The development of anti-FVIII neutralizing alloantibodies (inhibitors), occurring in about one-third of .. Non-neutralizing antibodies against factor VIII and risk of inhibitor development in patients with severe hemophilia A A. L. Kreuger. Inhibitors in Nonsevere Hemophilia A: What Is Known and Searching for the . Caram-Deelder C, Kreuger A L, Evers D, de Vooght K M K, van de Kerkhof D. Aledort, L. M. and Goodnight, S. H., Hemophilia treatment: its relationship to Lello, C.J., Lazerson, J., and Kreuger, D., Impact of hemophilia home therapy R ., Treatment of hemophiliacs with inhibitors: cost and effect on blood resources in .

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Inhibitor development is currently the most significant treatment complication seen in patients with hemophilia and is associated with considerable morbidity and a decreased quality of life. The mainstay of treatment is henophilia eradication of the inhibitor through immune tolerance. This review summarizes the current evidence regarding inhibitor risk factors, eradication, and hemostatic bypassing agents.

Hemophilia A is the most common congenital severe bleeding disorder and is the result of a deficiency in the clotting protein factor VIII. FVIII inhibitors interfere with the infused factor concentrates rendering them ineffective and necessitating the use of more costly and less effective alternative hemostatic agents [ Di Minno et al. Inhibitor development is currently the most significant treatment complication seen in kreger with hemophilia. While improvements in hemostatic agents for patients with inhibitors have resulted in decreased mortality, inhibitors are still associated with significant morbidity, including a higher rate of bleeding complications, increased disability and a decreased quality of life[ Brown et al.

IgG4 antibodies are predominant and do not fix complement [ Fulcher et al. Antibodies can be either inhibitory or noninhibitory. Inhibitory antibodies are primarily directed against the A2, A3 and C2 domains [ Fulcher et al. These functional epitopes include FIX, phospholipid and von Willebrand factor interaction sites.

Antibodies in inhibitor patients can simultaneously target multiple FVIII epitopes and these epitope targets can change over time [ Fulcher et hemophipia. Type I inhibitors are more common in severe hemophilia. Type II inhibitors are more common in inhibitor patients with mild hemophilia or in patients without hemophilia who develop an acquired FVIII inhibitor. The residual factor VIII level of the incubation mixtures is measured.

The dilutions and residual factor VIII are plotted against each other and the inhibitor titer is obtained by linear regression [ Lee et al. There is also a high inter-laboratory variation in the quantitation of inhibitors with a high number of false-positive and false-negative results [ Meijer and Verbruggen, ]. This is likely secondary to a variation in how laboratories carry out their assays use a mix of the Bethesda and Nijmegen methods and a lack of a reference antibody standard [ Meijer and Verbruggen, ].

These assays are also better at detecting and krduger type I inhibitors than type II inhibitors. Enzyme-linked immunosorbent or fluorescent based immune assays can detect both inhibitory and noninhibitory antibodies and may have improved detection for low-titer inhibitors but further validation is needed to support widespread use [ Dazzi et al. The International Society on Thrombosis and Hemostasis Scientific and Standardization committee has recommended that an inhibitor titer of 5 BU differentiates low- from high-responding inhibitors [ White et al.

Prof Johanna (Anske) (J. G.) van der Bom MD PhD

An antibody titer that is persistently below 5 BU despite repeat challenges with factor VIII is considered a low-responding inhibitor. A high-responsive inhibitor is applied if the assay has been greater than 5 BU at any time [ White et al. Most patients develop an inhibitor within a relatively short time period of exposure with a median of 9—12 exposure days [ Addiego et al.

A recent study from the UK revealed a previously unrecognized bimodal peak of inhibitor risk in early childhood and old age [ Hay et al. Further studies are needed to investigate this late peak of inhibitor formation and the mechanism that underlie this. Factor VIII inhibitors can be detected either with routine laboratory testing or by clinical presentation.

An inhibitor is clinically suspected when a patient experiences bleeding that does not adequately respond to hemostatic therapy. It is also prudent to check an inhibitor titer prior to an invasive procedure to ensure adequate hemostasis. Currently there is no consensus regarding the routine surveillance for inhibitors.

