Hemophilia is caused by a missing or faulty gene that tells your body how to make clotting proteins

Hemophilia occurs when your body cannot make enough of a protein needed to stop bleeding. The cause is always genetic — a mutation in the gene responsible for producing clotting factor VIII (in hemophilia A) or clotting factor IX (in hemophilia B). You inherit this faulty gene from one or both parents, even if neither parent has symptoms. The gene sits on the X chromosome, which is why the inheritance pattern differs between males and females.

Your blood clots through a cascade of chemical reactions. When you cut yourself, platelets rush to the wound and form a plug. Then clotting factors — proteins in your blood — work in sequence to reinforce that plug and stop the bleeding. If one of these factors is missing or doesn't work properly, the cascade breaks down and bleeding continues longer than it should. In hemophilia, the missing factor is either factor VIII or factor IX, depending on which type you have.

Key Takeaways

  • Hemophilia is caused by a mutation in a gene on the X chromosome that controls production of clotting factor VIII or IX.
  • Males are affected more often than females because they have only one X chromosome, so one faulty gene causes the disease.
  • Females can inherit hemophilia if they receive the faulty gene from both parents, or can be carriers if they inherit it from only one parent.
  • The faulty gene is inherited from parents, but about one-third of hemophilia cases result from a new mutation that occurs spontaneously.
  • Hemophilia A and B are caused by different genes, but both result in the same problem: your blood cannot clot normally.

How the X chromosome inheritance pattern works

Hemophilia follows what is called X-linked recessive inheritance. Males have one X chromosome and one Y chromosome (XY). Females have two X chromosomes (XX). Because males have only one X chromosome, a single faulty gene on that X causes hemophilia. Females need a faulty gene on both X chromosomes to have hemophilia, which is rare.

A female with a faulty gene on one X chromosome is a carrier. She usually does not have symptoms because her other X chromosome carries a working copy of the gene. However, she can pass the faulty gene to her children. A carrier mother has a 50 percent chance of passing the faulty gene to each child — sons who inherit it will have hemophilia, and daughters who inherit it will be carriers.

A father with hemophilia will pass his faulty X chromosome to all of his daughters (making them carriers) but to none of his sons, because sons inherit the Y chromosome from their father, not the X. This is why hemophilia in families often skips generations or appears to come from nowhere.

Spontaneous mutations and new cases

About one-third of people diagnosed with hemophilia have no family history of the disease. In these cases, the faulty gene arose as a spontaneous mutation — a random error in DNA copying that occurred in the egg or sperm cell of one parent, or very early in the child's development. Once this new mutation exists, it follows the same inheritance rules as any other hemophilia gene.

A spontaneous mutation can happen to anyone, regardless of family background or health history. It is not caused by anything the parents did or did not do during pregnancy. If a parent carries a spontaneous mutation, they can pass it to their children using the same X-linked pattern described above.

The difference between hemophilia A and hemophilia B

Hemophilia A and hemophilia B are caused by mutations in different genes, both located on the X chromosome. Hemophilia A results from a faulty gene for clotting factor VIII. Hemophilia B results from a faulty gene for clotting factor IX. The inheritance pattern is identical for both types — the only difference is which clotting protein is missing or defective.

Hemophilia A is more common, accounting for about 80 percent of cases. Hemophilia B accounts for about 20 percent. The severity of each type depends on how much clotting factor your body can produce. Some people with hemophilia produce very little factor (severe hemophilia), while others produce a moderate or mild amount (moderate or mild hemophilia).

Why females can have hemophilia symptoms even with one faulty gene

Although females typically need two faulty genes to have hemophilia, some female carriers experience bleeding symptoms. This happens through a process called X-inactivation. Early in female development, each cell randomly "turns off" one of its two X chromosomes. If a cell inactivates the X chromosome with the working gene and keeps active the X chromosome with the faulty gene, that cell cannot make normal clotting factor.

If enough cells happen to inactivate the normal X chromosome, a female carrier can have enough missing clotting factor to cause bleeding problems. The severity varies widely depending on how many cells made this random choice. Some female carriers have no symptoms at all, while others have mild or even moderate hemophilia.

A female can also have hemophilia if she inherits a faulty gene from both parents — one from each. This is uncommon but does occur. She may also develop hemophilia-like symptoms if she inherits one faulty gene and has Turner syndrome (a condition affecting sex chromosomes), or in rare cases of skewed X-inactivation.

What happens when the clotting factor gene is faulty

A faulty hemophilia gene can cause problems in several ways. The gene might produce a clotting factor that is present but does not work properly. It might produce very little factor at all. Or it might produce no factor whatsoever. The specific mutation determines how much functional clotting protein your body makes, which in turn determines whether your hemophilia is mild, moderate, or severe.

The mutation might be a small change in the DNA code — a single letter switched or deleted. Or it might be a large deletion or rearrangement of the gene. Large deletions tend to cause more severe hemophilia because they eliminate more of the gene's instructions. Small mutations sometimes allow the body to produce some working factor, resulting in milder disease.

Hemophilia severity depends on how much clotting factor you produce

Doctors classify hemophilia by the percentage of normal clotting factor present in your blood. Severe hemophilia means you have less than 1 percent of the normal amount. Moderate hemophilia means 1 to 5 percent. Mild hemophilia means 5 to 40 percent. The amount of factor you produce is determined by the specific mutation you inherited — some mutations allow more factor production than others.

A person with severe hemophilia may bleed spontaneously, without any injury. Someone with moderate hemophilia usually bleeds after minor trauma. Someone with mild hemophilia may bleed only after significant injury or surgery. The severity can vary even within families, because the same mutation sometimes produces slightly different amounts of factor in different people.

Frequently Asked Questions

Can hemophilia skip generations in a family?

Yes. If a woman is a carrier but has no symptoms, she may not know she carries the faulty gene. She can pass it to her son, who will have hemophilia, and to her daughters, who will be carriers. From the outside, it looks like hemophilia appeared out of nowhere in that generation.

If my mother is a carrier, will I definitely have hemophilia?

If you are male and your mother is a carrier, you have a 50 percent chance of inheriting the faulty gene and having hemophilia. If you are female and your mother is a carrier, you have a 50 percent chance of being a carrier yourself. You would need the faulty gene from both parents to have hemophilia.

Can hemophilia be caused by something other than genetics?

No. Hemophilia is always caused by a faulty gene on the X chromosome. You cannot develop hemophilia later in life from an injury, illness, or lifestyle choice. However, acquired bleeding disorders that resemble hemophilia can develop in adults due to other medical conditions, but these are different diseases.

Does the severity of hemophilia change over time?

The amount of clotting factor your body produces is set by your genes and generally does not change significantly over your lifetime. However, stress, illness, or certain medications can temporarily affect factor levels slightly. The severity classification you receive at diagnosis typically remains the same throughout your life.

If I have hemophilia, will all my children have it?

If you are a male with hemophilia, all of your daughters will be carriers, but none of your sons will have hemophilia (they inherit your Y chromosome, not your X). If you are a female with hemophilia, each child has a 50 percent chance of inheriting the faulty gene, regardless of sex.