Hemophilia

What is Hemophilia?

Hemophilia is a genetic disorder that affects blood clotting. The two most common forms are hemophilia A and hemophilia B. Though the cause is different, the main effect is the same: people with hemophilia bleed for longer than normal.

Untreated hemophilia is dangerous. It puts people at risk for spontaneous bleeding that is hard to stop. Bleeding may be internal, for example in the spaces around joints. Repeated bleeding episodes in joints can cause permanent damage.

There is no cure for hemophilia, but there are effective treatments. When hemophilia is detected early and treated properly, the long-term health outcomes are usually very good. Because of this, babies born in families with a history of hemophilia are usually given a genetic test. It is also possible to have hemophilia without a family history. Blood tests are used to diagnose hemophilia in newborns and people who develop bleeding problems later in life.

Affected Gene

hemophilia gene comparison

Factor VIII and factor IX proteins are just two of 13 coagulation factors in the blood that form a signaling chain. A cut or other injury starts the signal, and it ends with the formation of a solid blood clot, which seals off the injury and stops bleeding. If either factor VIII or factor IX are not working, blood cannot clot properly.

Hemophilia A and B are caused by changes in two different genes. For hemophilia A, the affected gene is F8. For hemophilia B it is F9. Both genes are on the X chromosome. The F8 gene codes for a protein called coagulation factor VIII (eight). F9 codes for the protein coagulation factor IX (nine).

Factor VIII, factor IX, and other coagulation factor proteins circulate in the blood. After an injury, coagulation factors in the area become active. Through a chain reaction, the factors work together to send a signal. In the final step, the signal brings proteins and blood cells together to form a blood clot. The blood clot seals off the injury. Bleeding stops, and healing begins.

Since the F8 and F9 genes are on the X chromosome, hemophilia is inherited differently in males and females (see Inheritance, below). As long as a person has one working copy (allele) of the F8 and F9 genes, their blood usually clots normally.

People with hemophilia have only non-working alleles of either the F8 or the F9 genes meaning they are missing either coagulation factor VIII or IX protein. Some have less working protein than usual, and others have none at all. Either way, the coagulation factor signal chain is cut off or weakened. A blood clot cannot form. Without a blood clot, the injury is not sealed off and the person continues bleeding.

Rare Bleeding Disorders
Bleeding disorders can also come from missing other coagulation factors, including I, II, V, VII, X, XI, XII, and XIII. These conditions are very rare, mainly because the genes that code for these proteins are on autosomes, not sex chromosomes. While it takes just one affected allele to cause hemophilia A or B (at least for males), it generally takes two to cause deficiencies in other coagulation factors. These disorders affect males and females equally. To learn more, visit the National Hemophilia Foundation

Inheritance

Because the F8 and F9 genes are on the X chromosome, they are inherited differently in males and females. X and Y are the sex chromosomes, and they specify whether a person is male (usually XY) or female (XX). Boys inherit their single X chromosome from their mothers. Girls inherit one X chromosome from each parent.

From the perspective of having the genetic disorder, hemophilia follows an X-linked recessive inheritance pattern. Boys with hemophilia inherit a single, non-working allele of either F8 or F9 from their mothers. For a girl to have hemophilia, it takes two non-working alleles. She inherits one from her mother (who is usually a carrier). A girl's second non-working allele comes from her father, who either has the condition, or has sperm that carry a new mutation.

From the perspective of the protein, coagulation factor is made from each allele a person has. The protein circulates in blood. In boys, blood contains protein made from their single allele of F8 or F9. In girls, two forms of protein circulate in the blood— one made from each allele.

The "Royal Disease"
Hemophilia was once prevalent in European royal families. British Queen Victoria carried hemophilia B, which she passed on to several of her children. Since royalty often married royalty, the disorder was passed to the Spanish, Russian, and German royal families.

hemophilia inheritance

Girls and boys inherit different numbers of X chromosomes. Girls get one X chromosome from each parent. Boys get their single X chromosome from their mother.

Normal Protein Expression

hemophilia expression

Factor VIII and IX proteins are made mostly in the liver. They circulate in blood tissue in an active form until they are activated by an injury.

The F8 and F9 genes are activated primarily in liver cells. F8 is also switched on in cells of the spleen and lymph nodes.

Liver cells make much of the body's factor VIII protein and nearly all its factor IX protein. But the proteins do not normally stay in the liver. They are released into another tissue—the blood. Coagulation factors in the blood circulate through all the body's tissues and organs. If an injury occures, coagulation factors are always nearby. They become active and help to trigger the formation of a blood clot.

Protein Function and Interactions

When a blood vessel is damaged, molecules spill into the bloodstream that are not normally there. This starts a very complex chain of events. First a few nearby platelets (a type of blood cell) are activated, and they stick to the injury. At the same time, the blood vessel damage triggers a chain reaction in the blood. Coagulation factor proteins sequentially activate one another (though not in numerical order).

The coagulation factor signal quickly leads to a blood clot. The signal triggers two processes. First, it activates a protein called fibrin. Many strands of fibrin come together into a meshwork at the site of the injury. Second, it activates more platelets. They get sticky and enter the fibrin meshwork, forming a plug-like blood clot.

