Genetic: Hemophilia

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Genetic: Hemophilia

Causes and Symptoms
The Future
For more information


Hemophilia is the name of a group of hereditary blood disorders characterized by deficiencies in the blood's ability to form clots. Although hemophilia varies in severity from person to person, all patients with the disease bruise easily and bleed for abnormally long periods of time when cut.

There are two major forms of hemophilia: hemophilia A, sometimes called classic hemophilia, which accounts for about 80 percent of cases; and hemophilia B, called Christmas disease, which accounts for the remaining 20 percent. Both types are caused by gene mutations, hemophilia A by a mutation of the F8 gene and hemophilia B by a mutation of the F9 gene. Both genes are located on the X chromosome, which means that females (who have two X chromosomes) can transmit the mutations that cause hemophilia, but males (who have only one X chromosome) get the disease.

There is a very rare form of hemophilia called acquired hemophilia, which means that the disease is not genetic but develops later in life. It results from an autoimmune reaction in which the body attacks its own production of coagulation factor VIII, one of the blood factors required for normal clotting.


Hemophilia is a disease that has been known for centuries, although ancient doctors could do little to treat it. It was not until 1803 that John Otto, a doctor in Philadelphia, noted that the disease ran in families but that only males suffered from it. Hemophilia became known as the royal disease in the later nineteenth century, when several descendants of Queen Victoria (1819–1901)—including the queen's youngest son, Leopold—died young from brain hemorrhages. Two of Victoria's daughters were carriers of the defective F8 gene and passed on the disease to the royal houses of Spain, Russia, and Germany.

It was not until the twentieth century that doctors were able to understand the cause of hemophilia. At first they thought that it resulted from unusually fragile blood vessels. In the 1920s, doctors thought that defective platelets, cells in the blood involved in clot formation, were to blame. By 1937, however, it was found that substances dissolved in blood plasma, the liquid part of blood, were a necessary part of the normal clotting process. These proteins in the plasma were called coagulation factors. By 1944, a doctor in Argentina found that there are two distinct forms of hemophilia, each caused by a deficiency of a specific coagulation factor. It was not until 1965, however, that another doctor discovered a way to separate the protein factors from the liquid part of blood plasma by a freeze-drying process. This method made it possible

for people with hemophilia to be treated without frequent high-volume blood transfusions, previously the only method of treatment.

To understand the significance of these advances and discoveries, it helps to understand how blood clots are usually formed. When a blood vessel is cut, it contracts to slow down the bleeding. Platelets in the blood go to the break or cut and form a clump or plug to patch the hole. The coagulation factors in the blood interact with the platelets and other chemicals in the blood to form a network or web that holds the clot in place. This complicated series of chemical reactions is called the coagulation cascade. People with hemophilia, however, have low amounts of coagulation factors. The severity of hemophilia depends on the level of the coagulation factors. A person with mild hemophilia has between 5 and 40 percent of normal coagulation factor activity; a person with moderate hemophilia has between 1 and 5 percent; a person with severe hemophilia has less than 1 percent of normal coagulation factor activity.


Hemophilia A is the more common form of the disorder, occurring in about one in every 4,000 male infants around the world. Hemophilia B affects about one in every 20,000 newborn boys. Girls who carry a defective F8 or F9 gene usually do not suffer from the disease; however, about 10 percent of girls with one abnormal copy of either defective gene will experience heavy menstrual periods and other mild problems with bleeding.

Safety of the Blood Supply

The discovery of freeze-drying techniques to separate clotting factors from whole blood in the 1960s reduced hemophiliacs' need for periodic visits to a hospital for long and costly transfusions of whole blood. Clotting factors that could be infused at home as well as in a doctor's office lengthened the life spans of hemophiliacs and also gave them more independence to lead relatively normal lives.

The situation changed abruptly in the early 1980s with the discovery of the AIDS virus. Although human blood in the United States was screened for syphilis after 1948 and hepatitis B after 1971, the blood supply had been contaminated with AIDS before screening was available. By the fall of 1982, only a few months after the Centers for Disease Control and Prevention (CDC) had issued its first bulletin about AIDS, hemophiliacs who had received clotting factors derived from human blood were being diagnosed with it. By 1985, when effective tests to screen donated blood for HIV had been developed and were in use, about 30,000 Americans, including 9,500 hemophilia patients, had already been infected via contaminated blood. Many hemophiliacs subsequently died from AIDS rather than hemophilia.

The development of genetically engineered clotting factors, made by using recombinant DNA technology without involving human blood or cells, later virtually eliminated the possibility of disease transmission. Two of the products are BeneFIX, designed to supply coagulation factor IX in patients with hemophilia B, and ReFacto, which supplies coagulation factor VIII in patients with hemophilia A.

As far as is known, both hemophilia A and hemophilia B are equally common in all racial and ethnic groups around the world. About 60

percent of persons diagnosed with hemophilia A and 44 percent of persons with hemophilia B have severe disease.

Causes and Symptoms

Both hemophilia A and B are caused by genetic mutations that affect the blood's ability to clot normally. Without enough factor VIII (in the case of hemophilia A) or factor IX (in the case of hemophilia B), the platelets that move to the cut or break in a blood vessel are not held securely within a network of protein fibers. They cannot form a clot strong enough to effectively stop the bleeding, which continues for a longer period of time than in normal people.

