI are complex and require careful discussion with the patient and family/caregivers.

The indications for ITI are individualized depending on the other available options for prophylaxis and treatment for the individual patient.

We generally pursue ITI in the following individuals:

●Those with severe hemophilia A and an inhibitor with a titer ≥5 Bethesda units (BU) that is present on repeated measurements at least two weeks apart.

●Many individuals with hemophilia A and a low titer inhibitor that is present on repeated measurements, especially those for whom factor replacement is difficult to manage due to altered pharmacokinetics.

It may be reasonable to defer ITI in an individual with hemophilia A or B for whom other options for prophylaxis or treatment are available or working (eg, emicizumab for hemophilia A, bypassing therapies for hemophilia A or B) and for whom the costs and burdens of ITI are considered prohibitive [102]. We are increasingly likely to use emicizumab in individuals with hemophilia A who have developed an inhibitor.

However, we prefer recombinant activated factor VII (rFVIIa) as first-line therapy for bleeding in patients with inhibitors receiving emicizumab (see "Treatment of bleeding and perioperative management in hemophilia A and B", section on 'Bypassing products (rFVIIa products or FEIBA)'). Caution must be used regarding adverse effects of emicizumab plus a high dose of an activated prothrombin complex concentrate (aPCC). As an example, we would avoid using an aPCC at ≥100 units/kg in an individual receiving emicizumab. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Emicizumab for hemophilia A'.)

ITI may also be used for hemophilia B; use of ITI for these individuals is complex because the success rate is lower, and those with an anaphylactic reaction will also require desensitization prior to ITI. In addition, high dose and frequent dosing of factor IX concentrates for ITI may predispose the hemophilia B patient to the development of nephrotic syndrome and/or membranoproliferative glomerulonephritis (MPGN) [103]. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis".)

If desired, a modified ITI regimen may be used in individuals receiving emicizumab (or bypass therapy). Use of emicizumab or bypassing agent prophylaxis in the absence of emicizumab may decrease the frequency of breakthrough bleeding. However, it is important that emicizumab and bypassing agents should not be given concurrently. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Emicizumab efficacy and adverse events'.)

Regardless of whether or not ITI is performed, it is imperative that the clinicians caring for the patient know the patient's inhibitor status and how to treat serious bleeding (spontaneous, traumatic, or surgical) and that care is coordinated with an HTC. (See 'Communication of inhibitor status' above.)

General considerations for ITI — ITI is challenging for the child/patient, parents/caregivers, and clinical team. The typical protocol for ITI involves administration of factor at regular doses for several months. Most patients require insertion of a central venous catheter for this procedure (if not present already). Some patients may have an initial anamnestic response with an increase in titer, and, in optimal circumstances, followed by a decline in titer to undetectable [104]. In addition, bypassing agent prophylaxis or emicizumab may be used to decrease the rate of intermittent breakthrough bleeding in some patients undergoing ITI.

For those with successful ITI, the typical duration of therapy to achieve tolerance is approximately one year, with a wide range of time periods reported to be required. In the international ITI study, which included good-risk patients (eg, young, inhibitor present for a short duration, no previous failed ITI attempts), the median time from start of ITI to a negative inhibitor titer was five to nine months, from negative titer to first normal factor recovery was 7 to 14 months, and from normal recovery to tolerance was 11 to 16 months [105]. Relapses can occur (six of 66 individuals in this study; two transient and four permanent). Attempts should be made to continue the therapy uninterrupted, as lapses in therapy may adversely affect success.

The success of ITI may be affected by a number of variables including the following [47]:

●Titer of inhibitor – The historic peak titer and titer at the start of ITI had been reported to influence ITI success, with a 2013 guideline from the United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) suggesting that success with ITI was greatest for individuals with a historic peak titer of <200 BU and a titer at the start of ITI of <10 BU/mL [47]. However, in a later study in which 39 individuals underwent ITI for a high-responding inhibitor and mostly started within one month of inhibitor detection, a titer >10 BU did not interfere with the success of ITI [100]. Thus, the optimal approach is unknown. We generally start ITI as soon as possible, rather than waiting for the titer to decline; however, this may change with increasing use of emicizumab based upon the age of the patient, the presence of a central venous access device, and the patient's and family/caregivers' risk/benefit calculations.

●Timing – Earlier initiation of ITI may also improve success rates. In a retrospective study involving 39 individuals who underwent ITI for a high-responding factor VIII inhibitor, those who started within one month of inhibitor detection had a success rate of 96 percent (defined as ability to use factor concentrates for bleeding), whereas those who started ITI after more than six months had a success rate of 64 percent [100]. Earlier studies documented a better response if ITI was initiated within five years of inhibitor detection rather than >5 years after detection [47].

