Hemophilia

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 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.

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 was 13.4 cases per 100,000 U.S. males (10.5 hemophilia A and 2.9 hemophilia B). By race/ethnicity, the prevalence was 13.2 cases/100,000 among white, 11.0 among African-American, and 11.5 among Hispanic males.

Causes and symptoms

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 from 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 called "sex-linked." The chromosome's flawed unit is referred to as the gene.

Both factors VIII and IX are produced by a genetic defect of 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 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 that 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 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.

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 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. 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.

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 of hemophilia present, as well as the severity.

Individuals with a family history of hemophilia may benefit from 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. 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. 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 gestation.

Treatment

The most important thing that individuals with hemophilia can do to prevent complications of this 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 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 in 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 that 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 contaminated with human immunodeficiency virus (HIV), the virus which causes AIDS. A large number of hemophiliacs were infected with HIV and some statistics show that HIV is still the leading cause of death among hemophiliacs. Currently, careful methods of donor testing, as well as methods of inactivating viruses present in donated blood, have greatly lowered this risk.

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.

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 that 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— A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease, and can be transmitted to offspring.

Platelets— Small disc-shaped structures that circulate in the blood stream and participate in blood clotting.

Trauma— Injury.

Resources

BOOKS

Khoury, Muin J., Wylie Burke, and Elizabeth J. Thomson, editors. Genetics and Public Health in the 21st Century: Using Genetic Information to Improve Health and Prevent Disease. New York: Oxford University Press, 2000.

Resnick, Susan. Blood Saga: Hemophilia, AIDS, and the Survival of a Community. Berkeley: University of California Press, 1999.

PERIODICALS

Stephenson, J. "New Therapies Show Promise for Patients with Leukemia, Hemophilia, and Heart Disease." JAMA 285 (January 1, 2001): 153+.

ORGANIZATIONS

National Hemophilia Foundation. 116 West 32nd St., 11th Floor, New York, NY 10001. (800) 42-HANDI. 〈http://[email protected]〉.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. 〈http://www.rarediseases.org〉.

OTHER

March of Dimes. 〈www.modimes.org〉.

National Organization for Rare Disorders. 〈www.rarediseases.org〉.

Hemophilia

Definition

Hemophilia is a coagulation disorder arising from a genetic defect of the X chromosome; the defect can either be inherited or result from spontaneous gene mutation. In each type of hemophilia (hemophilias A, B, and C), a critical coagulation protein is missing, causing individuals to bleed for long periods of time before clotting occurs. Depending on the degree of the disorder in the affected individual, uncontrolled bleeding may occur spontaneously with no known initiating event, or occur after specific events such as surgery, dental procedures, immunizations, or injury.

Description

The body's normal mechanism for blood clotting is a complex series of events (coagulation cascade) involving interaction between the injured blood vessel, blood cells called platelets, 13 specific coagulation factors (designated by Roman numerals I through XIII), and other substances that circulate in the blood.

When blood vessels are injured in a way that causes bleeding, platelets collect over the injured area, forming 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 occurs that results in the formation of a more reliable plug. The final plug or clot involves tightly woven fibers of a material called fibrin. The production of fibrin requires the interaction of a series of proteins, clotting factors I through XIII, in a process called amplification to rapidly produce the proper-sized fibrin clot from the small number of molecules initially activated by the injury. In the complex coagulation process, the absence or inactivity of just one clotting factor can greatly increase bleeding time. In hemophilia, certain clotting factors are either decreased in quantity, absent altogether, or improperly formed, preventing the formation of a clot and resulting in uncontrolled bleeding.

Hemophilia A is the most common type of coagulation 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 percent 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 musculoskeletal bleeding into their joints, skin, and muscles. Surgery or trauma can result in life-threatening hemorrhage and must be carefully managed.
• Individuals with 1–5 percent of normal factor VIII activity level have moderate hemophilia and are at risk for heavy bleeding after seemingly minor traumatic injuries.
• Individuals with 5–40 percent of normal factor VIII activity level have mild hemophilia and must prepare carefully for any surgery or dental procedures.

