by Donna M DiMichele, M.D.

Introduction

Throughout life, persons with haemophilia battle the complications of both the disease and its treatment. One of the most serious of these problems is the development of an inhibitor. An inhibitor is a type of antibody. The function of antibodies in the body is to try to destroy substances they do not recognize. In a person with haemophilia A or B, inhibitors directed against either factor VIII or IX may be created by the body following treatment to replenish the missing factor. The antibody attaches to the factor VIII or IX and neutralizes=97 or inhibits=97 its ability to stop bleeding.

An inhibitor is usually detected in one of two ways. Although the person with haemophilia may have no symptoms, the inhibitor may be discovered during routine screening performed at a comprehensive evaluation. Alternatively, an inhibitor may be suspected when, suddenly and unexpectedly, bleeding does not stop as quickly as it should in response to treatment with factor.=20

The presence of an inhibitor is usually confirmed using a specific blood test called the Bethesda inhibitor assay. The amount of antibody can be measured using this test, and is reported as a number of Bethesda units, or a Bethesda titer. Therefore, the higher the number of Bethesda units (or, the higher the Bethesda titer) the more inhibitor there is present.

Now for the last definition. When an antibody is detected, it will usually be classified as either high or low responding depending on how a person=92s immune system is stimulated upon repeated exposure to factor VIII or IX. If the immune system reacts briskly and strongly, the amount of inhibitor directed against factor VIII or IX can rise quickly to high levels (reflected in a high Bethesda titer). Without further exposure to the factor, the Bethesda titer may drop down to a low level, but this process could take many months to occur. When it has these characteristics, the inhibitor would generally be called high responding. Alternatively, the immune system may be stimulated in a different way such that its response to factor exposure is slower and weaker, and the Bethesda titer will remain low. This type of inhibitor is generally characterized as "low responding." Interestingly, the characteristics of an inhibitor can change over time, and at times the inhibitors have been noted to disappear spontaneously within several weeks or months without apparent treatment.=20=AO

Frequency and Nature of Inhibitors

Based on a number of studies from around the world, it is estimated that the incidence of antibody development in persons with severe (less than 1% factor) or moderately severe (1% to 5% factor) haemophilia A is between 20% and 33%. This information suggests that one third to one fifth of persons with factor VIII levels of 5% or less may develop an inhibitor sometime in their lives. However, among persons with haemophilia B, inhibitors are much less frequent, affecting only 1% to 4%.

The risk of developing an inhibitor does not remain the same during the lifetime of a person with haemophilia. Historically, the majority of inhibitors have been known to develop during childhood. Recent studies have been conducted with persons with haemophilia A who have received only the recombinant (genetically-engineered) factor VIII; these individuals have been more closely observed for inhibitor development than individuals who have received human plasma derived products. These studies suggest a trend toward earlier inhibitor development, that is, at a younger age and after fewer treatments with recombinant factor VIII. These same studies have made another interesting observation about the nature of the inhibitors that are developing with these newer factor VIII products. Historically, with the use of human plasma derived products, about 80% of inhibitors were of the high responding type and very few were temporary, that is, they disappear on their own. However, with the exclusive use of recombinant factor VIII, less than one half of the developing inhibitors were high responding, and as many as one third of them were temporary. We need more long-term experience with the new highly-purified factor VIII preparations, whether plasma-derived or genetically engineered, in order to determine whether we are truly observing a change in the nature of newly developing inhibitors with these products. Similar information on the nature of factor IX inhibitors is less available due to the low prevalence of inhibitors in the haemophilia B population. (Note: a short article on inhibitors in haemophilia B by WFH VP Medical, Carol Kasper appears on page 4 of the June 1997 Haemophilia World, published by the World Federation of Haemophilia)

Who will develop an Inhibitor and why?

Inhibitor development occurs more frequently in individuals with certain inherited conditions. As already mentioned, persons with haemophilia A are much more likely to develop inhibitors than those with haemophilia B. The incidence of inhibitors is highest among those with severe or moderately severe haemophilia. Inhibitor development occurs rarely among persons with mild disease, that is, factor levels of greater than 5%. Development of inhibitors also tends to be familial and occurs more frequently in the U.S.A. for example, among individuals of African heritage. Although the current explanation for these observed trends is far from complete, researchers are actively studying both the haemophilia gene and the immune system for answers.