●Dose – A wide range of factor doses have been used for ITI in hemophilia A. The international ITI study randomly assigned 115 good-risk children <8 years with severe hemophilia A and high titer inhibitors to receive ITI using high-dose factor VIII (200 units/kg once per day) or low-dose factor VIII (50 units/kg three times per week) [105]. Randomization was done after their inhibitor titer declined to <10 BU, which took an average of 5.5 months. ITI therapy was given for 9 to 33 months, with inhibitor titers checked once per month. A relatively large number were withdrawn from the study or lost to follow-up. Of 66 evaluable participants, 46 (70 percent) developed tolerance, with a similar success rate in both the high- and low-dose groups; however, the study was stopped early as the low-dose group had more breakthrough bleeding. The high-dose group tended to reach success milestones more quickly. Earlier observational studies suggested a higher success rate with higher doses of factor VIII [106].

●Race – Data on altering practice for individuals of African ancestry or Hispanic ethnicity is extremely limited [44]. A small retrospective study in 31 individuals with hemophilia A reported that ITI was more successful in non-African Americans than in African Americans (92 versus 58 percent success, respectively) [107]. However, the ITI was mostly done with recombinant products, which may differ in sequence from the F8 variants in African Americans (see 'Patient characteristics' above). A subsequent study (completed by 66 participants) did not detect an effect of race on the success of ITI [105]. More study of this subject is needed, but race should not limit the provider's decision to offer ITI.

ITI has a higher success rate in hemophilia A compared with hemophilia B. In a report from the North American Immune Tolerance Registry that included 188 courses of ITI, the overall success rate was 70 percent in hemophilia A and 31 percent in hemophilia B [108]. As noted above, comprehensive hemophilia treatment centers provide expertise for ITI and should be consulted for the development of any treatment plan in a hemophilic patient with an inhibitor.

ITI protocols for hemophilia A — A variety of ITI protocols have been used in hemophilia A with various doses and frequencies of factor VIII administration; these are summarized in a number of treatment guidelines and expert reviews from around the world [90,105,109-111]. Guidelines for ITI published by the UKHCDO are available and are updated periodically [47].

Our general approach is as follows, but this is only meant to serve as a general guide and is not meant to take the place of close consultation with the local hemophilia treatment center or other ITI expertise:

●We generally use a higher dose of factor VIII such as 100 to 200 units/kg, given as a single daily dose or in divided doses (eg, 100 units/kg twice daily). Divided doses give more exposure but are not always feasible.

●We generally start with the product the patient had been receiving when the inhibitor developed.

●We generally provide a bypassing agent prophylaxis only to those with significant breakthrough bleeding.

●We generally monitor the inhibitor titer on a regular basis during therapy (usually every two weeks; at least once every four weeks).

●We generally continue therapy as long as there is evidence of an evolving response (eg, decline in inhibitor titer by at least 20 percent in a six-month period).

●For those who do not have a declining titer, we generally change therapy in one of the following ways:

•Increase the dose or frequency based upon initial regimen

•Change to a plasma-derived factor VIII concentrate that contains von Willebrand factor (VWF)

•Add an immunosuppressive agent such as rituximab and/or mycophenolate mofetil

•Discontinue therapy based upon patient preference

●We generally start tapering the dose once the post-washout titer is negative on two consecutive occasions and the post-factor infusion trough level is >1 percent.

For individuals with ongoing ITI, we generally reserve immunosuppressive agents such as rituximab and/or mycophenolate mofetil for those with high titer inhibitors that do not decline with a VWF-containing factor VIII concentrate. This approach reduces the likelihood of toxicities associated with rituximab (eg, infusion reactions, infections, hepatitis B virus reactivation); we do not use rituximab in individuals with hepatitis B virus infection. Data supporting the efficacy of rituximab are limited [112-115]. Data are even more limited with mycophenolate mofetil, but success has been described in case reports [116-118].

Adverse effects of rituximab are discussed in more detail separately. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)

ITI protocols for hemophilia B — ITI protocols for hemophilia B are similar to those used in hemophilia A, with two notable exceptions that may greatly complicate treatment:

●Allergic reactions – Many individuals with factor IX inhibitors have allergic reactions to factor IX infusions such as pruritus, hives, and/or severe anaphylaxis. In retrospective reviews, over half of the reported factor IX inhibitors have been associated with some degree of allergic manifestation [62]. In a series of 18 children with severe allergic reactions to factor IX, the median age at which reactions developed was 16 months and the median number of exposure days was 11 [119]. In another study, 26 percent of individuals with complete F9 gene deletions had allergic reactions [34].