In hemophilia B, or Christmas disease, the deficient clotting factor is factor IX, but the symptoms are very similar to those of hemophilia A. Factor IX is produced in the liver and is dependent on interaction with vitamin K in order to function properly. A deficiency in vitamin K can affect the clotting factor's performance as well as a deficiency in the factor itself.

Hemophilia C is rare and much milder than hemophilia A or B. It involves reduced activity of factor XI and is characterized by mild bleeding such as nosebleeds (epistaxis) or prolonged menstrual bleeding, or mild bleeding after tonsillectomies or dental extractions.

Demographics

Hemophilia A affects between one in 5,000 to one in 10,000 males in most populations. Hemophilia B occurs in one in 40,000 to 50,000. The prevalence of hemophilia is estimated to be 13.4 cases per 100,000 U.S. males (10.5 hemophilia A and 2.9 hemophilia B). By race/ethnicity, the prevalence is 13.2 cases in 100,000 among white males, 11.0 among African-American males, and 11.5 among Hispanic males. Hemophilia C occurs primarily among individuals of Jewish descent.

Causes and symptoms

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 percent of all people with hemophilia A or B inherited the disease. The other 30 percent develop from a spontaneous genetic mutation.

Both factors VIII and IX are produced by a genetic defect of the X chromosome, so hemophilia A and B are both sex-linked diseases passed on from a female to male offspring. (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 called sex-linked.) Because a female child always receives two X chromosomes, she will nearly always 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 that 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. However, the vast majority of people with either hemophilia A or B are male.

About 30 percent 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 affected their X chromosome, resulting in the defect that causes hemophilia A or B. Once such a spontaneous genetic mutation takes place, offspring of the affected person can inherit the newly created, flawed chromosome.

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 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 do not usually require treatment. As a child becomes more active, bleeding may occur into the muscles, a much more painful and debilitating situation. 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.

Christmas disease varies from mild to severe, but mild cases are more common. The severity depends on the degree of deficiency of factor IX. Hemophilia B symptoms are similar to those of hemophilia A, including numerous large and deep bruises and prolonged bleeding.

Some of the most problematic and frequent bleeds occur into the joints, particularly 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, which interrupts breathing and can be life-threatening. A blow to the head, which might be totally insignificant in a normal child, can result in bleeding into the skull and brain. Because the skull has no room for expansion, the hemophiliac 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 severe, heavy, uncontrollable bleeding (hemorrhage) from injuries such as motor vehicle accidents and also from surgery.

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

When to call the doctor

Hemophilia is usually discovered when an injury initiates bleeding and the bleeding will not stop. In very young children, spontaneous musculoskeletal bleeding may occur around the time the child begins to walk; these episodes may be the first sign of hemophilia. In some children, a simple surgical procedure, such as a tooth extraction or injection, may present with uncontrolled bleeding. Any signs of deep bruises or the presence of prolonged bleeding after a bump or an injury that breaks the skin should be reported to a physician or emergency service immediately. Bleeding under the skin (hematoma), which looks like a severe bruise, should also be reported and medical care sought immediately.

Diagnosis

Various diagnostic tests are available to measure, under carefully controlled conditions, the length of time it takes to produce certain components of the final fibrin clot. The activated partial thromboplastin time (APTT) is performed and will typically be prolonged while a prothrombin time (PT) will likely be normal. Factor assays, measurement methods performed by the clinical laboratory, can determine the percentage of factors VIII and IX present compared to normal percentages. This information helps to confirm a diagnosis of hemophilia and identifies the type and severity of hemophilia present.

Families with a history of hemophilia can also have tests done during a pregnancy to determine whether the fetus will have hemophilia. Chorionic villous sampling is a test that examines proteins for deficiencies or defects that are characteristic of hemophilia. The test can be performed at 10 to 14 weeks; test performance is associated with a 1 percent risk of miscarriage. Amniocentesis is a method of withdrawing amniotic fluid from the placenta to allow examination of fetal cell DNA shed into the amniotic fluid, helping to identify genetic mutations. Amniocentesis can be performed at 15 to 18 weeks gestation and is associated with a one in 200 risk of miscarriage.

