Hemophilia is a bleeding disorder usually caused by defects (mutations) in the genes that code for the blood-clotting factors VIII, IX or XI.
What causes hemophilia A and hemophilia B?
Hemophilia A and B are the major forms of hemophilia and affect males more than females. Hemophilia A is the most common type that affects approximately 1 in 4,000 to 5,000 newborn boys, while hemophilia B affects 1 in 20,000 newborn boys.
Mutations in the gene coding for factor VIII cause hemophilia A (also known as classic hemophilia), while mutations in the gene coding for factor IX cause hemophilia B (also called Christmas disease). The genes encoding for factor VIII and factor IX are both situated on the X-chromosome.
Mutations in these genes cause a deficit of blood-clotting factors, which are proteins in the blood that work together with platelets to stop or control bleeding. As a result, blood clotting in hemophilia patients is impaired and results in uncontrolled bleeding.
The genetic material in humans is packaged in 23 chromosome pairs, with the last pair being two X chromosomes in females and one X and one Y chromosome pair in males. If a disease-causing mutation is in a gene located on the X chromosome, a male with this mutation will develop hemophilia.
A mutation in a gene situated on the X chromosome does not necessarily cause a disease in females because they have a second X chromosome carrying a healthy version of the gene that can compensate for the mutation. Such women are said to be “carriers” of the condition. In the case of hemophilia, a carrier female may have low levels of clotting factor and show symptoms of hemophilia, such as bleeding.
If there is a defective gene on one X chromosome and the other X chromosome becomes inactivated, which is known as X-inactivation or Lyonization, it results in hemophilia in females.
The genetic mutations in the genes may be passed to children by their parents, or arise spontaneously.
In almost 70 percent of cases, hemophilia is inherited. If a woman carries the defective gene in one of her X-chromosomes, her children, both male and female, have a 50 percent chance of inheriting it. If a carrier woman has a daughter and she inherits the faulty gene from her mother, she also will be a carrier. However, if a carrier woman has a son who inherits the faulty gene, he will develop the disease.
If a man has hemophilia, he will not pass the condition to his sons, but will pass the faulty gene to all his daughters, all of whom will be carriers. If the mother also is a carrier, the daughter has a risk of developing hemophilia.
Approximately 30% of hemophilia cases are due to spontaneous or random mutations within the gene. In these cases, the father does not have hemophilia, the mother is not a carrier and the child develops hemophilia as a result of a new mutation.
What causes hemophilia C?
Hemophilia C is caused by a deficiency of clotting factor XI due to mutations in the factor XI gene, which is situated on chromosome 4. The defective gene is inherited in an autosomal recessive manner, meaning that both males and females have the same risk of inheriting the condition. For the disease to develop, a faulty copy of the gene must be inherited from each parent, meaning that each parent must either have the disease themselves or be carriers of the disease. The reduced level or activity of factor XI results in moderate bleeding symptoms, usually occurring after trauma or surgery.
What causes acquired hemophilia?
This rare form of hemophilia does not result from inherited gene mutations. Rather, it is an autoimmune disorder. It is caused by the formation of auto-antibodies, which are cellular proteins that attack the body’s own molecules. In acquired hemophilia, auto-antibodies attack coagulation factor VIII and block its activity. As a result, there is abnormal bleeding into the skin, muscles, or other soft tissues. The symptoms usually begin in adulthood. The reason for the production of auto-antibodies is unknown in about half of the cases. However, sometimes it is associated with pregnancy, immune system disorders, cancer, or allergic reactions to drugs.
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