The symptoms of hemophilia may include:

  • Large or deep bruises, or unexplained bruises
  • Nosebleeds that start suddenly without any obvious injury
  • Tightness in the joints from blood collecting in the joint spaces
  • Blood in the stools or urine
  • Prolonged bleeding after minor cuts or injuries, or after routine dental work, tooth extractions, or minor surgical procedures

Patients with severe hemophilia may develop symptoms that indicate a medical emergency. These include sudden severe headache, neck pain, seeing double, repeated vomiting, or sudden pain, swelling, and warmth in the large joints (knees, elbows, hips and shoulders) or in the muscles of the arms and legs.


The diagnosis of hemophilia depends in part on its severity. Male babies with severe hemophilia are often diagnosed shortly after birth, particularly if they are circumcised. In some cases the disorder is diagnosed when the toddler begins to walk, bruises easily, or starts having nose-bleeds. Patients with milder hemophilia may not be diagnosed until they are older and have prolonged bleeding following dental work or minor surgery.

The most common test used to diagnose hemophilia is a blood test. A sample of the patient's blood is analyzed for the amount of clotting factor activity that is present. Genetic testing can also be used to diagnose people who have only mild symptoms of hemophilia A or B, as well as

identify women who are carriers of hemophilia gene mutations before they become pregnant.


There is no cure for hemophilia. Treatment is directed at preventing severe bleeding episodes and managing symptoms when they do occur.

Patients with mild hemophilia A may be treated with injections of a hormone called desmopressin or DDAVP, which stimulates the patient's body to release more of its own clotting factor. Patients with hemophilia B or moderate to severe hemophilia A are treated with clotting factors derived from donated human blood or from genetically engineered blood products called recombinant clotting factors.

Patients with hemophilia can be taught to inject themselves with desmopressin or clotting factors at home two or three times a week as a form of prophylaxis, or preventive measure.

Patients with severe hemophilia whose joints have been damaged by bleeding usually need physical therapy to restore range of motion and strength in the damaged joints. They may eventually need to have the joints replaced with artificial joints in adult life.


The life expectancy and quality of life for males with hemophilia have increased dramatically since the 1950s. Before 1960, the average life expectancy of a boy with hemophilia was 11 years. Early death was often preceded by severe pain from bleeding into the joints. As of the early 2000s, life expectancy has increased to fifty-five to sixty years. Older men with severe hemophilia who were treated in the late 1970s or early 1980s are still at risk of death from AIDS; 90 percent of these patients are HIV-positive. About 8 percent of patients with hemophilia eventually die from bleeding into the brain.

About 25 percent of children between six and eighteen years of age with severe hemophilia have below-normal academic skills and an increased risk of emotional and behavioral problems.


Hemophilia can be prevented in part by genetic testing of prospective parents. Although males with hemophilia cannot pass the disease on to sons, they can father daughters who will carry the disease to the next

generation. Hemophilia cannot be completely eliminated by family planning, however, as 34 percent of all hemophilia A cases and 20 percent of all hemophilia B cases are caused by spontaneous mutations in each generation.

The Future

Hemophilia will always be rare, but it is unlikely to ever be completely eliminated for two reasons. One is the role of spontaneous mutations in producing defective F8 and F9 genes in each new generation. The other reason is that most men with hemophilia now live long enough to father children and pass on the defective genes. Because of this change in life expectancy, researchers are presently concentrating on gene therapy as a possible cure for hemophilia. In gene therapy, a normal gene to replace the defective gene is inserted into the patient's genetic material by using a virus as a carrier. Research on gene therapy for hemophilia A is being conducted as of 2008.

SEE ALSO AIDS; Hepatitis A


Coagulation cascade: The complex process in which platelets, coagulation factors, and other chemicals in the blood interact to form a clot when a blood vessel is injured.

Coagulation factors: Proteins in blood plasma involved in the chain of chemical reactions leading to the formation of blood clots. They are also called clotting factors.

Gene therapy: An approach to treating disease by inserting healthy genes into a person's genetic material or by inactivating defective genes.

Plasma: The liquid part of blood, about 55 percent of blood by volume.

Platelets: Specialized cells in the blood that are involved in forming blood clots. Platelets are also called thrombocytes.

Prophylaxis: The use of a medication or other therapy to maintain health and prevent disease.

For more information


Britton, Beverly. Hemophilia. San Diego, CA: Lucent Books, 2003.

Raabe, Michelle. Hemophilia. New York: Chelsea House, 2008.

Sherman, Irwin W. Twelve Diseases That Changed Our World. Washington, DC: ASM Press, 2007. Chapter 1 is about hemophilia.


Biology Animations. Blood Clotting Animation. Available online at (accessed July 22, 2008). The animation describes the process of normal blood clotting. It takes about a minute to play.

Genetics Home Reference. Hemophilia. Available online at (updated March 2007; accessed July 21, 2008).

National Heart, Lung, and Blood Institute (NHLBI). What Is Hemophilia? Available online at (updated June 2007; accessed July 21, 2008).

National Human Genome Research Institute (NHGRI). Learning about Hemophilia. Available online at (updated February 15, 2008; accessed July 21, 2008).

World Federation of Hemophilia. Hemophilia in Pictures.Montréal, Canada: World Federation of Hemophilia, 2005. Available online in PDF or slideshow format at (accessed July 22, 2008). This is an easy-to-understand 41-page illustrated explanation of hemophilia, also available in French, Spanish, Russian, Chinese, and Arabic.

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Genetic: Hemophilia

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Genetic: Hemophilia