The body protects itself from disease with a host of defenses that are collectively called the immune system. The immune systems first lines of defense are barriers, such as the skin and mucus membranes. However, this is not the body's only defense. Once something has made its way past these barriers, the body mounts a cellular immune response. This cellular response results in the production of antibodies.
An antibody is produced in response to the presence of foreign substance in the body. The foreign substances that induce an immune response and interact with antibodies are called antigens. Antigens are traditionally defined as any substance that, when introduced into the body, is recognized as foreign and causes the production of antibodies.
In most cases, antibodies can help protect the body by destroying foreign substances (which are often viruses and bacteria) that can cause disease. People who have hemophilia, may not produce the coagulation protein needed for this process. Therefore in some cases, when it receives replacement factor, the body's immune system will perceive the normal clotting factor as different from itself or as an antigen to which an antibody is produced. These antibodies are called inhibitors. The antibody, or inhibitor, binds itself to the infused clotting factor making it difficult, if not impossible, to obtain a level sufficient to control bleeding.
Who is at Risk for Developing an Inhibitor?
Experts estimate that 1/3 to 1/5 of people with severe hemophilia A may develop an inhibitor sometime in their lives. For those people with severe hemophilia B, inhibitors somewhat less common, thought to affect between 1% to 4% of this group.
Inhibitors most often develop during childhood, especially during the first 50 exposure days. People with hemophilia have the greatest risk for developing an inhibitor during childhood. The incidence of inhibitors is highest among those with severe hemophilia, followed by moderate and mild deficiency or moderately severe hemophilia. The risk of inhibitor development is higher if someone in the patient's family also has an inhibitor, and is more frequent among African Americans.
How do You Know if You Have an Inhibitor?
Many times a person will not have symptoms associated with the presence of an inhibitors. In these cases, inhibitors are often discovered by laboratory testing during regular physician visits. For those who are symptomatic, an inhibitors is usually suspected when bleeding does not stop after being treatment with factor concentrate. Once an inhibitor is suspected, confirmation is made using a blood test called the "Bethesda inhibitor assay." This test measures the presence and amount of antibodies directed against a coagulation factor in a person's blood after being exposed to factor.
If the results of the Bethesda assay are positive, it means that there is a detectable level of antibodies working against the deficient coagulation factor being produced as a result of being treated with factor. The degree to which this affects a person is measured in "units." Inhibitors are classified into two categories based upon the highest unit level achieved. Those with a 5 or higher Bethesda unit result at any time are usually classified as having a "high responding" inhibitor level; those who measure below 5 units despite repeated exposure to factor concentrate, are classified as having a "low responding" inhibitor level.
People with high responding inhibitor levels often have quick and strong immune system responses directed against factor (VIII or IX), meaning that the inhibitor level can quickly increase to very high levels of antibodies. In some cases, if there is no further exposure to the replacement factor, the levels may drop over a period of months to years, even to an undetectable range. This does not mean that the inhibitor is gone, as it may reappear with further exposure, often times months later.
In cases where a person is said to have a "low responding" inhibitor level, the body's immune response to factor is slow--it produces a persistently low level of antibodies despite the person's continual exposure to factor concentrate.
A positive test result does not mean a person will always have an inhibitor. Treatment for inhibitors may cause them to disappear. Uncommonly, with the passing of time, inhibitors have spontaneously disappeared without treatment. These are often low responding inhibitors and are then classified as transient inhibitors.
Low Responding Inhibitors
For those people who have low responding inhibitor levels, continued therapy with factor replacement is often possible. This therapeutic approach provides control of both minor and more serious bleeds. To overcome the presence of inhibitors in these cases, physicians may use a greater amount of factor and might have to provide additional doses.
High Responding Inhibitors
For people with high responding inhibitors, utilizing factor is, in many cases, not possible because the inhibitor neutralizes even the largest possible dose of factor. In these cases treatment is based on the type of hemophilia and the nature of the bleed.
