Hemophilia is a bleeding disorder caused by a congenital, inherited mutation in a gene on the X chromosome that results in a lack of clotting factors in the blood.

The standard treatment for hemophilia is “prophylaxis therapy,” the regular administration of factor 8 concentrates for people with hemophilia A and factor 9 concentrates for people with hemophilia B to maintain a certain level of clotting factor concentration, and “on-demand replacement therapy,” which is used when actual bleeding occurs. However, if clotting factors are administered continuously, antibodies develop against them, and the concentrates no longer work.

When clotting factors are no longer effective, recurrent bleeding in the joints can lead to arthropathy, which can cause limited mobility and, in the worst cases, disability. It is estimated that 30-50 percent of people with hemophilia suffer from some form of disability. Preventing arthropathy, therefore, is key to the quality of life of people with hemophilia.

Until now, prophylaxis has consisted of intravenous injections of factor 8 concentrates two to three times a week. However, it is inconvenient to have to visit a hospital every time you need to receive an intravenous injection. On the other hand, JW Pharmaceuticals' Hemlibra (emicizumab), recently approved and covered by health insurance as a non-clotting factor drug, has improved dosing convenience by being a subcutaneous injection.

Korea Biomedical Review interviewed Professor Park Jeong-a of the Department of Pediatrics at Inha University Hospital, to learn about the importance of prophylaxis in treating hemophilia and the significance of Hemlibra's subcutaneous injection for improving dosing convenience.

Question: Can you give us a brief explanation of hemophilia?

Answer: Hemophilia is a bleeding disorder caused by a deficiency of blood clotting. Hemophilia A is classified as a deficiency of 8 blood clotting factors, and hemophilia B is classified as a deficiency of 9 factors. There is also hemophilia C, but it is rare in Korea, and it is not known much compared to hemophilia A and B because it often does not have many symptoms.

When a blood vessel is damaged and bleeding occurs, platelets adhere to damaged endothelial cells and aggregate together to form a primary hemostatic clot. When clotting factors are activated, they form a secondary hemostatic clot to stop bleeding. However, if one of the clotting factors is deficient, the secondary clot does not form, and the bleeding does not stop. This is why, in normal people, bruising from bleeding usually goes away after a few days, but in people with hemophilia, the bruising continues to grow. This means that the bleeding is still going on.

Q: When is hemophilia usually diagnosed?

A: Some people are diagnosed in childhood, others in adolescence. In countries like the United States, it's diagnosed earlier because they tend to be circumcised at birth. In Korea, hemophilia is suspected after vaccination and when there is a lot of bruising that cannot be healed. In mild cases, it is easy to detect in adolescents and adults, but severe cases are diagnosed around the age of one because the blood clotting factor is less than 1 percent. There are also quite a few people who are diagnosed after being injured in the military or having an accident because they know that they don't bleed well or that they don't heal well.

Q: When should healthcare providers suspect hemophilia?

A: If you have hemophilic arthropathy or hemorrhagic vasculopathy, (the joints) are usually swollen or injured. So, if you have hemorrhagic joints, it's a good indication of hemophilia. Also, if you get a bruise and it keeps spreading down, and if you don't have good hemostasis and it keeps going, you should be suspicious. Generally, if you get a large hematoma (a swollen, purplish, bloody spot) after a vaccination, it's most likely hemophilia, and you should seek medical attention.

Q: What’s the ultimate goal of hemophilia treatment?

A: If hemophilia is not treated or prevented properly, arthropathy can develop in the ankles, knees, and elbows starting at the age of 10. In Korea, 30 to 50 percent of people with hemophilia have some form of disability.

In the early 1900s, the overall survival rate of hemophilia was very low, with most people reportedly dying in their 20s. This has improved since the introduction of blood clotting factors. Life expectancy is now the same as in the general population, so the focus should be on how well people with hemophilia live and function in everyday life. The difference between having and not having a disability, i.e., having hemophilic arthropathy and not having hemophilic arthropathy, can be delayed or prevented with good prophylaxis.

