Hemophilia and genetics

DEFINITION Hemophilia is a sex-linked inherited genetic disorder in which the blood does not clot adequately. Although incidents of hemophilia are relatively rare, the study of this disease has yielded important information about genetic transmission and the factors involved in blood clotting.

Risk Factors

Hemophilia affects males almost exclusively because it is an X-linked (often called sex-linked) recessive trait. Although it is possible for women to have hemophilia, it is extremely rare, because women must have two copies of the defective gene to be affected. A female has two X chromosomes, and a male has an X and Y chromosome. Even though the trait is recessive, because men have a single X chromosome, recessive X-linked genes are expressed as if they were dominant.

Etiology and Genetics

When an injury occurs that involves blood loss, the body responds by a process known as hemostasis. Hemostasis involves several steps that result in the blood clotting and stopping the bleeding. With hemophilia, an essential substance is absent. For blood to clot, a series of chemical reactions must occur in a “domino effect.” The reaction starts with a protein called the Hageman factor or factor XII, which cues factor XI, which in turn cues factor X and so on until factor I is activated. Each factor is expressed by a different gene. If one of the genes is defective, the blood will not clot properly.

Hemophilia A is the most common type, affecting more than 80 percent of all hemophiliacs and resulting when clotting factor VIII is deficient. Hemophilia B (also known as Christmas disease) affects about 15 percent of hemophiliacs and results when clotting factor IX is deficient.

Hemophilia in males is inherited, along with their X chromosome, from the mother. The daughter of a hemophiliac father will carry the disease because she inherits one X chromosome (with the abnormal gene) from the father and one from the mother. Any son born to a carrier has a 50 percent chance of having hemophilia, since she will either pass on the X chromosome with the normal gene or the one with the abnormal gene. In order for a female to have hemophilia, she would have to inherit the abnormal gene on the X chromosomes from both her mother and her father.

Symptoms

Hemophilia can be mild, moderate, or severe, depending on the extent of the clotting factor deficiency. Mild may not be evident until adulthood, when prolonged bleeding is observed after surgery or a major injury. The symptoms of moderate or severe hemophilia often appear early in life. These symptoms may include easy bruising, difficulty in stopping minor bleeding, bleeding into the joints, and internal bleeding without any obvious cause (spontaneous bleeding). When bleeding occurs in the joints, the person experiences severe pain, swelling, and possible deformity in the affected joint. The weight-bearing joints, such as ankles and knees, are usually affected. Internal bleeding requires immediate hospitalization and could result in death if severe.

Screening and Diagnosis

People who experience prolonged or abnormal bleeding are often tested for hemophilia. Testing the specific blood-clotting factors can determine the type and severity of hemophilia. Although a family history of hemophilia may help in the diagnosis, approximately 20 percent of hemophiliacs have no such history of the disease.

Treatment and Therapy

Symptoms of hemophilia can be reduced by replacing the deficient clotting factor. People with hemophilia A may receive antihemophilic factors to raise their blood-clotting factor above normal levels so that the blood clots appropriately. People with hemophilia B may receive clotting factor IX during bleeding episodes in order to increase the clotting factor levels. The clotting factors may be taken from plasma (the fluid part of blood), although it takes a great deal of plasma to produce a small amount of the clotting factors. Risks include infection by the hepatitis virus or human immunodeficiency virus (HIV), although advanced screening procedures have greatly reduced such risks.

In 1993, the US Food and Drug Administration (FDA) approved a new recombinant form of factor VIII, and in 1997 the FDA approved a new recombinant form of factor IX for treating individuals with hemophilia A and B, respectively. The advantage of recombinant factors is that they are automatically free of plasma-derived viruses, thus reducing one of the primary risks endured by previous hemophiliacs. Patients with mild hemophilia may be treated with a synthetic hormone known as desmopressin acetate (DDAVP).

Treatment with the plasma clotting factors has increased longevity and quality of life. In addition, many patients are able to treat bleeding episodes as outpatients with home infusions or self-infusions of the clotting factors. However, problems do exist with the treatment of hemophilia. Various illnesses, such as HIV, liver disease, or cardiovascular disease, have resulted from contamination of the clotting factors. Several techniques are used to reduce the risk of contamination, and most difficulties were largely eliminated by the mid-1990s. Bleeding into the joints is often controlled by the use of elastic bandages and ice. Exercise is recommended to help strengthen and protect the joints. Painkillers are used to reduce the chronic pain associated with joint swelling and inflammation, although hemophiliacs cannot use products containing aspirin or antihistamines because they prolong bleeding.

Prevention and Outcomes

Hemophilia is not curable, although advances in the treatment of the disease are prolonging life and preventing crippling deformities. Patients and their families have also benefited from genetic education, counseling, and testing. Hemophilia centers can provide information on how the disease is transmitted, potential genetic risks, and whether a person is a carrier. This knowledge provides options for family planning, as well as support in coping with the disease.

Bibliography

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