A number of hypotheses have been proposed to explain this high rate of allergic reactions, including the smaller size of the factor IX protein and a greater discrepancy between the endogenous protein levels of factor IX and the protein load based upon doses used for replacement therapy, which is partially due to the larger volume of distribution of the factor IX protein (see 'Patient characteristics' above). Possible co-deletion of immune response modifier genes in individuals with F9 gene deletions has also been proposed [120].

Individuals with allergic reactions to factor IX infusions may need desensitization therapy prior to initiating ITI. This may involve skin testing and IV administration of gradually escalating doses or continuous infusions of factor IX in a monitored setting such as a hospital, under the direction of an allergist/immunologist, similar to that used for other hypersensitivity reactions and allergies [121,122]. These protocols are discussed in detail separately. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

●Nephrotic syndrome – In some cases, ITI for hemophilia B is complicated by the development of nephrotic syndrome. This phenomenon is typically associated with the allergic phenotype described above. Experience is limited, but features of this phenomenon appear to include development of a nephrotic picture approximately eight to nine months into the course of ITI using high-dose factor IX (100 to 325 units/kg per day), with periorbital edema, proteinuria, and low serum albumin [62]. Immune complexes may play a role. In one case, kidney biopsy demonstrated an appearance consistent with membranous glomerulonephritis [103].

Unlike typical childhood nephrotic syndrome, glucocorticoids generally are not effective therapy. The main treatment is to withdraw the protein (ie, discontinue factor IX).

These observations have led many experts to use a pre-ITI desensitization protocol in individuals with the allergic phenotype or to treat these individuals with a concomitant immunosuppressive agent such as cyclosporin, mycophenolate mofetil, dexamethasone, or intravenous immune globulin (IVIG); some avoid ITI in these individuals. Additional details of these approaches are described in case reports and treatment summaries [116,121-124].

As noted above, close consultation with the local hemophilia treatment center or other ITI expert is an essential component of the ITI approach in these individuals.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hemophilia A and B".)

SUMMARY AND RECOMMENDATIONS

●Definition – Inhibitors are antibodies directed against infused clotting factors that inhibit the functional activity or pharmacokinetics of the factor against which they are directed. (See 'Terminology and definitions' above.)

●Risk factors – Inhibitors occur most often in severe hemophilia (factor VIII or IX <1 percent). They are more common in hemophilia A than in hemophilia B and in individuals of African ancestry or Hispanic ethnicity (prevalence in severe hemophilia A in White people, 20 to 30 percent; in severe hemophilia A in Black people, up to 50 percent; in severe hemophilia B in White people, 1.5 to 3 percent; in severe hemophilia B in Black people, up to 5 percent). Risk factors include the specific genetic variant; "danger signals" to the immune system; immune response mediators; and details of prophylactic therapy (product, age at first dose of factor, intensity). (See 'Pathogenesis' above and 'Epidemiology' above.)

●Detection – Inhibitors may be clinically silent or discovered when factor infusions become ineffective in treating or preventing bleeding or in raising the factor level. Infusion reactions may occur, and factor IX inhibitors often cause allergic reactions to infused factor IX. Routine screening is appropriate. (See 'Typical presentation' above and 'Routine screening and preoperative testing' above.)

●Titer – Inhibitors are tested using the Bethesda assay (with Nijmegen modification). This establishes the diagnosis of an inhibitor and quantifies the titer. Titers ≥5 Bethesda units (BU) are considered high titer, and high titer inhibitors are considered high-responding, even if they subsequently decline to <5 BU. Knowledge of the most current inhibitor titer is essential, as this determines acute treatment of severe/life-threatening bleeding episodes.(See 'Inhibitor diagnosis and characterization (titer)' above.)

●Prevention – General best practices include working collaboratively with the local comprehensive hemophilia treatment center (HTC), discussing nonfactor prophylaxis options, and ensuring that individuals with hemophilia B have their genetic alteration identified and receive their first 20 factor IX infusions in a monitored setting with resuscitation capabilities. (See 'Follow best practices' above and "Hemophilia A and B: Routine management including prophylaxis", section on 'Emicizumab for hemophilia A'.)

●Elimination – If an inhibitor develops, immune tolerance induction (ITI) is used for eradication most commonly in factor VIII deficiency. The indications for ITI are evolving due to the availability of nonfactor products for prophylaxis in hemophilia A. Guidance from the local HTC or other ITI expert is essential. ITI can be conducted while an individual is receiving emicizumab; data are evolving. (See 'Immune tolerance induction' above.)

●Bleeding – Treatment of bleeding and surgery in individuals with inhibitors is discussed separately. (See "Treatment of bleeding and perioperative management in hemophilia A and B", section on 'Inhibitors'.)

●Chronic complications – (See "Chronic complications and age-related comorbidities in people with hemophilia".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges extensive contributions of Donald H Mahoney, Jr, MD to earlier versions of this topic review.