Treatment of bleeding in the presence of the Inhibitors

The treatment of hemophilic bleeding in a person with an inhibitor can be a challenging experience for both the patient and the treater. In persons with low responding inhibitors and low Bethesda titers, therapy with either factor VIII or IX replacement is frequently possible. In these cases, there is usually good control of both minor and more serious bleeds, although higher doses of the factor and/or more frequent factor infusions may be required to overcome the antibody. However, when there is a large amount of antibody in the system as reflected in a high Bethesda titer, specific treatment with factor VIII or IX is usually not possible because even large factor doses are neutralized by the inhibitor. In rare instances, when high levels of inhibitor exist but there is life-threatening bleeding that can only be treated with specific factor therapy, some of the antibody can be removed from the body through a process called plasmapheresis. This is only a temporary measure, however, since giving the factor will then stimulate the body to make large amounts of new antibody within several days. For most bleeding episodes, the person with haemophilia and high responding inhibitor will usually have to rely on alternative treatment that is selected on the basis of the type of haemophilia and the nature of the bleed.

For both haemophilia A and B, the mainstay of this therapy is generally either prothrombin complex concentrates (PCC=92s) or activated prothrombin complex concentrates (APCC=92s). These products contain other activated clotting factors that can stimulate the formation of a clot and stop bleeding, thus bypassing the specific requirement for factor VIII or factor IX. Used in the treatment of inhibitor bleeding since the late 1970s, they are generally effective. However, there are several drawbacks which limit the use of =97 and satisfaction with =97 this treatment. This type of therapy is short-acting by its very nature, and when given too frequently may cause either more bleeding or excess clotting. This clotting problem can be made worse if antifibrinolytic drugs (Amicar=AE or Cyclokapron=AE) are used along with PCCs or APCCs. Furthermore, because of small amounts of factor VIII and larger amounts of factor IX in these products, they too can stimulate new antibody production to factor IX in haemophilia B. Finally, these products still have the potential to transmit hepatitis and other viruses to the recipient.

Recombinant factor VIIA, a new clotting factor currently being researched for the treatment of bleeding in persons with haemophilia A and B who have inhibitors, may solve some of the problems associated with PCC or APCC therapy. However, recombinant factor VIIA is not yet licensed by the United States Food and Drug Administration, and more experience with this treatment is necessary before we truly understand its effectiveness and any potential side effects. Such studies are currently underway.

For persons with haemophilia A, the use of porcine factor VIII=97 derived from pig plasma=97 is similar enough to its human counterpart to work effectively in the human clotting system, yet is different enough to go unrecognized by some of the human factor VIII inhibitors. This product has been shown to be effective in stopping major bleeds in patients whose inhibitor does not destroy porcine factor VIII. However, allergic side effects and a temporary drop in the platelet count can occur with the use of this product; the latter almost never causes problems. Importantly, porcine factor VIII can stimulate the immune system to produce more antibodies against both itself and factor VIII.

Immune tolerance: Treatment of the Inhibitor=20

Although there are several therapeutic options for haemophilia bleeding in persons with an inhibitor, there are none that can guarantee the same good outcome as specific factor VIII or IX treatment. Consequently, persons with inhibitors frequently suffer from many more infectious, orthopaedic, and life-threatening complications from their haemophilia and have greater disability in their day-to-day lives than those in whom inhibitors do not appear. Importantly, they also may not benefit from the potential future cure of haemophilia with gene therapy.

Therefore, for most such individuals, the eradication of the inhibitor is the best option. The only currently available method to accomplish this is a process called immune tolerance. In this therapy, regular (usually daily or every other day) infusions of factor VIII or IX are administered for a period of weeks to years, with or without drugs that dampen the immune system=92s reaction to the factor. The goal is to train the immune system to better accept treatment with the missing clotting factor, that is, to be more tolerant of it. Immune tolerance treatment, although time-consuming and costly, is effective 60% to 80% of the time, based on almost twenty years of experience with its use. And, with safer factor V111 and 1X products on the market, it is gradually gaining greater acceptance among patients and treaters. There is a national study currently in progress which is designed to help determine the most effective and cost-efficient method of administering immune tolerance therapy.

Inhibitors: The future=20

Despite the very serious nature of this haemophilia complication, there are reasons for a person with an inhibitor to be truly optimistic. Never has there been more interest in the problem of inhibitor development on the part both of the researcher and the treater. Through this intensive and cooperative effort eventually will come the knowledge needed to treat this problem more effectively, and, most importantly, to prevent it altogether.

Acknowledgments

Dr Donna DiMichele is director of the Regional Haemophilia Care Center at the New York Hospital/Cornell University Medical Center. The above article originally appeared in The National Haemophilia Foundation (U.S.A.).

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