Hemophilia

According to the Centers for Disease Control and Prevention, there are 13,321 people with hemophilia A in the United States, and 3,638 persons with hemophilia B. At this time, there is no cure for hemophilia. People with this bleeding disorder require treatment, the frequency or intensity of which is dependent on their level of deficiency. This treatment is best provided by the network of federally recognized comprehensive hemophilia treatment centers (HTCs). In this regard, a study reported in the medical journal Blood in July 2000 revealed important statistics related to outcome and risk of death in people with hemophilia based upon their source of care:

– J. Michael Soucie, Ph.D., Epidemiologist/Surveillance, Hematologic Diseases Branch, Division of AIDS, STD and TB Laboratory Research, National Center for Infectious Disease, Centers for Disease Control and Prevention

Incidence of Hemophilia

The CDC reports that in the United States, hemophilia occurs 1:5,032 male live births. Worldwide, the rate of occurrence of hemophilia is 15 – 20:100,000 male live births.

The number of bleeding events per year persons with hemophilia experience is related to the level of deficiency of their clotting factor level. Hemophilia is classified by the functional level of the clotting factor present in the blood. Normal levels of factor VIII and IX are usually between 50% - 150%; persons with hemophilia have significantly less than normal amounts. The classification of hemophilia is as follows:

The National Hemophilia Foundation (NHF), the major national advocacy organization for persons with bleeding disorders, says that persons with mild hemophilia comprise 25% of the hemophilia population, moderate 15% and severe 60%. Mild and moderate deficient hemophilia and von Willebrand disease are under-recognized disorders. Many medical providers do not realize that not all people with hemophilia are diagnosed as a child, and that oftentimes a person may not be diagnosed until later in life.

Those affected with severe hemophilia commonly experience frequent bleeding events, which are often spontaneous and may occur weekly. On average, the moderate deficient population experiences less frequent bleeding, usually 4 to 6 times a year. Those with mild hemophilia tend to have infrequent bleeding events; such events are usually associated with injury, trauma or surgery.

Incidence of Other Bleeding

Disorders Although von Willebrand disease is fairly common, hemophilia is considered an uncommon disorder. Other bleeding disorders, for the most part, are considered to be rare, as the deficiencies and statistics on rates of occurrence indicate below:

Incidence of Hepatitis

NHF estimates that 75% of those individuals with hemophilia who are above the age of 12 have the hepatitis C virus (HCV). Up to one third of these individuals who were treated with clotting factor concentrates and other blood products between the years 1979-1985 may also be co-infected with HIV (the AIDS virus). As published by the NHF, in the United States and Europe the prevalence of the hepatitis A virus (HAV) in individuals with hemophilia who have had multiple blood donation exposures is 40% - 67%.

These distressing statistics largely reflect previous exposure to both viruses through clotting factor products from the early to mid-1980s. At that time, viral screening technology had not yet identified these viruses, and inactivation processes were not yet developed to rid the blood supply of these viral contaminants. People with hemophilia requiring clotting factor concentrates during that period of time may have been infected. In the early 1990s recombinant (DNA-involved) technology was developed in order to manufacture clotting factor concentrates not from human blood donors. These recombinant products have an excellent safety record with no evidence of any viral transmission having occurred.

Vaccines are available to protect people against hepatitis A and B. There is no vaccine – nor cure – for hepatitis C. It is recommended that all people with a bleeding disorder be immunized against hepatitis A and B regardless of the present safety of the clotting factor concentrates.

Clotting Factor

The primary treatment for hemophilia is replacement of the deficient clotting factor through concentrates or medications that may increase a patient’s factor level. This replacement therapy will increase a person’s factor level for a specific period of time dependent on the amount of clotting factor infused and the factor that the person is deficient in. Replacement or infusion therapy will stop a bleeding episode or prevent bleeding (for example, prior to surgery). Factor concentrates are manufactured by a limited number of pharmaceutical companies including (but not limited to) Baxter BioScience, Genetics Institute, Aventis–Behring and Bayer. Factor concentrates are administered by venipuncture (placing a needle in a blood vein) or through a surgically implanted infusion device such as a port–a–cath.