Treatment

The treatment of hemophilia involves replacing or supplementing the deficient coagulation factors. Various preparations of factors VIII and IX are available to replace missing factors as needed. Cryoprecipitate, for example, is a single- or multiple-donor human plasma preparation rich in coagulation factors; it is made available as a frozen concentrate. Fresh frozen plasma is a single-donor preparation of factor-rich plasma; it is used primarily for replacing factor XI in individuals with hemophilia C. Concentrated 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. These preparations are administered directly into the individual's veins (intravenous administration).

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

Appropriate treatment of hemophilia can decrease suffering and be lifesaving in the presence of hemorrhage. Complications associated with treatment, however, can also be quite serious. About 20 percent of all individuals with hemophilia A begin to produce antibodies in their blood against the specific factor protein; the presence of antibodies may then rapidly destroy infused factor VIII. The presence of such antibodies may greatly hamper efforts to prevent or stop a major hemorrhage.

Individuals who receive coagulation factors prepared from pooled donor blood were once at risk for serious infections that could be passed through the infusion of human blood products, such as the hepatitis virus and HIV. Concern has also been raised about the possibility of hemophiliacs contracting a fatal slow virus infection of the brain (Creutzfeldt-Jakob disease) from blood products. However, more sensitive testing techniques have been developed and as of 2004 were employed by the companies producing pooled precipitates from human plasma. These improved methods of donor testing, as well as methods of inactivating viruses present in donated blood, have greatly lowered the risk of infection.

Molecular biological techniques have introduced gene therapies as new treatment possibilities for hemophilia. Gene therapy involves sophisticated methods of transferring new genes to hemophiliacs, correcting deficiencies or defects in the clotting mechanism. These methods are being researched in the early 2000s.

Prognosis

Variations in the type and severity of hemophilia makes it difficult to generalize a prognosis, however, for individuals with mild hemophilia, the prognosis is quite good. Those with more severe hemophilia can also live relatively normal lives with careful management and avoidance of injury. Many individuals achieve normal life expectancy. Without treatment of bleeding episodes, severe muscle and joint pain and eventually permanent damage can occur. Much depends upon the physical activity level of the individual and the possibility of accidental injuries or surgeries required for other conditions, which cannot be predicted.

Prevention

Because of its genetic origins, hemophilia cannot be prevented in those born with the inherited defects or factor deficiencies. However, individuals who have a family history of hemophilia may benefit from genetic testing and counseling before deciding to have a baby.

The most important way for individuals with hemophilia to prevent complications of the disease is to avoid activities that may lead to injury. Those individuals who require dental work or any type of surgery may need to be pre-treated with an infusion of factor VIII to avoid hemorrhage. Hemophiliacs should also avoid medications or drugs that promote bleeding; aspirin is one such medication and many prescription drugs have anticoagulant properties.

Parental concerns

When a child has an inherited coagulation disorder such as hemophilia, parents will be concerned about the possibility of trauma or injury that may lead to potentially dangerous bleeding episodes. The watchfulness of parents along with effective management of hemophilia by physicians can help the child to lead a relatively normal life. Careful avoidance of injury is essential. Counseling is available to help children handle the psychosocial aspects of living with hemophilia. Education is available from public health organizations to help parents be informed about their child's condition.

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 trigger a cascade of chemical reactions which produces increasingly larger quantities of different chemicals, resulting in an appropriately-sized, strong fibrin clot.

Coagulation factors —Specific coagulation proteins in the blood required for clotting. Coagulation proteins are designated with roman numerals I through XIII.

Fibrin —The last step in the blood coagulation process. Fibrin forms strands that add bulk to a forming blood clot to hold it in place and help "plug" an injured blood vessel wall.

Hemorrhage —Severe, massive bleeding that is difficult to control. The bleeding may be internal or external.

Mutation —A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease. This change can be transmitted to offspring.

Platelet —A cell-like particle in the blood that plays an important role in blood clotting. Platelets are activated when an injury causes a blood vessel to break. They change shape from round to spiny, "sticking" to the broken vessel wall and to each other to begin the clotting process. In addition to physically plugging breaks in blood vessel walls, platelets also release chemicals that promote clotting.

Trauma —Serious physical injury. Also refers to a disastrous or life-threatening event that can cause severe emotional distress, including dissociative symptoms and disorders.

See also Coagulation disorders.

Resources

BOOKS

Britton, Beverly. Diseases and Disorders: Hemophilia. Farmington Hills, MI: Gale, 2003.

