Advances and MASAC Guideline Recommendations for the Treatment of Hemophilia - Episode 11
Meera B. Chitlur, MD: Inhibitors in hemophilia are polyclonal IgG4 [immunoglobulin G4] antibodies that neutralize the effect of replacement product or replacement protein. Therefore, we are unable to use the replacement factor concentrate any longer for treatment of bleeding in these patients.
The causative mutation that results in hemophilia is the major driver for development of inhibitors. The larger the deletion, the higher the likelihood of developing inhibitors in patients. Other genetic risk factors include race, ethnicity, polymorphisms that are involved in other immunoregulatory genes, and the MHC [major histocompatibility complex]. Nongenetic risk factors include the timing of replacement, especially if it is done at a highly immunomodulatory time such as a major bleed or surgery. In addition to that, the type of product has been questioned as a potential risk factor for inhibitor development. Intensity of treatment at the first, or any, exposure is a potential nongenetic risk factor that can lead to inhibitor development.
Prophylaxis has been extensively discussed as a potential modulator of inhibitor development and might potentially prevent the development of inhibitors. Development of inhibitors is the most challenging complication in patients with hemophilia, and personally, I find those patients’ cases to be the most challenging. Once patients develop inhibitors, the bleeding severity increases exponentially to the point where many patients become wheelchair bound and are unable to function on a day-to-day basis. Even daily activities result in significant bleeding in these patients, which makes it an extremely difficult and a painful process for them. Once a patient develops an inhibitor, our first response is to try to eradicate the inhibitor.
Eradication of inhibitors involves ITI, or immune tolerance induction therapy, which is essentially replacing high doses of recombinant or plasma-derived protein on a daily basis, in addition to administering bypassing agents to treat any breakthrough bleeding or prevent any bleeding during this period. ITI is both challenging and expensive. It’s challenging because in a child, this would mean daily venous access, and sometimes it requires the placement of a central venous catheter to facilitate access to a vein on a daily basis. Large doses of factor concentrate have to be used to try to overcome this inhibitor that has formed in the patient. This is obviously where the expense comes into play. These patients also experience a significantly increased frequency of bleeding as well as severity of bleeding, and this requires treatment with bypassing agents on a regular basis, often multiple times a day. This is an extremely challenging period of treatment for these patient populations.
As of this time, I think we as hematologists still consider the eradication of inhibitors to be necessary in our patients. Even with the arrival of new treatment options for these patients, which may decrease the morbidity and mortality associated with inhibitor development, we still feel that it will be necessary to eradicate the inhibitor to optimally manage the care of these patients.
ITI refers to an attempt to eradicate the inhibitor, and this process involves replacement, through daily high doses, of factor concentrate. But the treatment of bleeding still involves treatment with bypassing agents, which are aPCCs, or recombinant factor VII.
These products are typically administered on a daily basis to patients who have significant bleeding associated with inhibitor formation. This helps to somewhat mitigate the daily episodes of bleeding that these patients can experience. However, many patients will have breakthrough bleeding, which means that we have to administer bypassing agents more frequently than just once a day.
The half-life of aPCCs is about 8 to 12 hours. If it’s a major bleed, I might need to administer aPCCs every 8 hours. If it’s not so major, I may be able to give 1 dose and get away with it. For recombinant factor VIIa, the dosing can be as frequent as every 2 hours. Sometimes, we may be able to do this 2 or 3 times a day to manage minor bleeds.
Transcript edited for clarity.