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Chapter 136 Inhibitors in Hemophilias 2025

the results of the recombinant FVIII trials showed that almost half development increases the incidence of inhibitors in comparison with
(11/23) of the inhibitors in the Kogenate trial were transient in plasma-derived preparations (37.2% vs. 23.2%; hazard ratio [HR],
nature, decreasing the prevalence of inhibitors upon extended obser- 1.87). The same effect was noted when the analysis was restricted to
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vation. A similar pattern was observed in the Recombinate trial; the high-titer alloantibodies. If the contrasting outcomes of the
alloantibodies disappeared in 14 of 22 study subjects who developed previous trials on the topic are considered, it appears difficult to
an inhibitor despite continued treatment, eventually reducing the foresee the influence of this study on the clinical practice.
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prevalence rate to 11.1%. The older studies likely missed these A longstanding issue has been that concerning the switch from
ephemeral inhibitors. A Dutch study suggested that although tran- one concentrate brand to another. This issue has been clarified by a
sient inhibitors may develop earlier during treatment with ultrapure study focused on the full-length and the B-domain recombinant
plasma-derived and recombinant FVIII concentrates compared with preparations that showed that switching was not associated with an
lower-purity plasma products, the overall risk for inhibitor develop- increased inhibitor development. 57
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ment is similar. The debate continues with conflicting results in
both PUPs and previously treated patients (PTPs). 44–46 A recent Mild Hemophilia
UKHCDO case-control study examined inhibitor occurrence over In patients with mild or moderate hemophilia A, inhibitors appear
25 years of observation and identified “high-intensity treatments” to develop at a cumulative incidence of 3% to 13%, commonly after
rather than the type of FVIII product as the main risk factor for periods of intense FVIII replacement associated with surgery or
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inhibitor development. Similarly an analysis of pooled data from inflammatory states. A recent, large international cohort study on
over 2900 hemophiliacs indicated that the duration of study observa- 1112 patients (median age 38, interquartile range [IQR] 18–56 years)
tion and follow-up and testing frequency for inhibitor presence, but evidenced a cumulative incidence of 5.3% after a median exposure
not the source or purity of concentrate, explained most of the differ- of 28 days, that increased to 6.7% at 50 and to 13.3% at 100 days.
ences in inhibitor development seen in earlier studies. 42 Most of the tested mutations (15/19) were located in the light chain,
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Proposed causes of variable immunogenicity among FVIII prod- evenly distributed among the A3, C1 and C2 domains. A particu-
ucts have included neoantigen formation during their manufacture larly risky mutation (T295A) was described in 3 of 16 patients
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and their content of von Willebrand factor (vWF) protein, which is (17%). This study suggests that the capacity for immune tolerance
present in low- and intermediate-purity plasma-derived products but in these infrequently treated individuals may be compromised with
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absent in recombinant FVIII concentrates. It has been suggested aging and that immune challenge with FVIII replacement should be
that vWF may interfere with FVIII-dendritic cell interactions, alter avoided whenever possible by using desmopressin (DDAVP) to
FVIII molecular conformation, or mask T- or B-lymphocyte epitopes. enhance endogenous FVIII activity levels. Continuous lifelong vigi-
The former scenario has been illustrated by the fact that some, previ- lance for the inhibitor occurrence is warranted, particularly after
ously low immunogenic plasma-derived FVIII concentrates were occasional, intensive FVIII exposure.
rendered more immunogenic after extra viral-attenuation steps were
added to their manufacturing processes. 48–50 However, when recom- Venous Access
binant FVIII products were administered to patients previously and A disturbingly high incidence of infections may occur in FVIII
extensively treated with lower-purity FVIII products, the rate of inhibitor patients with central venous access catheter devices
inhibitor formation was low, consistent with a low immunogenicity (CVADs), particularly those with external devices set for immune
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in this setting (relative overall risk for inhibitors, 0.8; for high-titer tolerance induction (ITI) (124 episodes in 41 patients). This fact
inhibitors 0.9; for plasma-derived products versus recombinant FVIII may be related to frequent, unprofessional catheter accessing related
products 1.0; for switching FVIII products, 1.1). 45,51 A large prospec- to the administration of replacement therapy. CVAD-associated
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tive, randomized study comparing the immunogenicity of vWF- infection did not seem to affect the ability to achieve tolerance. The
containing products with recombinant FVIII concentrates in PUPs presence of CVADs per se does not appear to be associated with
and minimally treated patients is ongoing. Nonetheless, most experts increased inhibitor formation. 47
believe that the risk for inhibitor formation with the various FVIII
concentrates is similar. Other Factors
Recently, clinical prediction models for inhibitor development in Other miscellaneous proposed environmental influences on inhibitor
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the pediatric and adolescence ages evidenced the fact that treaters development, such as breastfeeding and receiving replacement therapy
consider family history of inhibitors (and related major FVIII defects) during a vaccination course, remain to be confirmed as significant
and early intensive treatment as elements associated with a high risk, risk factors.
whereas early onset of prophylaxis and avoidance of elective surgery
were considered as factors that are associated with a low risk of
inhibitor development. Interestingly, the type of concentrate was not Pathobiology of Factor VIII Alloantibody
included in the prediction model. Though the results stemmed from Inhibitor Formation
the surveys are interesting, their probabilistic nature and the fact that
a number of minor risk factors were not considered suggests that Circulating antigens provided by the exogenous FVIII undergo initial
interventional studies including very large numbers of patients are endocytosis and subsequent proteolysis by antigen-presenting cells,
needed to validate these exercises, because combinations of risk and digested peptides bind to MHC II molecules for presentation to
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factors are many. T-cell receptor on CD4 T lymphocytes. Co-stimulation signals
A recent prospective study on the influence of treatment-related subsequently mediate differentiation of T-lymphocytes into either
determinants demonstrated that intensive on-demand treatment for T H 1 or T H 2 subsets. T H 2 cells secrete IL-4, IL-5, and IL-10 cytokines,
hemorrhage or surgery increased the risk, whereas prophylaxis which promote the synthesis of noncomplement-binding immuno-
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decreased the risk especially in patients with low-risk mutations. A globulins, predominantly IgG4, by B lymphocytes. IgG4-mediated
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similarly focused prospective study on inhibitor development humoral responses display the following features: (1) are unable to
showed that risky gene mutations, first treatment before the age of 3 form large immune-complexes, (2) have low potential of inducing
months, and the dose of FVIII had a significant impact whereas the immune inflammation, (3) are expressed in conditions of chronic
type of concentrate did not. antigen exposure and (4) maintain a “normal” half-life. These features
Recently, a prospective study focused to the type or brand of accord with the clinical observations of uncomplicated anamneses in
concentrate, either in PUPs or PTPs, demonstrated that different hemophiliacs and account for an inhibitor half-life in the range of
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concentrates failed to elicit inhibitors with different cumulative 25–30 days. Interestingly, IgG4 subclass antibodies (either inhibit-
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incidence or incidence rates. In contrast with this study, Peyvandi ing or noninhibiting) are absent in hemophiliacs without inhibitors
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et al, in PUPs, elegantly demonstrated that exclusive use of recombi- and in healthy subjects. Most recently it has been shown that the
nant FVIII during the period of maximum risk of inhibitor presence of anti-FVIII IgG1 subclass may herald the appearance of