Khoury, Muin J., Wylie Burke, and Elizabeth J. Thomson, eds. Genetics and Public Health in the 21st Century: Using Genetic Information to Improve Health and Prevent Disease. New York: Oxford University Press, 2000.

McDougald, Monroe. Hemophilia Care in the New Millennium. Lancaster, UK: Kluwar Academic Publishers, 2001.

Rodriguez-Merchan, E. C., et al. Inhibitors in Patients with Hemophilia. Oxford, UK: Blackwell Publishing, 2002.

ORGANIZATIONS

National Hemophilia Foundation. 116 West 32nd St., 11th Floor, New York, NY 10001. Web site: <www.hemophilia.org>.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812–8923. Web site: <www.rarediseases.org>.

WEB SITES

"Hemostatis and Coagulation." The Merck Manual Online, 2003. Available online at <www.merckcom/pubs/mmanual/section11/chapter131.131c.htm> (accessed October, 22, 2004).

March of Dimes. Available online at <www.modimes.org> (accessed October 22, 2004).

L. Lee Culvert Jennifer F. Wilson, MS

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 is 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 under-standing 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 suffer from the disease, 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 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 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 hemophilia 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 do not 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 villus 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 suffering 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 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 that may be passed through blood. Hepatitis, a severe and potentially fatal viral liver infection, may be contracted from pooled factor preparations. Recently, much concern has been raised about the possibility of hemophiliacs contracting a fatal slow virus infection of the brain (CJD or Creutzfeldt-Jakob disease ) from blood products. Unfortunately, pooled factor preparations in the early 1980s were contaminated with human immunodeficiency virus (HIV), the virus that causes AIDS. A large number of hemophiliacs were infected with HIV and some statistics show that HIV is still the leading cause of death among hemophiliacs. Currently, careful methods of donor testing, as well as methods of inactivating viruses present in donated blood, have greatly lowered this risk.

The most exciting new treatments currently being studied 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.

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.

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 person with hemophilia will depend on issues such as physical activity level and accidental injuries. Statistics on prognosis are not generally available.

Health care team roles

Hemophilia is usually diagnosed by a pediatrician or family physician. These doctors, assisted by a hematologist, usually also provide care. Nurses may provide supportive care.

Prevention

People who know that their family includes hemophiliacs should receive careful genetic counseling before deciding to have a baby. There is no way to prevent the 30% of hemophilia cases that are caused by new, spontaneous mutations.

Resources

BOOKS

Ayalew, Tefferi. Primary Hematology. Totowa, NJ: Humana Press, 2001.

Beutler, Ernest, et al. Williams Hematology. 6th ed. New York: McGraw Hill, 2000.

Collins, Robert D., and Stephen H. Swerdlow. Pediatric Hematopathology. St Louis, MO: Churchill Livingstone, 2001.

Forbes, C. D., R. Madhok, and Louis M. Aledort. Hemophilia. Philadelphia: Lippincott Williams & Wilkins, 1997.

Handin, Robert I. "Disorders of Coagulation and Thrombosis." In Harrison's Principles of Internal Medicine, edited by Anthony S. Fauci, et al. 14th ed. New York: McGraw-Hill, 1998, 736-744.

Kessler, Craig M. "Coagulation Factor Deficiencies." In Cecil Textbook of Medicine, edited by Lee Goldman, and J. Claude Bennett. 14th ed. Philadelphia: W.B. Saunders, 2000, 1004-1013.

Mazza, J. Manual of Clinical Hematology. Philadelphia: Lippincott Williams & Wilkins, 2001.

Montgomery, Robert R., and J. Paul Scott. "Factor VIII or Factor IX Deficiency (Hemophilia A or B)." In Nelson Textbook of Pediatrics, edited by Richard E. Behrman, et al. 16th ed. Philadelphia: W.B. Saunders, 2000, 1508-1511.

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/〉. [email protected].

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〉. [email protected].

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.ama-assn.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/〉. [email protected].

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〉. [email protected].

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/〉. [email protected].

OTHER

Blood Net. 〈http://bloodnet.org/toppage2.htm〉.

Canadian Hemophilia Society. 〈http://www.hemophilia.ca/english〉.