Some people with severe hemophilia are treated in a replacement therapy program called prophylaxis. This is the regular infusion of clotting factor in order to prevent bleeding episodes and reduce or eliminate joint disease and destruction. Prophylactic infusion programs use a considerable amount of factor to help reduce the number of bleeding episodes. However, despite the cost of these programs, children treated on prophylaxis programs are growing up with normal joints, decreased days lost from school, and an ability to actively participate in physical activities.

Clotting factor is an expensive therapy. These products are typically provided to patients through home healthcare companies or through pharmacies operated by comprehensive hemophilia treatment centers (HTCs). Some manufacturers have also entered the clotting factor distribution business, shipping factor products directly to patients. It is worth noting that there may exist large differences between the dispensing agency’s acquisition (purchase) price of factor and its retail (selling) price. It is important for consumers to be aware of these issues so they are able to make informed decisions about their healthcare and to help limit the cost of their therapy. In 1997, the NHF estimated that the average annual cost for factor products (either recombinant or human plasma derived) used by an individual with severe hemophilia was between $50,000 and $100,000. For severe patients, the costs of prophylaxis and emergent factor therapy often exceed this range.

Today, clotting factor research continues to focus on the development of recombinant clotting factors that are completely free of human proteins both in the final formulation (the vials consumers receive) and in the manufacturing process. Researchers are also investigating production of these concentrates in more concentrated forms, which will require less volume for the patient to infuse. Gene therapy trials now under way may, in years to come, have a dramatic impact on the use of clotting factor. If successful, gene therapy may reduce – if not eliminate Ð the need for clotting factor, a development keenly awaited by the hemophilia community worldwide. However, much work remains to be done before gene therapy programs are commonly available.

Inhibitors

Inhibitors are antibodies that when they develop “inhibit” or inactivate the actions of clotting factor, thereby limiting the usefulness of normal replacement therapy. Inhibitors tend to develop in patients early in the course of their disease and often within the first 30 infusion days. In severe patients, this typically occurs during childhood. However, in patients with moderate or mild deficiency, inhibitors may occur later due to the infrequency of replacement therapy. The incidence of inhibitors in the severe factor VIII deficient population is about 28%, and in moderate and mild deficient patients it is between 3% to 13%. In contrast, in severe factor IX deficiency, the incidence of inhibitors is 3% to 5%.

Inhibitors are classified based upon the level of antibody produced. The kind of inhibitor a patient produces will determine the treatment program required. If an inhibitor cannot be eliminated, then treatment becomes more complicated, and often less effective. Patients with factor IX deficiency and inhibitors pose some specific and challenging treatment issues. These patients may have associated reactions with any infusion product containing factor IX, and the reactions may be severe. Immune tolerance induction in patients with factor IX deficiency with an inhibitor may also be associated with some unusual medical problems including development of a degenerative renal disorder called nephrosis.

Patients with inhibitors use infusion products that are different than the normal clotting factor concentrates. These products, their use and possible side effects require a detailed discussion with the treating hematologist. Patients with inhibitors are best managed in conjunction with a federally recognized comprehensive treatment center.

If the inhibitor is identified and treated early, it may often be eliminated through treatment programs called immune tolerance induction therapy. These programs may take as long as 1-2 years to be successful. The success rate is dependent on a variety of issues such as the length of time the inhibitor has been present, the highest level of inhibitor antibody reached in the past, the present level of the inhibitor when a program is started, and so on. If an immune tolerance induction protocol (treatment plan) has been successful, the patient may be placed in a prophylaxis program in order to provide continued suppression of the inhibitor.

Patient Prognosis

Today, with the expertise and guidance offered by the specialists and multidisciplinary staff at federally recognized comprehensive hemophilia treatment centers, and with the advanced technology used to manufacture present-day replacement therapy products, persons with hemophilia may expect to live longer, more productive lives. This is a significant advancement from just 20 years ago. Indeed, the future continues to hold increasing promise of better therapies and outcomes for people with hemophilia and other bleeding disorders.