Intradermal Injection Can Cause Inhibitor Development

By Dr. David Clark

11/4/23  Inhibitor development in hemophilia A can often be reversed by a method called immune tolerance induction (ITI) in which high factor VIII doses are given repeatedly over a period of time.  However, ITI doesn’t work very well for hemophilia B, for unknown reasons.  A group of US researchers wondered whether giving hemophilia B inhibitor patients factor IX injections into the skin (intradermal injections, ID) might work better.  It didn’t, but their method may have given them an important insight into hemophilia B inhibitor development.

They found out that factor IX injection into the skin is actually a great way to give someone an inhibitor.  Your skin is not just a simple covering for your body – it is a much more complex tissue that really protects you from a lot of outside dangers.  It contains enzymes that can break down any foreign proteins that try to enter your body through the skin, plus a number of immune system components, including antibodies, that can fight off bacteria and viruses.

In hemophilia B mice, the researchers found that injection into the skin triggers inhibitor formation at about a 100 times lower dose than is typically needed to produce inhibitor formation by intravenous (IV) injection.  Interestingly, however, they also found that ID factor injections seemed to keep the mice from developing the anaphylactic reactions that are often seen in B inhibitor patients.  An anaphylactic reaction is a major allergic reaction that can be life-threatening.

So, what does this mean for inhibitor patients and also for products being developed for subcutaneous (SC) injection?  Most B inhibitor patients probably did not acquire their inhibitors by ID contact, but it’s possible and needs more study.  For the SC products being developed, it could be a concern?  SC products are injected under the skin, not into it, but still in close proximity.  As the authors point out, we have already seen cases in which manufacturers of currently-licensed EHL products have tried to develop an SC version.  Development of two potential EHL-SC products was discontinued because of increased inhibitor development.  This has been the case even with products that do not produce inhibitor formation when injected IV.  This could be a can of worms that needs to be further explored.  [Sherman A et al., Res Pract Thromb Haemost, online ahead of print 11/4/23]