Hemophilia Federation of America. 〈http://www.hemophiliafed.org〉.

Hemophilia Home Page. 〈http://www.web-depot.com/hemophilia〉.

Hemophilia Resource Network. 〈http://www.hemophilia.net〉.

National Heart, Lung and Blood Institute. 〈http://www.nhlbi.nih.gov/health/public/blood/other/hemo_97.htm〉.

Vanderbilt University College of Medicine. 〈http://www.mc.vanderbilt.edu/peds/pidl/hemeonc/hemophil.htm〉.

Hemophilia

What Is Hemophilia?

What Causes Hemophilia?

How Do People Know They Have Hemophilia?

Diagnosis

Treatment

Prevention of Bleeding Episodes

Living with Hemophilia

The Future

Resources

Hemophilia (he-mo-FIL-e-a) is a hereditary disorder in which the blood does not clot normally and excessive bleeding results.

KEYWORDS

for searching the Internet and other reference sources

Bleeding disorders

Blood transfusion

Clotting factors

Coagulation disorders

Fibrin

Hematology

Most people take certain bodily functions for granted: breathing, digestion, healing. We do not have to think about them; they just happen. Blood clotting is one of these things—at least it usually is. But for the approximately 20,000 people in the United States with hemophilia A or B, a simple thing like losing a tooth or falling off a bicycle can cause life-threatening complications. This is because their blood does not clot, or coagulate, normally. And without clotting, any injury will just continue to bleed.

What Is Hemophilia?

Hemophilia is an inherited deficiency of a blood-clotting factor that results in excessive bleeding. When a healthy person is injured, a sequence of events occurs to cause the blood to turn from liquid to solid (a clot) and to stop flowing. First, platelets (tiny capsule-shaped cells in the blood) begin to stick together and form a small plug at the point of bleeding. Platelets contain an enzyme, or protein, that causes fibrinogen (fy-BRIN-o-jen), a substance in the blood, to change to fibrin (FY-brin), a hard substance that does not dissolve. Like firemen racing to a burning building, fibrin rushes to the area of blood vessel injury and piles up, helping the platelets to block the opening and stop the blood flow.

Fibrin can perform this task only by using substances in the blood manufactured by the body called clotting factors. The clotting factors are numbered I through XIII. In hemophilia A, clotting factor VIII is deficient. Factors I through VII function properly, but then the clotting

process is interrupted and blood from a wound continues to flow. Hemophilia B, which occurs less frequently, is caused by a deficiency of factor IX. Sending fibrin to clot blood without these factors is like sending firemen to a fire without enough water to put it out.

What Are Chromosomes and Genes?

A chromosome is a paired, thread-like structure found in the nucleus or central, controlling part of the body’s cells that determines the development of characteristics for each individual person. The one obvious characteristic to be determined is whether a person is male or female. A female has two X chromosomes, and a male has one X and one Y.

Chromosomes are composed of genes, units that determine everything from the color of eyes to how a body functions. The X chromosome carries genes that control the production of clotting factors VIII and IX. In people with hemophilia, these genes cause the body to produce too little VIII or IX. But even if a woman (XX) has one X chromosome with the hemophilia gene, the other X chromosome is probably normal, and her body will produce enough factor VIII or IX to ensure that the blood will clot. The Y chromosome, however, has no part in the production of blood-clotting factors. Boys (XY) who inherit a defective X chromosome from their mothers have no other X chromosome to fall back on to prevent them from having hemophilia.

Hemophilia varies in severity. Most healthy people have 100 percent levels of clotting factor VIII or IX in their blood. In contrast, people with the most severe forms of hemophilia have less than 1 percent of the normal amount. Unable to clot blood at all, they can begin to hemorrhage, or bleed internally, even without external injuries.

Those with moderate hemophilia have factor VIII or IX levels between 1 and 5 percent. Excessive bleeding follows minor injury as well as dental extractions and surgeries. Mild hemophilia is seen in those with factor VIII or IX levels between 6 and 50 percent. For this group, excessive bleeding is usually associated only with major injuries, surgical procedures, or tooth extractions. People with mild cases may not be diagnosed as having hemophilia until adulthood, when unexplained and excessive bleeding accompanies an operation or a visit to the dentist.