During a life or limb-threatening bleeding episode, physicians can remove antibodies from the body using a process called plasmapheresis, which lowers the level of antibodies to allow treatment with factor concentrate to treat the bleed. However, this is a temporary solution and within a few days the body will produce large amounts of new antibodies. For the person with a high responding inhibitor, most bleeding episodes are treated using bypassing products that include prothrombin complex concentrates (PCCs), activated prothrombin complex concentrates (APCCs) (i.e. Feiba VH, produced by Baxter)
These bypassing products contain other factors that can stimulate the formation of a clot and stop bleeding. While these treatments are effective, they do have limitations. If they are used too often they can cause bleeding or they can generate the over-production of clots. In general the main problems associated with bypassing products include the lack of uniform and/or universal efficacy, and at times, the development of excessive blood clotting where it is not wanted, called thrombosis. The production of clots may also be exacerbated if the person is being treated with antifibrinolytic drugs. Also, some bypassing agents contain small amounts of the deficient clotting factor, which can stimulate the continued production of more inhibitors, not allowing the inhibitor level to fall over time. Some of these bypassing products are manufactured from human plasma and are therefore at risk, although very small, of HIV and/or hepatitis transmission. No hepatitis B or C or HIV transmissions have been reported with the use of PCCs and APCCs over the last 16 years in the United States.
Recombinant factor VIIa (NovoSeven, produced by Novo Nordisk), is made by recombinant DNA technology. The drug, which was licensed for use in patients with inhibitors to factor VIII or IX and available in the United States since 1999, has been shown to be effective in the treatment of both minor and life-threatening bleeding. No human plasma proteins are used in its production, and it is not stabilized with albumin. Thus, the risk of transmission of human viruses is essentially zero. Multiple doses can be required to stop bleeding depending on the situation.
It is important to note that the proper diagnosis and treatment of inhibitors is complex, and there are many variables affecting treatment choice; no two patients or situations are identical. In all cases, these choices should be discussed with appropriate healthcare providers with expertise in this area.
The cost associated with treating the person who has inhibitors is often high, and the impact that this cost has on a person and/or family depends on the exact type of treatment as well as the insurance coverage.
If a person is being treated at a hospital, it is important to contact the department that oversees the financial issues associated with treatment. Often this is the finance department. The people in these departments can often find out if a treatment is covered by a person's insurance and to what degree. In many cases an insurance company will cover only a portion of a person's treatment.
In many hospitals there is a social work department that can assist people in identifying resources to help defray the costs of treatment.
There is often a significant difference between an inpatient hospital setting and an outpatient treatment facility in terms of insurance coverage.
In many outpatient settings there will be a person or department that can assist people in learning what is covered and what is the patient's responsibility.
Financial assistance may also available to people through their county's social services departments. In these cases financial need may have to be established.
Another option that may be worth exploring is "risk sharing." This is a program often setup by the manufacturers that produce the medications used to treat inhibitors that lower the costs associated with treatment for those with limited or no health insurance.
While the treatments discussed in the preceding sections provide options for treating a bleed, they do not have the same positive, long-term outcomes as treatment with replacement factor (VIII or IX) in patients without inhibitors. These less-than-optimal treatments can also lead to secondary problems such as infections, bleeding into joints and organ damage.
Because of these complications, many healthcare providers believe that ridding of the body of inhibitors is the best option. This is done using a course of therapy known as "immune tolerance." There are different treatment programs used for immune tolerance, but most require repeated exposure to the deficient clotting factor.
People who opt for immune tolerance expose themselves to daily doses of factor over a period of weeks, and in some cases, years. Some people going through this therapy are also given immune suppressive drugs, which can predispose one to infections. The risks and benefits of each treatment program and the medications used should be discussed in detail with a healthcare provider. The goal of immune tolerance therapy is to eventually "teach" the body to tolerate the factor and to not mount an immune response so that normal replacement therapy can be used to prevent or control bleeding.
Overall, immune tolerance treatment is highly effective and is thought to work approximately 60% to 80% of the time.