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Hemophilia: NHLBI

Article title: Hemophilia: NHLBI

Conditions: Hemophilia

Source: NHLBI


HEMOPHILIA

Background: Hemophilia is the oldest known hereditary bleeding disorder. There are two types of hemophilia, A and B (Christmas Disease). Both are caused by low levels or complete absence of a blood protein essential for clotting. Patients with hemophilia A lack the blood clotting protein, factor VIII, and those with hemophilia B lack factor IX. There are about 20,000 hemophilia patients in the United States. Each year, about 400 babies are born with this disorder. Approximately 85% have hemophilia A and the remainder have hemophilia B.. The severity of hemophilia is related to the amount of the clotting factor in the blood. About 70% of hemophilia A patients have less than one percent of the normal amount and, thus, have severe hemophilia. A small increase in the blood level of the clotting factor, up to five percent of normal, results in mild hemophilia with rare bleeding except after injuries or surgery. Enormous strides made in assuring the safety of the blood supply and in the genetic aspects of hemophilia research allow us now to focus on issues which will improve the quality of life of the hemophilia patient and, ultimately, develop a cure.

Challenges: The most important challenges facing the hemophilia patient, health care provider, and research community today are:

  1. Safety of products used for treatment;

  2. Management of the disease including inhibitor formation, irreversible joint damage, and life-threatening hemorrhage; and

  3. Progress toward a cure.

1. Safety of Products Used for Treatment: In the past 10 to 15 years, advances in screening of blood donors, laboratory testing of donated blood, and techniques to inactivate viruses in blood and blood products have remarkably increased the safety of blood products used to treat hemophilia. Although treatment-related infection with the AIDS virus or most of the hepatitis viruses is a thing of the past, these measures do not completely avoid viruses such as hepatitis A and parvo virus. These infections are rare; nevertheless, they can pose a threat. Researchers are working to improve procedures to destroy these viruses.

There is a great deal of concern about Creutzfeldt-Jakob disease (CJD), a rare transmissible nervous system disease that is inevitably fatal, being transmitted through transfusion. The infection of many hemophilia patients with the AIDS virus before the virus was discovered has elicited a great deal of concern in the hemophilia community about CJD and its potential transmission through blood-derived treatment products. A disorder related to CJD , bovine spongiforme encephalopathy or "mad cow disease", and its suspected relationship to an especially severe form of CJD, has generated considerable interest recently in Britain. No one has ever detected the transmission of CJD disease through blood or blood products, although a number of CJD victims have been blood donors, even within weeks of coming down with the disease. Collaborative studies are underway by the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke to determine, in experimental animals, if the CJD agent(s) can be transmitted by blood.

To ensure absolute safety from transfusion-transmitted viruses and other agents, hemophiliacs may now be treated with factor VIII which has been produced through biotechnology. This product, recombinant factor VIII, is manufactured by a process entirely free of blood products. It, thus, contains only the factor VIII necessary to treat the disease and none of the other components of blood or attendant unwanted agents. Although the cost of this product exceeds that of the blood-derived product, it is clearly the treatment of choice for those, such as newborns, who have not yet been exposed to blood products. A factor IX product has also been produced by such a process and is currently in clinical trials. Once this product is shown to be safe and effective, all hemophiliacs will have available a treatment for bleeding which is totally free of any contaminating agents.

2. Management of the disease including inhibitor formation, irreversible joint damage, and life-threatening hemorrhage: While current treatment has greatly improved the outlook for most hemophiliacs, the development of antibodies (inhibitors) that block the activity of the clotting factors has complicated treatment for some patients. Approximately 15 percent of severe hemophilia A patients and 2.5 percent of hemophilia B patients develop such antibodies after exposure to transfused factors. When inhibitors are present in large amounts, the patient may require very high and expensive quantities of transfused clotting factors to stem bleeding, and, in some instances, even that may not be effective. The factor VIII products produced through biotechnology have been found to cause inhibitors in only about 5 percent of patients and are, thus, safer in this respect. Nevertheless, these inhibiting antibodies will remain a concern for hemophilia patients unless our ability to understand and control the immune system is improved. A number of NHLBI-supported scientists are directing research at this problem.

The major cause of disability in hemophilia patients is chronic joint disease - "arthropathy" - caused by uncontrolled bleeding into the joints. Life-threatening hemorrhage is a constant risk. Traditional treatment of hemophilia in the United States has involved "on-demand" treatment, meaning that patients are treated with factor replacement only after bleeding symptoms are recognized. These bleeds ultimately result in severely impaired joints. Several European countries are treating hemophiliacs by periodic infusion (prophylaxis) regardless of bleeding status. This approach maintains the factor level high enough that bleeding, joint destruction, and life-threatening hemorrhage are almost entirely avoided. There are, nevertheless, serious disadvantages such as the need for frequent infusions, the requirement for almost continuous access to veins by catheters, and the considerable cost of factor. In the United States, it is estimated that most patients on prophylaxis which is begun in the first few years of life will easily exceed the common life-time insurance cap of $1,000,000 by the second decade of life. The treatment decisions are not easy ones.

3. Progress toward a cure: Although treatment for hemophilia has become safer, therapeutic products are still not risk free. The ultimate goal is to offer a cure for the disease. Hemophilia is known to be caused by defects in the genes for factor VIII and factor IX. The challenge is to transfer normal genes into a patient so that they will produce the normal clotting protein. A small amount of active factor produced by the patient's own body will correct the disease. Although much remains to be studied before such treatment can be offered to patients, there have been a number of studies done in animals such as mice and dogs in which a factor VIII or IX gene has been inserted and has produced the proper blood product for periods that exceed one year. Major issues that remain to be resolved include the low level of production of the clotting factor, reduction of immune reactions that stop the production after a period, and development of ways to insert the gene directly into the body without manipulating cells outside the body. Until recently, dogs with naturally occurring hemophilia were used for testing of gene therapy techniques; however, the number of such animals is very limited. Recently, a mouse model of hemophilia produced through genetic technology was announced. The availability of this small animal will accelerate the development of technologies for ultimate use in humans.

Prospects: It is clear that tremendous progress has been made to reduce the exposure of hemophilia patients to transfusion-transmitted disease through making the blood supply safer and by providing replacement products from sources not involving blood. However, concern remains for hemophiliacs still dependent on blood products and the threat of agents which may contaminate the blood supply and are not avoided or inactivated with currently available techniques. It is also known from international studies that crippling joint involvement can be avoided through periodic and regular transfusion. The expense, danger of indwelling catheters, and inconvenience of the treatment regimen are all negative factors. All of these issues will become less important, even irrelevant, if the disease can be cured. At the present time, there are sufficient indications that gene therapy will ultimately be this cure. The technology for gene therapy is not as simple as was first thought. Yet because of its special characteristics, hemophilia will likely be among the first genetic diseases to be successfully treated.

May 13, 1996


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