What Causes Hemophilia?

Hemophilia is not contagious like a cold or flu. It is usually inherited, which means that it often runs in families. Hemophilia almost exclusively affects boys. It is caused by a defective gene that is unintentionally passed from mothers to sons via the X chromosome.

Usually, female “carriers” have normal levels of clotting factors themselves. If a man with hemophilia marries a woman who is a carrier, there is a possibility of having a daughter with hemophilia, but this is rare. Up to one third of the people with hemophilia have no family members who have the condition or who are carriers. In these cases, a mutation (a change in a gene) has produced a new hemophilia gene, which may be passed on to following generations.

How Do People Know They Have Hemophilia?

Although hemophilia is present at birth, babies who are not circumcised (a surgical procedure to remove the foreskin of the penis) seldom experience problems until they begin to crawl. Once they start to bump into hard surfaces or fall, they begin to bleed into muscles or joints, places where two bones meet. Such internal bleeding can cause joints to bruise and swell painfully.

Joint bleeding is serious, because it can lead to arthritis (inflammation of the joints), deformity, and disability. Prompt treatment is necessary to prevent severe pain and swelling. As boys with hemophilia grow older, they often learn to recognize joint bleeding before the pain or swelling appears as a “funny,” tingling feeling.

Bleeding into a muscle, most often the calf, thigh, or forearm, commonly occurs after injury; sometimes this occurs spontaneously. The resulting swelling, which may develop over several days, may create pressure inside the muscles and damage nerves and blood vessels. Symptoms include muscle

European Royalty and Hemophilia

History’s most famous carrier of the gene for hemophilia was Victoria (1819-1901), Queen of England and grandmother to most of the royalty in Europe. In 1853, Queen Victoria gave birth to her eighth child, Leopold, Duke of Albany, who had hemophilia and died at the age of 31 from internal bleeding after a fall.

Two of Queen Victorias four daughters, Alice (b. 1843) and Beatrice (b. 1857), also carried the gene for hemophilia and subsequently transmitted the disease to three of Victoria’s grandsons and to six of her great-grandsons.

Alice’s daughter Alexandra also was a carrier of hemophilia, and she transmitted the disease to her son Alexis (b. 1904), whose father was Czar Nicholas II (1868–1918) of Russia. Alexis is perhaps the most famous of the European royals with hemophilia. Alexis was the heir to his father’s throne and his medical condition caused much anxiety in the royal household. Historians are still discussing the role Alexis’s condition played in the Russian revolution of 1918.

HIV and Hemophilia

One of the greatest risks faced by those with hemophilia in the late 1970s and early 1980s was the possibility of contracting HIV, the AIDS virus. This happened when people got transfusions of clotting factors drawn from infected blood. It is estimated that 55 percent of people with hemophilia were infected with HIV in this way between 1979 and 1985.

In those days, blood donations were not tested for HIV. And people with hemophilia were especially likely to get infected for two reasons: They got many transfusions and each transfusion contained pooled clotting factors drawn from the blood of many, many donors in order to get enough clotting factors to be effective. If any one of those donors was infected with HIV, the person with hemophilia was at risk.

Today, however, the blood supply is much safer. Potential blood donors are screened to eliminate those who might have been exposed to HIV, and all blood is tested for the virus. These measures apply to all blood transfusions. In addition, clotting factors drawn from blood are treated with heat and other virus-killing techniques, although these methods are not used for other kinds of transfusions because they can damage other blood products.

The safety measures produced dramatic results. From 1986 to 1999, according to the National Hemophilia Foundation, no one with hemophilia contracted HIV from a transfusion in the United States. Now new technology allows clotting factors to be genetically engineered without the use of blood donations.

tightness, pain, skin temperature change, and tingling or numbness. Early treatment is needed to prevent paralysis or permanent immobility.

Any type of neck or head injury can be extremely dangerous for anyone with hemophilia. Neck and throat hemorrhages can obstruct breathing. Head injury, even a minor fall or bump on the head, can cause bleeding into the brain; the symptoms include irritability, headache, confusion, nausea, vomiting, and double vision.