Many providers check inhibitor titers at regular intervals within the highest risk period of the first 50 exposure days and then annually [ Kempton and White, ]. There can be drawbacks to routine surveillance, including the detection of transient inhibitors which can result in significant patient anxiety. It was discovered that there is endogenous restoration of the reading frame that results in a small amount of FVIII production that is likely sufficient to induce tolerance [ Young et al.


A recent meta-analysis of FVIII genetic mutation and inhibitor development included data from 30 different studies with a total of patients with severe hemophilia A [ Gouw et al.

To date, this is the largest study on FVIII genetic mutation and inhibitor formation providing more precise estimates of inhibitor risk.

Prof Johanna (Anske) (J. G.) van der Bom MD PhD – Prof Johanna (Anske) (J. G.) van der Bom MD PhD

Compared with the risk of inhibitor formation in inversion 22, large deletions and nonsense mutations had an increased inhibitor risk with an associated odds ratio OR of 3. The risk of inhibitor formation from intron 1 inversion OR 0. Patients of African or Hispanic hemophiliz have an increased risk of inhibitor formation [ Aledort and Dimichele, ; Astermark et al.

Early studies demonstrating these associations were criticized secondary to a lack of control for FVIII genotype. A recent study by Miller and colleagues when controlling for genotype still demonstrated an increased risk of inhibitor formation in patients of African or Hispanic descent [ Miller et al.

Critics of the study by Viel and colleagues report concerns regarding adequate control of confounding and how the mutational analysis was completed [ Eckhardt et al. Further studies are required to confirm this finding.

To date MHC phenotype has not consistently been demonstrated as a risk factor for inhibitor formation [ Astermark et al. Additional studies regarding Inhibitosr polymorphisms have revealed inconsistent results [ Bafunno et al. Variation in study results is likely secondary to study design and the specific hemophilia population that is being studied. Further studies are needed to confirm these findings.

Inhibitor formation is a complex immune response that depends not only on the genetic factors discussed previously but also on treatment-related risk factors.

Interpretation of the current studies regarding environmental risk factors is complicated secondary an retrospective designs, variable methodologies and lack hejophilia control for confounding factors. There are conflicting data regarding age at first treatment as a risk factor for inhibitor formation.

Additional studies that controlled for known confounders i. FVIII genetic mutation, treatment intensity were unable to inhkbitors an association with age [ Chalmers et al. It is likely that the association between inhibitor development and age of first factor exposure is explained by early intensive therapy [ Kempton and White, ].

Several studies have demonstrated an increased rate of inhibitor formation after intensive treatment i. However, a case—control study by Santagostino and colleagues did not confirm these findings [ Santagostino et al. Overall it does appear that there is an increased risk of inhibitor formation after an intense initial FVIII exposure.

This association is not a reason to withhold life-saving therapy but should prompt a clinician at the time of a significant early exposure to monitor closely for the development of an inhibitor. There is an ongoing debate regarding the immunogenicity of factor products with a concern that recombinant products have an increased risk of inhibitor formation over rkeuger of plasma-derived products. This increased immunogenicity is hypothesized to be secondary to alterations in posttranslational modifications of FVIII and a lack of von Willebrand binding [ Dasgupta inhibiotrs al.

There are conflicting reports in the literature that have led to this state of uncertainty. In comparing studies in previously untreated patients PUPs there is a difference in the overall reported cumulative incidence of inhibitor formation in plasma derived The difficulty in inhibitirs the cumulative incidence from these studies is the high degree of inhibigors in patient inhibitor risk factors, study methodology, frequency of inhibitor testing and length of follow up [ Mannucci et al.

Two recent systematic reviews attempted to control for this known heterogeneity, and were unable to demonstrate a difference in inhibitor formation [ Franchini et al. In the mreuger by Iorio and colleagues, study design, study period, testing frequency and median follow up explained most of the variability and the source of factor concentrate lost statistical significance [ Iorio et al.

To address this very important clinical question a prospective international hemo;hilia clinical trial SIPPET — Survey of Inhibitors in Plasma Product Exposed Toddlers is currently enrolling patients and is comparing inhibitor incidence in previously untreated patients exposed to either plasma or recombinant factor products [ Mannucci et al.