Q: Please explain the treatment process for hemophilia.

A: When a person is diagnosed with hemophilia, they are classified according to severity. Usually, it is based on the concentration of clotting factors: 1 percent or less is considered severe, between 1-5 percent is moderate, and more than 5 percent is mild. However, there may be a difference between the actual clinical presentation and the concentration of clotting factors. Some patients are severe and don't have much bleeding clinically, and some patients are mild and have a lot of bleeding. So, in patients who don't bleed a lot, we supplement with clotting factors to prevent further joint bleeding when they do bleed or get injured. For patients who bleed frequently or easily, prophylaxis is a regular infusion of clotting factors, even if they are not bleeding.

Q: When should they start prophylaxis?

A: Prophylaxis is usually started before age 3 for severe hemophilia A or B. This usually prevents arthropathy until the age of 10. Repeated joint bleeding before age 10 has been linked to arthropathy after age 10. Therefore, treating the disease during its latent stage is important to have healthy joints as an adult.

Q: Taking injections for the rest of your life is difficult. Do you also adjust the frequency?

A: People with hemophilia need to have injections about twice a week. However, in the case of factor A, it has a very short half-life of between 12 and 19 hours. Factor B has a longer half-life and can gradually increase from twice a week to once every 10 days. In both cases, however, injecting regularly to maintain a certain concentration is important. The problem is that these are intravenous (blood vessel) injections, which can be painful for patients. Furthermore, children have a very difficult time with veins.

Q: If so, it seems important for patients to take their medication more conveniently.

A: Right. I had a patient who came to the clinic up to three times a week for injections, and every time, the patient’s mother and father would come and spend half the day in the injection room, wrestling with a crying, screaming child to get the injections in. Imagine if that repeats two or three times a week. Fortunately, this child was an indication for Hemlibra, and with a change in medication, she now comes to the clinic about once a month. Hemlibra is a subcutaneous injection, so she visits once a month to get the injection, and then two weeks later, her parents give her the injection at home. Since the switch, there hasn't been any major bleeding, and the bruising has decreased. The quality of life for the parents and the child has changed.

Q: How many patients have switched to Hemlibra? And which patients do you think should switch to it?

A: I have about five patients who have switched from clotting factors to Hemlibra. Once you have antibodies to clotting factors, it's better to switch. The first indication would be antibody status because you can have anaphylactic reactions like anaphylaxis. If you have antibodies, it's useless. The second group is patients who require intravenous (IV) injection two to three times a week and those who have difficulty finding a vein and need a central vein.

Also, Hemlibra has been shown to maintain a clotting factor concentration of 5-15 percent, so if you can live with that and have no problems, you may want to consider switching. However, a highly active athlete may need a higher clotting factor level, so this should be considered carefully. As for Hemlibra, we don't know how effective it is in activities requiring high clotting factors, so more research is needed.

Q: In hemophilia, preventing joint deterioration through prophylaxis seems as important as managing bleeding. However, we know that prophylaxis has not had a very good track record. What do you think is the reason?

A: Children under 10 tend to do well because their parents take care of them, but after age 10, they tend to do less because they have to take care of themselves. In addition, children who have reached puberty are very reluctant to show their injections. They may not even tell their schools or friends that they have hemophilia, so they often skip their injections. For this reason, the rate of prophylaxis decreases with age.

Q: We need to communicate the importance of preventive care, especially to young people.

A: That's correct. Good prophylaxis can reduce arthropathy, so it's important to take care of oneself and not skip it. You might wonder why I need to get a needle if I'm not bleeding, but at the end of the day, the quality of life for people with hemophilia depends on preventing joint damage through prophylaxis.

Q: In conclusion, what would you like to say to people with hemophilia or their caregivers?

A: Hemophilia is a lifelong disease. There are so many treatments and so much more convenience. It's progressing at a rapid pace. I think it's all about how healthy you can live, and the most important thing is prevention. It's important to start preventing from a young age to stay healthy. They say to start as early as possible, but it's never too late. If you start now, you can minimize the damage to your joints and improve your quality of life.