Hemophilia A

Definition

Hemophilia is a genetic disorder--usually inherited--of the mechanism of blood clotting. Depending on the degree of the disorder present in an individual, excess bleeding may occur only after specific, predictable events (such as surgery, dental procedures, or injury), or may occur spontaneously, with no known initiating event.

Description

The normal mechanism for blood clotting is a complex series of events involving the interaction of the injured blood vessel, blood cells (called platelets), and over 20 different proteins which also circulate in the blood.

When a blood vessel is injured in a way that causes bleeding, platelets collect over the injured area, and form a temporary plug to prevent further bleeding. This temporary plug, however, is too disorganized to serve as a long-term solution, so a series of chemical events occur, resulting in the formation of a more reliable plug. The final plug involves tightly woven fibers of a material called fibrin. The production of fibrin requires the interaction of several chemicals, in particular a series of proteins called clotting factors. At least thirteen different clotting factors have been identified.

The clotting cascade, as it is usually called, is the series of events required to form the final fibrin clot. The cascade uses a technique called amplification to rapidly produce the proper sized fibrin clot from the small number of molecules initially activated by the injury.

In hemophilia, certain clotting factors are either decreased in quantity, absent, or improperly formed. Because the clotting cascade uses amplification to rapidly plug up a bleeding area, absence or inactivity of just one clotting factor can greatly increase bleeding time.

Hemophilia A is the most common type of bleeding disorder and involves decreased activity of factor VIII. There are three levels of factor VIII deficiency: severe, moderate and mild. This classification is based on the percentage of normal factor VIII activity present:

• Individuals with less than 1% of normal factor VIII activity level have severe hemophilia. Half of all people with hemophilia A fall into this category. Such individuals frequently experience spontaneous bleeding, most frequently into their joints, skin, and muscles. Surgery or trauma can result in life-threatening hemorrhage, and must be carefully managed.
• Individuals with 1-5% of normal factor VIII activity level have moderate hemophilia, and are at risk for heavy bleeding after seemingly minor traumatic injury.
• Individuals with 5-40% of normal factor VIII activity level have mild hemophilia, and must prepare carefully for any surgery or dental procedures.

Individuals with hemophilia B have symptoms very similar to those of hemophilia A, but the deficient factor is factor IX. This type of hemophilia is also known as Christmas disease.

Hemophilia C is very rare, and much more mild than hemophilia A or B; it involves factor XI.

Causes & symptoms

How hemophilia is inherited

Hemophilia A and B are both caused by a genetic defect present on the X chromosome. (Hemophilia C is inherited in a different fashion.) About 70% of all people with hemophilia A or B inherited the disease. The other thirty percent have hemophilia because of a spontaneous genetic mutation.

The following concepts are important to understanding the inheritance of these diseases. All humans have two chromosomes which determine their gender: females have XX, males have XY. Because the trait is carried only on the X chromosome, it is called "sex-linked." The chromosome's flawed unit is referred to as the gene.

Since both factors VIII and IX are produced by a genetic defect of the X chromosome, hemophilia A and B are both sex-linked diseases. Because a female child always receives two X chromosomes, she nearly always will receive at least one normal X chromosome. Therefore, even if she receives one flawed X chromosome, she will still be capable of producing a sufficient quantity of factors VIII and IX to avoid the symptoms of hemophilia. Such a person who has one flawed chromosome, but does not actually suffer from the disease, is called a carrier. She carries the flaw which causes hemophilia and can pass it on to her offspring. If, however, she has a son who receives her flawed X chromosome, he will be unable to produce the right quantity of factors VIII or IX, and he will suffer some degree of hemophilia. (Males inherit one X and one Y chromosome, and therefore have only one X chromosome.)

In rare cases, a hemophiliac father and a carrier mother can pass on the right combination of parental chromosomes to result in a hemophiliac female child. This situation, however, is extraordinarily rare. The vast majority of people with either hemophilia A or B are male.

About 30% of all people with hemophilia A or B are the first member of their family to ever have the disease. These individuals have had the unfortunate occurrence of a spontaneous mutation; meaning that in their early development, some random genetic accident befell their X chromosome, resulting in the defect causing hemophilia A or B. Once such a spontaneous genetic mutation takes place, offspring of the affected person can inherit the newly-created, flawed chromosome.

Symptoms of hemophilia

In the case of severe hemophilia, the first bleeding event usually occurs prior to eighteen months of age. In some babies, hemophilia is suspected immediately, when a routine circumcision (removal of the foreskin of the penis) results in unusually heavy bleeding. Toddlers are at particular risk, because they fall frequently, and may bleed into the soft tissue of their arms and legs. These small bleeds result in bruising and noticeable lumps, but don't usually need treatment. As a child becomes more active, bleeding may occur into the muscles; a much more painful and debilitating problem. These muscle bleeds result in pain and pressure on the nerves in the area of the bleed. Damage to nerves can cause numbness and decreased ability to use the injured limb.

