What are Inhibitors?

Put simply, inhibitors are antibodies to a clotting factor protein. Due to the abnormally low levels of clotting factor in a hemophiliac's body, their immune system may not recognize the protein as a safe and normal occupant of the person's blood. In these cases the person's immune system targets the clotting factor that is administered as treatment, thus removing it from the bloodstream and diminishing the effectiveness of factor replacement therapy or rendering it ineffective all together.

In cases where a drop in the efficacy of their replacement therapy is noticed, patients are often tested for an inhibitor. According to the CDC as many as 33% of hemophiliacs may develop inhibitors to the clotting factor they infuse to resolve and/or prevent bleeding episodes. Inhibitors are diagnosed with a blood test that measures the inhibitor levels (or titer) in the blood. The titer is measured in Bethesda Units (BU) with the mere presence of a titer indicating an inhibitor while any titer over 5 is normally considered to be a high responding inhibitor.

There are generally 4 methods of treatment for people with inhibitors.

• For people with low responding inhibitors it might be possible to simply give them high doses of the clotting factor they are deficient in. By doing so, there are not enough inhibitors present to remove all of the administered clotting factor protein, allowing the clot to form. With this treatment protocol the person with inhibitors typically has frequent bleeds and may accrue permanent joint damage due to them. Infusing larger doses more frequently when the individual has a bleed is the normal form of bleed management under this treatment methodology.
• The use of bypassing agents. In this treatment inhibitor patients are given a different clotting factor protein in an attempt to bypass the part of coagulation that requires the protein they are missing. For example, factor VII is often given to people with inhibitors to fVIII or fIX. Factor VII can bypass the inhibitor because it activates a different branch of the clotting cascade that can cause clot formation without using factors VIII or IX. Some products contain multiple factors and can therefore effectively do the same thing.
• High Dose ITI, Immune Tolerance Induction (also known as ITT, Immune Tolerance Therapy), where the individual with the inhibitor is given large volumes of clotting factor for a long period of time, often bringing the individual's factor level to 200% each day (far more than what would normally required to stop or prevent a bleed). The idea is that this will force the body into accepting the factor protein as a normal inhabitant of the blood. If all goes well, ITT takes on average about a year for positive results and has been shown to work for 63-80% of the inhibitor cases out there. It is important to note that in harder cases it can take much longer or not work at all.
• Low Dose ITI, while having no official dosage or frequency tied to it, often raises the individual's factor level to 100% every other day. This has been shown to have nearly the same success rate as High Dose Therapy with a few very large differences.

High Dose -Vs- Low Dose Immune Tolerance Comparison
High Dose	Low Dose
Less bleeding episodes during therapy (less bleeding typically means less long term damage and fewer complications down the road)	Studies have shown a 2 fold increase in bleeding events when compared to high dose therapy
Often 4 times as much Factor VIII needed for the therapy	Uses much less Factor VIII and thereby saves money of Factor VIII Costs
Does not typically need to infuse additionally to stop a bleeding episode.	Uses bypassing agents such as rFVIIa to stop occurring bleeds. These products are much more expensive than the Factor VIII product.
Due to the frequency of the IVs, individuals may see scarring and damage to the veins from repeated use as well as be more reluctant to comply. Most doctors make the decisions to implant CVADs into patients undergoing ITI, thus removing the vein issue.	Needing to infuse less often typically results in less damage to the infusion site(s) and more compliance.

For a good look into High Dose -Vs- Low Dose ITI, a great study called "Getting rid of refractory hemophilia" is discussed in the Journal of Hematology called Blood.