Hemophilia causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Causes

• Hemophilia is caused by a mutation or change, in one of the genes, that provides instructions for making the clotting factor proteins needed to form a blood clot. This change or mutation can prevent the clotting protein from working properly or to be missing altogether. These genes are located on the X Chromosome. Males have one X and one Y chromosome (XY) and females have two X chromosomes (XX). Males inherit the X chromosome from their mothers and the Y chromosome from their fathers. Females inherit one X chromosome from each parent.

• The X chromosome contains many genes that are not present on the Y chromosome. This means that males only have one copy of most of the genes on the X chromosome, whereas females have 2 copies. Thus, males can have a disease like hemophilia if they inherit an affected X chromosome that has a mutation in either the factor VIII or factor IX gene. Females can also have hemophilia, but this is much rarer. In such cases both X chromosomes are affected or one is affected and the other is missing or inactive. In these females, bleeding symptoms may be similar to males with hemophilia.

A female with one affected X chromosome is a "carrier" of hemophilia. Sometimes a female who is a carrier can have symptoms of hemophilia. In addition, she can pass the affected X chromosome with the clotting factor gene mutation on to her children. Learn more about the inheritance pattern for hemophilia.

• Even though hemophilia runs in families, some families have no prior history of family members with hemophilia. Sometimes, there are carrier females in the family, but no affected boys, just by chance. However, about one-third of the time, the baby with hemophilia is the first one in the family to be affected with a mutation in the gene for the clotting factor.

Haemophilia A

Hemophilia A is caused by an inherited X-linked recessive trait, with the defective gene located on the X chromosome. Females have two copies of the X chromosome. So if the factor VIII gene on one chromosome does not work, the gene on the other chromosome can do the job of making enough factor VIII.

Males have only one X chromosome. If the factor VIII gene is missing on a boy's X chromosome, he will have hemophilia A. For this reason, most people with hemophilia A are male.

If a woman has a defective factor VIII gene, she is considered a carrier. This means the defective gene can be passed down to her children. Boys born to such women have a 50% chance of having hemophilia A. Their daughters have a 50% chance of being a carrier. All female children of men with hemophilia carry the defective gene.

Haemophilia B

Hemophilia B is caused by an inherited X-linked recessive trait, with the defective gene located on the X chromosome.

Females have two copies of the X chromosome. If the factor IX gene on one chromosome does not work, the gene on the other chromosome can do the job of making enough factor IX.

Males have only one X chromosome. If the factor IX gene is missing on a boy's X chromosome, he will have Hemophilia B. For this reason, most people with hemophilia B are male.

If a woman has a defective factor IX gene, she is considered a carrier. This means the defective gene can be passed down to her children. Boys born to such women have a 50% chance of having hemophilia B. Their daughters have a 50% chance of being a carrier.

All female children of men with hemophilia carry the defective gene. In 1990, George Brownlee and Merlin Crossley showed that two sets of genetic mutations were preventing two key proteins from attaching to the DNA of people with a rare and unusual form of haemophilia B – haemophilia B Leyden – where sufferers experience episodes of excessive bleeding in childhood but have few bleeding problems after puberty. This lack of protein attachment to the DNA was thereby turning off the gene that produces clotting factor IX, which prevents excessive bleeding.

Haemophilia C

It is caused by a deficiency of coagulation factor XI and is distinguished from haemophilia A and B by the fact it does not lead to bleeding into the joints. Furthermore, it has autosomal inheritance, since the gene for factor XI is located on chromosome 4 (close to the prekallikrein gene); and it is not completely recessive, individuals who are heterozygous also show increased bleeding. Many mutations exist, and the bleeding risk is not always influenced by the severity of the deficiency.