The therapeutic use of factor replacement therapy—the mainstay of hemophilia treatment—is impeded by a stubborn problem that can sometimes drastically reduce its efficacy: the development of inhibitors to the coagulation factors administered. 

Why does factor replacement therapy go swimmingly well in many patients with hemophilia, yet for some patients, inhibitors develop almost immediately? The short answer is that nobody knows for sure. Scientists speculate that a combination of genetic and environmental factors is to be blamed. 

Patient Predisposition 

In Expert Review of Hematology, Schep and colleagues wrote about what is coined the “danger theory” that predisposes a hemophilia patient to develop inhibitors. This idea is that a number of factors can trigger the activation of “danger signals” that increase the likelihood of a patient developing inhibitors during factor replacement therapy. The term “danger signal” is aptly named, as the development of inhibitors is indeed a dangerous development for any patient with hemophilia.

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Some of the proposed “danger signals” of the development of inhibitors in hemophilia A are infection, trauma, surgery, and severe bleeds. The more people are aware of the “danger signals” that may precipitate the development of inhibitors, the more they can take preventive measures and seek medical help when the events are unavoidable. In addition, if a patient is deemed vulnerable, the patient’s physician can more closely monitor his or her condition during transfusion.

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In theory, any of these “danger signals” can predispose a patient to developing inhibitors (though the evidence for this is still subpar). However, keep in mind that the development of inhibitors is likely a multifactorial process influenced by both genetic and environmental factors.

Experts agree it is currently impossible to trace a single factor to the development of inhibitors or to incorporate all possible risk factors into in vitro or in vivo model-based studies. There is considerable debate about whether it is useful at all to dissect the risk factors. If we do try to collect data on this issue on a large scale, it will probably be to decide the appropriateness of surgical intervention, early prophylaxis, or the usefulness of nonreplacement strategies. 

Eliminating Inhibitors 

Immune tolerance induction (ITI) is an intervention that can eradicate the production of inhibitors. It is known to downregulate the generation of neutralizing antibodies in about 70% of cases. The downside is that it is both costly and invasive. 

Nevertheless, the elimination of inhibitors to clotting factors is not just desirable, it is quite literally a matter of life and death. Carcao and colleagues in the Expert Review of Hematology have a few suggestions on how to accomplish this. 

Emicizumab was inducted into medical usage over the last few years and “ushered in a new era of hemophilia management,” according to Carcao et al. Emicizumab is a humanized bispecific monoclonal antibody that mimics the cofactor function of activated FVIII. Its promise lies in a particularly important function: the reduction of the need for inhibitor eradication. 

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This is the solution proposed by Carcao et al regarding how to eradicate inhibitors to exogenous coagulation factors. First, they advocated that all patients with hemophilia and inhibitors be offered at least one attempt at ITI. Should the procedure fail, or if the patient is unable to undergo treatment for any reason, emicizumab monotherapy may be started. 

“Evidence is emerging about the use of emicizumab to prevent bleeds during ITI,” Carcao and colleagues wrote. “Results of ongoing studies are expected to answer unresolved questions about the safety, efficacy, and feasibility of concomitant emicizumab and FVIII in ITI.”

Another question is whether emicizumab functions perfectly well as a monotherapy, or whether its combination with clotting factor replacement therapy strengthens its therapeutic response. Experts remain divided about this issue. Carcao and colleagues highlighted a few key questions that still need to be answered: 

  • Should ITI be actively promoted as a means to eradicate inhibitors? 
  • Should emicizumab be incorporated into ITI regimens? 
  • Should emicizumab be continued post-inhibitor eradication? 
  • Should emicizumab be combined with FVIII (for hemophilia A)? 
  • If FVIII is prescribed, what are the ideal dose, frequency, and length of time? 

These questions highlight the long road ahead in our quest to gain mastery of this disease and to fully utilize the levers of therapeutics at our disposal. Encouragingly, research that prompts important questions such as the ones mentioned above indicates that medical researchers are inching closer to a breakthrough in hemophilia therapeutics. For the thousands of patients suffering from hemophilia, that day cannot come soon enough. 


Schep SJ, Boes M, Schutgens REG, van Vulpen LFD. An update on the ‘danger theory’ in inhibitor development in hemophilia AExpert Rev Hematol. 2019;12(5):335-344. doi:10.1080/17474086.2019.1604213

Carcao M, Mancuso ME, Young G, Jiménez-Yuste V. Key questions in the new hemophilia era: update on concomitant use of FVIII and emicizumab in hemophilia A patients with inhibitorsExpert Rev Hematol. 2021;14(2):143-148. doi:10.1080/17474086.2021.1875817