Most coagulation factors, including factor IX protein, are enzymes. Enzymes make specific chemical changes to target molecules, which are often other proteins. Factor VIII protein is a partner to factor IX. It brings factor IX and its target protein together, so that factor IX can activate its target. The target is released, and it continues the chain. This interaction takes place near the injury, on the outside membrane of platelets. This close interaction is why missing either factor VIII or factor IX protein has the same effect.

Without factor VIII or IX, fibrin molecules are scarce and slow to form. Far fewer platelets become sticky, and without fibrin they do not stay in place very well. A person bleeds longer than usual, and bleeding can restart after stopping. Blood is lost or it pools in tissues and organs. Too much blood loss causes weakness and confusion. Excess blood in and around organs interferes with their normal function. Pooled blood is especially harmful around joints, where it can do permanent damage. An injured blood vessel needs to be sealed off to heal.

hemophilia protein

To learn more about the blood coagulation cascade—plus a good general description of the causes, diagnosis, and treatment of hemophilia—watch this video from Osmosis.org

Symptoms and Features of Hemophilia

hemophilia symptoms

In people with poorly treated hemophilia, a bump or jolt can cause bleeding from blood vessels in the joints. Blood builds up inside the membrane that surrounds the joint, causing swelling and pain. Over time, repeated bleeding incidents can damage the joint.

The effects of hemophilia are different from person to person, both in severity and timing of symptoms. Often, symptoms first appear around the time a child learns to walk, as they start to get more bumps and bruises. Effects can first appear later in life as well, especially for mild forms.

The main feature of hemphilia is abnormal bleeding. It can range from mild to severe. Much of the variability depends on the specific gene variant(s) (allele(s)) a person has.

  • Mild: Affected people may bleed longer than normal after a serious injury or surgery. Some people with mild hemophilia never notice effects.
  • Moderate: Affected people bleed longer than normal after a cut, accident, or surgery. They may occasionally bleed spontaneously, but usually there is a known cause.
  • Severe: Affected people may have many large bruises or bleed excessively for no clear reason. They may also have frequent, hard-to-stop nosebleeds.

Internal bleeding is a big concern for everyone with hemophilia, especially since it might not be noticed right away. In addition to causing blood loss, internal bleeding affects muscles and joints. In the short-term, it causes swelling, stiffness, and pain. Over time, it can damage tissue and lead to chronic joint disease with arthritis-like symptoms. If too much bleeding occurs in the brain, it can cause seizures, paralysis, and even death.

Alleles, Protein, and Variability

Men with hemophilia have one non-working allele of either the F8 or F9 gene. Affected women usually have two non-working alleles of F8, or two non-working alleles of F9. It is rare, but carrier women who have one healthy allele and one non-working allele, can have mild symptoms.

There are many alleles of F8 and F9 that cause hemophilia. Each disorder-causing allele codes for a protein that works a little differently, which is why the effects vary from person to person.

Hemophilia is often diagnosed with a blood test that measures how well a person's factor VIII or IX proteins work. Blood is collected, and clot formation is measured over time. The measure is called "clotting activity." Low clotting activity means a person's coagulation factor proteins don't work well. They have severe hemophilia. The graph shows the clotting activity in blood from people with different types of hemophilia: mild, moderate, and severe.

Alleles that cause mild hemophilia usually code for a protein that has some activity. For example, some F8 alleles code for factor VIII protein that still interacts with factor IX, but more weakly than usual. Some F9 alleles code for factor IX protein that can still activate its target, it just works slowly.

Other alleles cause severe hemophilia. They code for proteins with very little or no activity. For example, sometimes only a small piece of the protein is made, or the protein does not make it into the blood.

Depending on which allele a person has, they may respond more or less well to some treatments. For example, people with alleles that cause severe hemophilia are more likely to have a dangerous immune response to injected protein therapies. Their immune system recognizes the healthy injected protein as different from their own and attacks it. An immune response is more common in people missing factor VIII than in people missing factor IX.

A test can measure how well a person's coagulation factors work. Different alleles code for proteins that work more or less well, and thus have different clotting activities. Even people with the same allele often have different clotting activity, and an individual's clotting activity can change over time.

Other Factors

hemophilia other

People with hemophilia tend to be healthier when they have quick access to good medical care.

Even when people have the same allele of F8 or F9, they do not always experience the same effects. Symptoms range from very mild to severe. They may appear at any time from childhood through adulthood. Some people never have symptoms.

Variation in genes other than F8 and F9 change the effects of hemophilia. For example, variations in genes influence blood vessel strength and elasticity. Strong, stetchy blood vessels are less likely to spontaneously tear and cause internal bleeding. Variations in genes that influence the number of platelets a person makes influence how well blood clots. Many gene variations influence the immune system. These variations affect how well hemophilia treatments work. Hemophilia is often treated with injection of healthy coagulation factor protein. Natural variation in immune system genes changes how well the body tolerates the injected protein.