Two cohort studies, an Italian cohort and the CANAL concerted action on neutralizing antibodies in severe hemophilia A study, reported a kreger risk of inhibitor formation for patients receiving prophylaxis versus on-demand therapy [ Gouw et al. This was not confirmed in a cohort study from the UK [ Maclean et al. This study, however, has been criticized for not having contemporaneous controls, jnhibitors the quite spectacular results need to be confirmed in prospective studies.


Table 1 provides a summary of all the known current risk factors for inhibitor formation. Ter Avest and colleagues created a clinical scoring system that utilizes three clinical factors family history of inhibitor, iinhibitors mutation and amd treatment at initial exposure to predict inhibitor formation [ ter Avest et al. The risk score is cumulative and includes two points for a positive family history of inhibitors, two points for a high-risk gene mutation and three points if the initial FVIII treatment is intensive.

The limitations of this clinical scoring system include the use of a primarily white cohort and the lack of inclusion of other well established risk factors. While a risk score can help identify patients at the highest risk for inhibitor formation we are still left with a quandary as to how to effectively minimize this risk.


As mentioned previously, some propose the institution of early prophylaxis, although further data are needed to confirm these findings. Rivard and colleagues completed a prospective trial in 11 pediatric patients with severe hemophilia using recombinant factor VIIa to try and postpone exposure to FVIII until after 2 years of age [ Rivard et al. Owing to inadequate hemostasis with recombinant factor VIIa, especially in mouth bleeding, only 3 out of 11 children could postpone FVIII exposure until after 2 years of age [ Rivard et al.

Owing to the significant clinical ramifications of inadequate hemostasis in patients with high-titer FVIII inhibitors, the overarching therapeutic goal is eradication of the inhibitor. At this time ,reuger only proven method for eradication is immune tolerance induction ITI. There is currently no consensus regarding the specifics of ITI treatment, including the factor product source plasma derived versus recombinantfactor dose, timing or the use of immune modulation.

Multiple immune tolerance registries were established to help determine patient- and kreugr factors associated with immune tolerance outcome [ Coppola et al. This wide range in success rates is likely secondary to a lack of standardization in study methodologies, treatment protocols, and eradication definitions. Other predictors have been identified but have not been consistent across studies.

Table 2 provides a complete list of predictors for ITI. This study was stopped early secondary to increased bleeding events in the low-dose arm. There was no difference in the proportion of ITI success between the two arms but the time to achieve ITI success was shorter in the high-dose arm.

It appears that a high-dose strategy achieves tolerance at a faster rate and this may explain the associated decreased bleeding rate. Controversy also remains regarding the source of product for immune tolerance and the impact on ITI success.

The role of von Willebrand factor in achieving tolerance is unclear. The current published data are limited by small sample size, retrospective design and lack of control for known confounders. At this time the available evidence does not support the superiority of one product source over another for use heemophilia ITI. Although not common to most ITI protocols the use of immune modulation has been reported as a method to improve tolerance success.

The reported benefit appears to be decreased time to tolerance but the overall success rate is comparable to ITI protocols without the risks associated with immune modulation [ Berntorp et al. Recently there has been an interest in the use of the monoclonal anti-CD20 antigen rituximab that inhibits B cells and interferes with IgG production.

A phase II andd clinical trial used rituximab as a single agent kreugrr patients with high-titer inhibitors whose condition had failed to respond to prior ITI attempts. The results of this trial were presented as an oral presentation at the American Society of Hematology Annual Meeting [ Leissinger et al.

The authors reported that only 3 out of 16 subjects enrolled It appears that as a solo agent in patients previously treated with inhibitors, rituximab had a small effect but further studies are needed to determine if rituximab could be more effective if used with ITI.

Currently there is ongoing research in mouse models focusing on novel products kreugr methods to modulate the immune krfuger to factor VIII [ Miao, ; Waters and Lillicrap, ]. Multiple methods have been used to manipulate antigen presentation, including oral or nasal administration of FVIII peptides, infusion of immature dendritic cells or apoptotic fibroblast cells [ Qadura et al.

While these methods demonstrated a decrease in the immune response to FVIII they were unable to completely mitigate this response.