Some of the most problematic and frequent bleeds occur into the joints, particularly into the knees and elbows. Repeated bleeding into joints can result in scarring within the joints and permanent deformities. Individuals may develop arthritis in joints which have suffered continued irritation from the presence of blood. Mouth injuries can result in compression of the airway, and, therefore, can be life-threatening. A blow to the head, which might be totally insignificant in a normal individual, can result in bleeding into the skull and brain. Because the skull has no room for expansion, the hemophiliac individual is at risk for brain damage due to blood taking up space and exerting pressure on the delicate brain tissue.

People with hemophilia are at very high risk of hemorrhage (severe, heavy, uncontrollable bleeding) from injuries (such as motor vehicle accidents) and also from surgery.

Diagnosis

Various tests are available to measure, under very carefully controlled conditions, the length of time it takes to produce certain components of the final fibrin clot. Tests (called assays) can also determine the percentage of factors VIII and IX present compared to known normal percentages. This information can help in demonstrating the type of hemophilia present, as well as the severity.

Treatment

Various types of factors VIII and IX are available to replace a patient's missing factors. These are administered intravenously (directly into the patient's veins by needle). These factor preparations may be obtained from a single donor, by pooling the donations of as many as thousands of donors, or by laboratory creation through highly advanced genetic techniques.

The frequency of treatment with factors depends on the severity of the individual patient's disease. Patients with relatively mild disease will only require treatment in the event of injury, or to prepare for scheduled surgical or dental procedures. Patients with more severe disease will require regular treatment to avoid spontaneous bleeding.

While appropriate treatment of hemophilia can both decrease suffering and be life-saving, complications associated with treatment can also be quite serious. About 20% of all patients with hemophilia A begin to produce chemicals within their bodies which rapidly destroy infused factor VIII. The presence of such a chemical may greatly hamper efforts to prevent or stop a major hemorrhage.

Individuals who receive factor prepared from pooled donor blood are at risk for serious infections which may be passed through blood. Hepatitis, a severe and potentially fatal viral liver infection, may be contracted from pooled factor preparations. Recently, a good deal of concern has been raised about the possibility of hemophiliacs contracting a fatal slow virus infection of the brain (Creutzfeldt-Jakob disease) from blood products. Unfortunately, pooled factor preparations in the early 1980s were almost all contaminated with human immunodeficiency virus (HIV), the virus which causes AIDS. Currently, careful methods of donor testing, as well as methods of inactivating viruses present in donated blood, have greatly lowered this risk. But a large number of hemophiliacs were infected with HIV. In fact, some statistics show that HIV is still the leading cause of death among hemophiliacs.

The most exciting new treatments currently being researched involve efforts to transfer new genes to hemophiliacs. These new genes would have the ability to produce the missing factors. As yet, these techniques are not being performed on humans, but there is great hope that eventually this type of gene therapy will be available.

Prognosis

Prognosis is very difficult to generalize. Because there are so many variations in the severity of hemophilia, and because much of what befalls a hemophiliac patient will depend on issues such as physical activity level and accidental injuries, statistics on prognosis are not generally available.

Prevention

Prevention is two pronged: one involves prevention of complications in the already-diagnosed hemophiliac patient; the other involves preventing the disease in subsequent offspring. The most important thing an individual with hemophilia can do to prevent complications of his disease is to avoid injury. Those individuals who require dental work or any surgery may need to be pre-treated with an infusion of factor to avoid hemorrhage. Also, hepatitis vaccines should be given to hemophiliacs. Medications or drugs which promote bleeding (such as aspirin) should be avoided.

Certainly, people who know that their family includes hemophiliacs should receive careful genetic counseling before deciding to have a baby. Families with a positive history of hemophilia can also have tests done during a pregnancy to determine whether the fetus is a hemophiliac.

Key Terms

Amplification

A process by which something is made larger. In clotting, only a very few chemicals are released by the initial injury; they result in a cascade of chemical reactions which produces increasingly larger quantities of different chemicals, resulting in an appropriately-sized, strong fibrin clot.

Factors

Coagulation factors are substances in the blood, such as proteins and minerals, that are necessary for clotting. Each clotting substance is designated with roman numerals I through XIII.

Fibrin

The final substance created through the clotting cascade, which provides a strong, reliable plug to prevent further bleeding from the initial injury.

Hemorrhage

Very severe, massive bleeding which is difficult to control. Hemorrhage can occur in hemophiliacs after what would be a relatively minor injury to a person with normal clotting factors.

Mutation

In genetic inheritance, a permanent change in part of a chromosome.

Platelets

Blood cells involved in the clotting process.

Trauma

Injury.

Further Reading

For Your Information

Books

• Corrigan, James J. "Hemorrhagic and Thrombotic Diseases." In Nelson Textbook of Pediatrics, edited by Richard Behrman, et al. Philadelphia: W.B. Saunders Co., 1996.
• Hay, William W., et al. Current Pediatric Diagnosis and Treatment. Norwalk, CT: Appleton & Lange, 1995.

  Periodicals

• Berntorp, E., et al. "Modern Treatment of Haemophilia." Bulletin of the World Health Organization. 73, 5 (September-October 1995): 691+.

  Organizations

• National Hemophilia Foundation, 116 West 32nd Street, 11th Floor, New York, NY 10001. (800) 42-HANDI. http://www.info@hemophilia.org.

Gale Encyclopedia of Medicine. Gale Research, 1999.