Causes of Hemophilia

Hemophilia is a bleeding disorder typically caused by mutations in the genes that provide instructions for making certain proteins — blood clotting factors VIII, IX, or XI — which are needed for proper blood clotting. Depending on the specific mutation, these blood clotting factors either fail to function properly or are not present at all.

Mutations in each of those genes also result in different types of hemophilia. Mutations in F8, the gene that provides instructions for making factor VIII, cause hemophilia A, also known as classic hemophilia. Those found in F9, the gene that encodes for factor IX, lead to hemophilia B, or Christmas disease, named for Stephen Christmas, the first person diagnosed with the condition in 1952. Finally, mutations in F11, the gene encoding for factor XI, result in hemophilia C.

While F8 and F9 genes reside on the X chromosome, F11 is found on chromosome 4. This affects how these different types of hemophilia are inherited.

Although inherited mutations are the more common cause of hemophilia, spontaneous mutations may trigger the disease in some cases. In certain rare cases, an autoimmune reaction can also lead to the onset of a type of acquired hemophilia.

Inherited mutations

Approximately 70% of hemophilia cases are inherited.

The genes for clotting factors VIII and IX are found on the X chromosome. Since females inherit two X chromosomes and males inherit only one, hemophilia tends to affect males more frequently. A female with a faulty X chromosome is said to be a hemophilia carrier, as she can still pass the condition to her biological children, depending largely on the child’s gender and on which of the two X chromosomes is inherited.

Despite having two X chromosomes, women may still be affected by hemophilia when their non-mutation-bearing X chromosome becomes inactivated, or when they inherit faulty mutation-bearing X chromosomes from both parents.

Hemophilia C stems from mutations in the F11 gene, which is found on chromosome 4. Each person inherits two copies of F11 regardless of gender, meaning that the disorder affects males and females equally. However, it occurs less frequently than hemophilia A and B.

Mutations underlying hemophilia C are usually inherited in an autosomal recessive manner, meaning that a person must inherit a faulty copy of the gene from each parent to develop the disease. In some cases, hemophilia C is inherited in an autosomal dominant way, meaning that a single faulty copy of F11 is sufficient to trigger the condition.

Spontaneous mutations

Approximately 30% of hemophilia cases stem from spontaneous mutations that have not been inherited.

Spontaneous mutations can occur in a variety of ways. These include mistakes made in DNA replication, such as inadvertently substituting one nucleotide — a DNA building block — for another in the DNA sequence of a gene encoding for a clotting factor.

Other causes

In very rare cases — approximately one in a million people — an autoimmune disorder can lead to the onset of an acquired form of hemophilia.

The immune system normally produces proteins called antibodies that latch onto viruses, bacteria, and other disease-causing entities that could harm the body, triggering reactions leading to the destruction of those invaders. In autoimmune diseases, however, the body mistakenly produces antibodies against itself.

In the case of acquired hemophilia, the body attacks its own clotting factors, usually factor VIII. This reduces the amount of factor VIII available to effectively promote blood clot formation and prevent major bleeds.

Although the specific cause of acquired hemophilia remains unknown, it is sometimes associated with other illnesses (usually immune disorders or cancer), allergic reactions to certain medications, or pregnancy.

 

Last updated: July 8, 2021

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