People with hemophilia have a higher quality of life today than ever before, but complications can still occur. As many as one third of people with hemophilia will develop an antibody — called an inhibitor — to the product used to treat or prevent bleeding episodes. Developing an inhibitor is one of the most serious and costly complications of hemophilia.
People with hemophilia use treatment products called clotting factor concentrates. This treatment improves blood clotting and is used to stop or prevent a bleeding episode.
Inhibitors develop when the body’s immune system stops accepting the factor (factor VIII for hemophilia A and factor IX for hemophilia B) as a normal part of blood. The body thinks the factor is a foreign substance and tries to destroy it using inhibitors. The inhibitors stop the factor from working. This makes it more difficult to stop a bleeding episode. People with hemophilia who develop an inhibitor do not respond as well to treatment. Inhibitors most often appear during the first year of treatment but they can appear at any time.
Caring for people with inhibitors poses a special challenge. The healthcare costs associated with inhibitors can be staggering because of the cost and amount of treatment product required to stop bleeding.
Multi-joint arthropathy, and the additional burdens of pain and mobility problems further compound the cost of care. People with hemophilia who develop an inhibitor are twice as likely to be hospitalized for a bleeding complication – particularly interventional surgery to manage joint damage. Physical therapy intervention, therefore, is an important component of overall inhibitor management.
Scientists do not know exactly what causes inhibitors. Risk factors that have been shown in some studies to possibly play a role include:
A blood test is used to diagnose inhibitors. The blood test measures inhibitor levels (called inhibitor titers) in the blood. The amount of inhibitor titers is measured in Bethesda units (BU). The higher the number of Bethesda units, the more inhibitor is present. “Low titer” inhibitors have a very low measurement, usually less than 5 BU. “High titer” inhibitors have a very high measurement, usually much higher than 5 BU.
Inhibitors are also labeled “low responding” or “high responding” based on how strongly a person’s immune system reacts or responds to repeated exposure to factor concentrate. When people with high-responding inhibitors receive factor concentrates, the inhibitor titer measurement increases quickly. The increased inhibitor titer prevents the clotting factor from stopping or preventing a bleeding episode. Repeated exposure to clotting factor will cause more inhibitors to develop.
When people with low-responding inhibitors receive factor concentrates, the inhibitor titers do not rise. Therefore, people with low-responding inhibitors can usually still use clotting factor products to stop or prevent a bleeding episode.
Treating people who have inhibitors is complex and remains one of the biggest challenges in hemophilia care today. If possible, a person with inhibitors should be cared for at a hemophilia treatment center (HTC). HTCs are specialized health care centers that bring together a team of doctors, nurses and other health professionals experienced in treating people with hemophilia.
Some treatments for people with inhibitors include the following:
Traditional immune tolerance induction therapy consists of once-daily doses of clotting factor into the vein. Continuous factor replacement therapy has been used as an alternative to traditional bolus dosing since the 1990s. Today, it is most often used peri-operatively to ensure hemostasis throughout a medical procedure and recovery, but it may also be prescribed to induce immune tolerance.
Continuous factor replacement at home is achieved by using a portable infusion pump. The infusion pump contains a small cartridge that holds the mixed clotting factor solution, and is typically changed out every day with a fresh dose. The pump is programmed to deliver the daily factor dose at steady levels over a 24-hour period. It is thought that, instead of a once-daily bolus dose of factor (which results in initial peak levels of factor levels that decrease throughout the day), a steady level of clotting factor over the same 24-hours might be more effective at overcoming an antibody response.
Sometimes referred to as “co-protein” or “whole molecule” products, clotting factor products that contain both the factor VIII (FVIII) and von Willebrand factor (VWF) proteins have been used with some success at tolerizing hard-to-treat factor VIII inhibitors. Moreover, some researchers suggest that FVIII/VWF products may shorten the duration of immune tolerance therapy.
In nature, von Willebrand factor is bound to factor VIII on the same binding sites as those that are targeted by some inhibitors. In other words, VWF effectively blocks the antibody from attacking FVIII. Researchers, therefore, believe that FVIII/VWF products may be a viable treatment option for some, especially where immune tolerance induction has failed with a recombinant or monoclonal factor VIII product.
For people with inhibitors, the bypassing agent, FEIBA NF (from Baxter Healthcare), is commonly prescribed for treating bleeds. Moreover, recent research shows that treating prophylactically with FEIBA NF can significantly reduce the frequency of bleeds in severe hemophilia A patients with inhibitors. http://www.feiba.com/hcp/prophylaxis.html »
Rituxan (rituximab), from Genentech and Biogen Idec, is a genetically engineered antibody, designed to attach to the B cell, which is a type of lymphocyte (or white blood cell) that plays a significant role in the body’s immunity. Rituxan attaches to a specific receptor site on the B-lymphocyte, called CD20. It is hypothesized that Rituxan may help to reduce the immune response of an inhibitor to factor and possibly “reset” the immune system. The mechanism of action as it relates to the FVIII/FIX inhibitor is unknown and research continues.
Rituxan is a prescription medicine. It is not a chemotherapy medicine; however, it has been used in conjunction with chemotherapy, immunoglobulin therapy, and/or prednisone. Rituxan is usually given with immune tolerance therapy or concurrent factor infusions. Rituxan is administered intravenously and may result in a variety of side effects, including allergic reactions.