Environmental factors also account for differences between individuals. In some poeple, physical activity can help, since strong muscles and a healthy weight protect joints. Living near or being able to travel to a treatment center that specializes in bleeding disorders can also make a difference. It helps people start treatment early, stick to a schedule, and stay healthier.

Some women show symptoms of hemophilia, even when they have just one affected allele. This can happen when they carry a severely affected allele, in which case they produce less clotting factor than usual. It can also be related to X inactivation. At a certain stage in a girl's embryonic development, one X chromosome is inactivated in each of her cells. If the X chromosome with the healthy allele is inactivated in most of her liver cells, she may not be able to make enough coagulation factor protein. In many carrier women, symptoms appear only under certain conditions, like after childbirth. Usually, their symptoms are mild.

Treating and Managing Hemophilia

Hemophilia treatments have come a long way in terms of effectiveness and safety. The first treatment—direct blood trasfusion—was developed around 1840. However, even as recently as the 1950s, many people with hemophilia died in childhood. In the 1970s, people learned to concentrate coagulation factors from healthy blood donors. This treatment became safer when we learned to screen for and kill potential viruses (like HIV or hepatitis C) in donor blood. Now coagulation factor proteins can be made without donor blood, making them even safer.

Modern approaches to managing hemophilia are aimed at preventing bleeding before it starts. This reduces joint damage and other effects from bleeding. Most approaches use a combination of medical and lifestyle behaviors. Today, many people with hemophilia lead long and healthy lives. For some, at-home treatment is even an option.

Medical Approaches

  • Regular injection of the missing coagulation factor proteins can prevent bleeding before it starts. This preventative treatment is called prophylaxis. In severe cases, it is done 2-3 times per week.
  • Injection of coagulation factors can also treat bleeding when it happens.
  • Treatment with hormones can stimulate the body to make more coagulation factors.
  • Injected therapeutic antibodies can do the job of missing factor VIII, especially in those whoe immune systems attack the injected factor VIII protein.
  • Medicated creams or sprays can be applied to a cut to promote blood clotting.
  • Staying up to date on vaccinations like hepatitis A and B can help prevent blood-borne infections.
  • Physical therapy can ease pain from joint damage.
  • Carefully planned dental procedures and surgeries can help prevent or prepare for bleeding.
  • Awareness of how other medications affect blood can be helpful, since many can thin blood or prevent clotting.
  • Hemophilia is a potential target for gene therapy. There are a number of studies and clinical trials in progress.

Lifestyle Behaviors

  • Physical activity can protect joints by strengthening muscles and maintaining weight.
  • Low-impact activities like swimming or biking can ease stress on joints.
  • Good dental hygiene can prevent procedures that may cause bleeding.
  • Learning basic first aid, like elevating and applying pressure to wounds, can help stop bleeding.
  • Educating friends, family, teachers, and coaches about hemophilia can help them know what to do in case of an accident.
  • A medical alert bracelet can tell emergency response teams a coagulation factor injection may be needed.
  • Discussions with a counselor can help patients (or parents) improve mental health, especially when it comes to balancing physical activity with staying safe.

hiker receiving injection

People with hemophilia can give themselves injections of coagulation factors—even when they travel to remote places.

References

References

Fijnvandraat, K., Cnossen, M. H., Leebeek, F. W., & Peters, M. (2012). Diagnosis and management of haemophilia. British Medical Journal, 344, e2707.

Pan, J., Dinh, T. T., Rajaraman, A., Lee, M., Scholz, A., Czupalla, C. J., & Jiang, H. (2016). Patterns of expression of factor VIII and von Willebrand factor by endothelial cell subsets in vivo. Blood, 128, 104-109.

Peyvandi, F., Garagiola, I., & Young, G. (2016). The past and future of haemophilia: diagnosis, treatments, and its complications. The Lancet 388, 187-197.

Rallapalli, P. M., Kemball‐Cook, G., Tuddenham, E. G., Gomez, K., & Perkins, S. J. (2013). An interactive mutation database for human coagulation factor IX provides novel insights into the phenotypes and genetics of hemophilia B. Journal of Thrombosis and Haemostasis, 11(7), 1329-1340.

Rallapalli, P. M., Kemball-Cook, G., Tuddenham, E. G., Gomez, K., & Perkins, S. J. (2013). Factor IX mutation database.

Rallapalli, P., Kemball-Cook, G., Tuddenham, E., Gomez, K., & Perkins, S. (2016). Factor VIII variant database.


APA format:

Genetic Science Learning Center. (2019, June 10) Hemophilia. Retrieved February 28, 2024, from https://learn.genetics.utah.edu/content/genetics/hemophilia

CSE format:

Hemophilia [Internet]. Salt Lake City (UT): Genetic Science Learning Center; 2019 [cited 2024 Feb 28] Available from https://learn.genetics.utah.edu/content/genetics/hemophilia

Chicago format:

Genetic Science Learning Center. "Hemophilia." Learn.Genetics. June 10, 2019. Accessed February 28, 2024. https://learn.genetics.utah.edu/content/genetics/hemophilia.