Most inhibitors develop during the first 20 days of factor exposure and are the result of a complex interplay of various
genetic and nongenetic factors.8 An understanding of the mechanisms of inhibitor development as well as associated
risk factors allows for heightened prevention strategies and risk stratification to improve outcomes.
A number of genetic risk factors for inhibitor development have been identified. The most extensively studied is the FVIII
gene mutation.8 Subsequent studies have found that the development of inhibitors corresponds with the type and location of F8 mutations.
In general, it is believed that patients with null mutations (large deletions, inversions, and nonsense mutations) are more susceptible
to developing inhibitors, while missense mutations are usually associated with a low risk of inhibitor development.8
The seminal Malmö International Brother Study established that a family history of inhibitor development is associated
with approximately a three-fold higher risk of inhibitor development. For reasons not yet completely understood,
there is approximately a two-fold increased risk of inhibitor development in non-Caucasian patients.8
Unlike genetic factors, environmental and treatment-related risk factors are potentially modifiable and may therefore offer the
hope of improved outcomes. Increasing evidence supports the concept of an immune response based on the “danger model.” In this model,
alarm signals arise from injured tissues, thereby activating the immune system and leading to inhibitor development.8 Danger conditions
include severe bleeds, trauma, and surgery that involves major tissue injury. When danger conditions are present, high-dose and/or
prolonged hemophilia treatment occurs in association with signals that upregulate cellular T and B lymphocyte response.8
The intensity of treatment at first factor exposure has been found to play a key role.8,11
...recent study results regarding prophylaxis and inhibitor development and how the findings will impact prophylaxis treatment guidelines.
The most controversial treatment-related risk factor is the type of FVIII concentrate administered. There have been mixed study results
concerning the incidence of inhibitor development with recombinant versus plasma-derived factor concentrate.
The CANAL study by Gouw and
colleagues found no significant difference in the risk of inhibitor development between pdFVIII and rFVIII products,
nor did switching between factor products appear to confer additional risk.8,11 These results are at variance with the prospective long-term
rFVIII registration studies, however, which clearly showed an increased risk of inhibitor development with recombinant products
(Table 2).8,11 The differences in study results may be attributed to different study designs, and older studies may have underestimated
the overall incidence of inhibitor development.8,11
In general, it is believed that environmental conditions at first FVIII exposure are involved in a delicate interplay with
the patient’s genetic background and F8 mutation type, leading to the determination of risk