Hemophilia

Hemophilia

Definition

Hemophilia is a genetic disorder of the mechanism of blood clotting that is usually inherited. 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 occur spontaneously, with no known initiating event.

Description

The normal mechanism for blood clotting is a complex series of events involving the interaction of injured blood vessels, blood cells (called platelets), and over 20 different proteins that 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. 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 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 an injury.

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

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

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 30% develop the disease as a result of a spontaneous genetic mutation.

The following concepts are important to understanding the inheritance of these diseases. All humans have two chromosomes determining their gender: females have XX, males have XY. Because the trait is carried only on the X chromosome, it is termed sex-linked. The chromosomes are comprised of units referred to as genes.

Both factors VIII and IX are produced by genes located on the X chromosome, so 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 abnormal 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 abnormal chromosome, but does not actually experience disease symptoms, is called a carrier. She carries the abnormal gene that causes hemophilia and can pass it on to her offspring. If, however, she has a son who receives her abnormal X chromosome, he will be unable to produce the right quantity of factors VIII or IX, and he will have 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 rare. The vast majority of people with 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 hemo-philia A or B. Once such a spontaneous genetic mutation takes place, offspring of the affected person can inherit the newly-created, abnormal chromosome.

Hemophilia A affects between one in 5,000 to one in 10,000 males in most populations.

One recent study estimated the prevalence of hemophilia to be 13.4 cases per 100,000 U.S. males (10.5 hemophilia A and 2.9 hemophilia B). By race or ethnicity, the prevalence was 13.2 cases per 100,000 among white, 11.0 among African-American, and 11.5 among Hispanic males.

Causes and symptoms

In the case of severe hemophilia, the first bleeding event usually occurs prior to 18 months of age. In some babies, hemophilia is suspected immediately when a routine circumcision (removal of the foreskin of a 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 usually don't need treatment. As a child becomes more active, bleeding may occur into the muscles. This is a much more painful and debilitating problem. Such muscle bleedings result in pain and pressure on the nerves in the area of the bleeding. 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 that 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 in someone with hemophilia. Because the skull has no room for expansion, a 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.

Some other rare clotting disorders such as Von Willebrand disease present similar symptoms but are not usually called hemophilia.

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 normal percentages. This information can help in demonstrating the type, as well as the severity, of hemophilia present.

Individuals with a family history of hemophilia may benefit from genetic counseling before deciding to have a baby. Families with a history of hemophilia can also have tests done during a pregnancy to determine whether the fetus has hemophilia. The test, called chorionic villous sampling, examines proteins for the defects that lead to hemophilia. This test, which is associated with a 1% risk of miscarriage, can be performed at 10-14 weeks of gestation. The test called amniocentesis examines the DNA of fetal cells shed into the amniotic fluid for genetic mutations. Amniocentesis, which is associated with a one in 200 risk of miscarriage, is performed at 15-18 weeks of gestation.

Treatment

The most important thing that individuals with hemophilia can do to prevent complications of their 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 VIII to avoid hemorrhage. Also, hemophiliacs should be vaccinated against hepatitis. Medications or drugs that promote bleeding, such as aspirin, should be avoided.

Various types of factors VIII and IX are available to replace a person's missing factors. These are administered intravenously (directly into a person'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 a person's disease. People with relatively mild disease will only require treatment in the event of injury, or to prepare for scheduled surgical or dental procedures. Individuals with more severe disease will require regular treatment to avoid spontaneous bleeding.

While appropriate treatment of hemophilia can both decrease discomfort and be life-saving, complications associated with treatment can also be quite serious. About 20% of all people with hemophilia A begin to produce chemicals in their bodies that rapidly destroy infused factor VIII. The presence of such a chemical may

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.

Montgomery, Robert R., and J. Paul Scott, "Factor XI Deficiency (Hemophilia C)." In Nelson Textbook of Pediatrics, edited by Richard E. Behrman, et al. 16th ed. Philadelphia: W.B. Saunders, 2000, 1511.

Naeim, Faramarz. Atlas of Bone Marrow and Blood Pathology. Philadelphia: W.B. Saunders, 2000.

PERIODICALS

Aledort, L.M. "Economics of Hemophilia Care." Haemostasis, vol. 30, no. 6 (2000): 333-336.

Chorba, T.L., et al. "Effects of HIV Infection on Age and Cause of Death for Persons with Hemophilia A in the United States." American Journal of Hematology, vol. 66, no. 4 (2001): 229-240.

Kashyap, R., and V.P. Choudhry. "Management of Hemophilia in Developing Countries." Indian Journal of Pediatrics, vol. 68, no. 2 (2001): 151-157.

Miller, D.G., and G. Stamatoyannopoulos. "Gene Therapy for Hemophilia." New England Journal of Medicine, vol. 344, no. 23 (2001): 1782-1784.

Roth, D.A., N.E. Tawa, Jr., J.M. O'Brien, D.A. Treco, R.F. Selden, and Factor VIII Transkaryotic Therapy Study Group. "Nonviral Transfer of the Gene Encoding Coagulation Factor VIII in Patients with Severe Hemophilia A." New England Journal of Medicine, vol. 344, no. 23 (2001): 1735-1742.

Santavirta, N., et al. "Coping Strategies, Pain, and Disability in Patients with Hemophilia and Related Disorders." Arthritis and Rheumatism, vol. 45, no. 1(2001): 48-55.

ORGANIZATIONS

American Academy of Family Physicians, 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (913) 906-6000. <http://www.aafp.org/>. fp@aafp.org.

American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, IL 60007-1098. (847) 434-4000. Fax: (847) 434-8000. <http://www.aap.org/default.htm>. kidsdoc@aap.org.

American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106-1572. (800) 523-1546, x 2600 or (215) 351-2600. <http://www.acponline.org>.

American Medical Association, 515 N. State Street, Chicago, IL 60610. (312) 464-5000. <http://www.amaassn.org/>.

American Society of Hematology, 1900 M Street NW, Suite 200, Washington, DC 20036. (202) 776-0544. Fax: (202) 776-0545. <http://www.hematology.org/>. ash@hematology.org.

National Hemophilia Foundation, 116 West 32nd Street, 11th Floor, New York, NY 10001. (800) 424-2634 or (212) 328-3700. Fax: (212) 328-3777. <http://www.hemophilia.org/home.htm>. info@hemophilia.org.

World Federation of Hemophilia, 1425 René Lévesque Boulevard West, Suite 1010, Montréal, Quebec, Canada, H3G 1T7. (514) 875-7944. Fax: (514) 875-8916. <http://www.wfh.org/>. wfh@wfh.com.