People with hemophilia bruise very easily, but skin bruises are rarely serious. Bleeding from small cuts and scrapes can usually be stopped by applying firm pressure to the area for several minutes. Deep cuts, on the other hand, can bleed profusely and require treatment.

Diagnosis

Using DNA testing (direct analysis of the genes), it is possible to determine whether a woman is a “carrier” of the hemophilia gene. Blood tests can measure the level of clotting factors in the blood. Tests can be performed on fetuses to see if they have inherited hemophilia.

Treatment

People with hemophilia often need to be given the blood-clotting factors they lack. These factors may be drawn from the blood donations of many people and purified. Or, since the mid-1990s, they may be produced by genetic engineering, which does not require blood donations. The clotting factors are transfused through the person’s vein, often at a hospital or doctor’s office. With proper training, a person can perform transfusions at home, or parents can do it for their children.

One medication that should not be used by those with hemophilia is aspirin, a pain reliever, since it interferes with normal blood clotting and increases people’s tendency to bleed.

How often transfusions are needed depends on how severe the illness is and how often the person gets injured. In cases of major injury or surgery, a person may need transfusions two or three times a day for days or weeks. Even without being injured, some people with severe hemophilia may get transfusions on a regular basis to prevent problems. People with mild cases of hemophilia may rarely or never need transfusions.

A medication called DDAVP (desmopressin), which is not a blood product, can sometimes help to release any extra factor VIII stores in people with mild or moderate hemophilia A. This temporary treatment may help a person avoid a transfusion after a minor injury, for instance.

Prevention of Bleeding Episodes

As soon as a child is diagnosed with hemophilia, parents should try to prevent or reduce the occurrence of bleeding. Doctors recommend choosing soft toys without sharp corners and padded clothing—particularly at the elbows and knees—while a child is learning to walk. Children should be immunized, but the injections should be given under the skin rather than into the muscles to prevent hemorrhages. Children should also be taught to clean their teeth regularly and to visit the dentist to prevent tooth decay and gum disease.

Did You Know?

• Hemophilia A occurs in about one out of every 5,000 male births; hemophilia B in about one out of every 30,000.
• The average person with hemophilia infuses 80,000 to 100,000 units of blood-clotting factor a year.
• Care for a typical severe hemophilia patient costs $100,000 to $150,000 per year.
• Severe hemophilia accounts for 60 percent of all those with the disease.

Living with Hemophilia

Hemophilia is usually not a fatal disorder, and people with hemophilia often live long and active lives. Activities such as swimming, walking, and bicycling can help build up muscles that support the joints. Contact sports such as football or wrestling, however, are prohibited because of the high risk of head or neck injury.

Explaining hemophilia to friends and family can help boys feel less self-conscious about their condition and educate others about the importance of prompt treatment.

The Future

At present, there is no cure for hemophilia, but trials with gene therapy are under way. Many of them are concentrating on replacing the gene that causes hemophilia with a normal one that will raise the level of deficient clotting factors to promote coagulation.

Other researchers have produced genetically engineered animal cells into which they have inserted the genetic sequence to produce human factor VIII.

See also

Clotting

Genetic Diseases

Hemorrhage

Resources

Books and Magazines

White, Ryan, and Anne Marie Cunningham. Ryan White: My Own Story. Signet, 1992.

Hemalog. A quarterly magazine for people with bleeding disorders.

Organizations

National Hemophilia Foundation http://www.infonhf.org/

World Foundation of Hemophilia http://www.wfh.org/

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/>. [email protected].

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>. [email protected].

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/>. [email protected].

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>. [email protected].

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/>. [email protected].

OTHER

Blood Net. <http://bloodnet.org/toppage2.htm>.

Canadian Hemophilia Society. <http://www.hemophilia.ca/english>.

Hemophilia Federation of America. <http://www.hemophiliafed.org>.

Hemophilia Home Page. <http://www.web-depot.com/hemophilia>.

Hemophilia Resource Network. <http://www.hemophilia.net>.

National Heart, Lung and Blood Institute. <http://www.nhlbi.nih.gov/health/public/blood/other/hemo_97.htm>.

Vanderbilt University College of Medicine. <http://www.mc.vanderbilt.edu/peds/pidl/hemeonc/hemophil.htm>.

L. Fleming Fallon, Jr., MD, DrPH