Inhibitors in hemophilia: nature or nurture?

There has long been debate regarding the respective roles of inherited or environmental factors in the development of hemophilic inhibitors.

Factor VIII (FVIII) gene mutations, polymorphisms of key biologic response modifiers (interleukin 10, tumor necrosis factor alpha), ethnicity, and family history have all demonstrated importance in the formation of inhibitors. However, the role of treatment-related factors such as prophylaxis, age at first exposure, intensity of treatment, and type of FVIII used have been more controversial. In the 2 articles by Gouw and colleagues in this issue of Blood, the foundational roles of FVIII gene mutation and family history are again confirmed, while light is shed on the controversy regarding FVIII product and intensity of treatment.

Both articles are based on the same multicenter, retrospective, consecutively enrolled and previously untreated patient population (PUP), followed at 13 referral hemophilia treatment centers in Europe and 1 in Canada. The studies' strength lies in the cohort design, where consecutive, unselected patients were analyzed. Additionally, almost the entire cohort had all relevant data captured with at least 50 exposure days (EDs). Survival analyses were by time-dependent determinants with patients compared using similar numbers of EDs. Weaknesses to both reports are their retrospective design and the low percentage of African patients, a group known for difficult-to-eradicate inhibitors.

In the first article, “Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study,” only clinically relevant inhibitors were reported, which might explain the slightly lower inhibitor percentage (26%) compared to previous PUP trials. Risk of inhibitor development between plasma-derived FVIII (with or without VWF) and recombinant products was the same, and switching between FVIII products did not increase the risk of inhibitors (RR, 1.1; CI, 0.6-1.8). This equivalency of inhibitor development between plasma and recombinant FVIII is at odds with a report by Goudemand et al.¹  The study by Goudemand et al was also a retrospective cohort design, but differed by comparing a single plasma FVIII product to 2 full-length recombinant FVIII products. Conversely, the current study grouped 23 different plasma-derived products in its comparison, which might have contributed to the noted lack of difference.

An important conclusion from the second article, “Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study,” was that the recognized increased incidence of inhibitor development seen in infants²  appeared related to the kind of treatment intensity seen during surgery and with large bleeds. Each of these conditions is more likely to be defined by tissue damage and inflammation. Intensive exposure to FVIII (> 5 days) has also been demonstrated to be a risk factor for inhibitor development in persons with mild hemophilia A.³  Additionally, the authors were able to confirm the previously described association between prophylaxis and a decreased risk of inhibitor formation (see the figure).⁴ 

These studies support the role that genetic factors play in inhibitor development and have helped to better define the contribution of treatment-related factors. However, since all patients with severe FVIII deficiency do not develop inhibitors, further investigation is needed to better define the interactions between immunologic danger signals, the immune response, and genetic and environmental risk factors. Until that time, the debate between the role of nature and nurture in the development of hemophilic inhibitors will linger.