Hemophilia is usually an inherited bleeding disorder in which the blood does not clot properly. This can lead to spontaneous bleeding as well as bleeding following injuries or surgery.
Blood contains many proteins called clotting factors that can help to stop bleeding. People with hemophilia have low levels of either factor VIII (8) or factor IX (9). The severity of hemophilia that a person has is determined by the amount of factor in the blood. The lower the amount of the factor, the more likely it is that bleeding will occur which can lead to serious health problems.
In rare cases, a person can develop hemophilia later in life. The majority of cases involve middle-aged or elderly people, or young women who have recently given birth or are in the later stages of pregnancy. This condition often resolves with appropriate treatment.
Hemophilia occurs in about 1 of every 5,000 male births. Currently, about 20,000 males in the United States are living with the disorder. Hemophilia A is about four times as common as hemophilia B, and about half of those affected have the severe form. Hemophilia affects people from all racial and ethnic groups.
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.
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.
Hemophilia can result in:
- Bleeding within joints that can lead to chronic joint disease and pain.
- Bleeding in the head and sometimes in the brain which can cause long term problems, such as seizures and paralysis.
- Death can occur if the bleeding cannot be stopped or if it occurs in a vital organ such as the brain.
There are several different types of hemophilia. The following two are the most common:
- Hemophilia A (Classic Hemophilia)
This type is caused by a lack or decrease of clotting factor VIII.
- Hemophilia B (also called Christmas Disease)
This type is caused by a lack or decrease of clotting factor IX.
Common signs of hemophilia include:
- Bleeding into the joints. This can cause swelling and pain or tightness in the joints; it often affects the knees, elbows, and ankles.
- Bleeding into the skin (which is bruising) or muscle and soft tissue, causing a build-up of blood in the area (called a hematoma).
- Bleeding of the mouth and gums, and bleeding that is hard to stop after losing a tooth.
- Bleeding after circumcision (surgery performed on male babies to remove the hood of skin, called the foreskin, covering the head of the penis).
- Bleeding after having shots, such as vaccinations.
- Bleeding in the head of an infant after a difficult delivery.
- Blood in the urine or stool.
- Frequent and hard-to-stop nosebleeds.
Many people who have or have had family members with hemophilia will ask that their baby boys get tested soon after birth. About one-third of babies who are diagnosed with hemophilia have a new mutation not present in other family members. In these cases, a doctor might check for hemophilia if a newborn is showing certain signs of hemophilia.
To make a diagnosis, doctors would perform certain blood tests to show if the blood is clotting properly. If it does not, then they would do clotting factor tests, also called factor assays, to diagnose the cause of the bleeding disorder. These blood tests would show the type of hemophilia and the severity.
The amount of bleeding that can be expected in an individual with hemophilia depends upon the severity of the deficiency. Normal plasma levels of FVIII and FIX range from 50% to 150%. People with no measurable factor VIII or IX (FVIII or FIX<1%) are considered to have the severe form of hemophilia. Severe hemophilia can result in frequent bleeding episodes. In many cases, bleeding, particularly into joints, can occur spontaneously, without any trauma or injury that can be remembered by the patient or family.
Factor levels of 1% to 5% of normal are indicative of moderate hemophilia. These patients may have abnormal bleeding after minor trauma but should not experience spontaneous bleeding. However, after repeated bleeding into the same joint, spontaneous bleeding may occur in that joint, even if the individual has moderate hemophilia.
Persons with 6% to 49% of factor activity are considered to have mild hemophilia and are expected to have relatively few problems with bleeding, except during surgery or after severe trauma. Carrier women can have lower than normal plasma levels of factor VIII or IX and thus can experience symptoms of mild hemophilia.
The best way to treat hemophilia is to replace the missing blood clotting factor so that the blood can clot properly. This is done by infusing (administering through a vein) commercially prepared factor concentrates. People with hemophilia can learn how to perform these infusions themselves so that they can stop bleeding episodes and by performing the infusions on a regular basis (called prophylaxis), can even prevent most bleeding episodes.
Good quality medical care from doctors and nurses who know a lot about the disorder can help prevent some serious problems. Often the best choice for care is to visit a comprehensive Hemophilia Treatment Center (HTC), such as the UC Davis Hemostasis and Thrombosis Center. A HTC not only provides care to address all issues related to the disorder, but also provides health education that helps people with hemophilia stay healthy.
Clotting Factor Products
The two main types of clotting factor concentrates available are:
- Plasma-derived Factor Concentrates
Plasma is the liquid part of blood. It is pale yellow or straw-colored and contains proteins such as antibodies, albumin, and clotting factors. Several factor concentrate treatment products are available that are made from human plasma proteins. All blood and parts of blood, such as plasma, are routinely tested for viruses. The plasma is collected from many people, and then it goes through several processes to separate it into components, such as clotting factors. The clotting proteins are then made into a freeze-dried product, which is tested and treated to kill any potential viruses before it is packaged for use.
- Recombinant Factor Concentrates
Until 1992, all factor replacement products were made from human plasma. In 1992, the U.S. Food and Drug Administration (FDA) approved recombinant factor VIII (8) concentrate, which does not come from human plasma. This concentrate is genetically engineered using DNA technology. Commercially prepared factor concentrates are treated to remove or inactivate bloodborne viruses. Additionally, recombinant factors VIII (8) and IX (9) do not contain any plasma or albumin, and therefore, cannot spread any bloodborne viruses.
Some people who infuse with clotting factor concentrates may develop an inhibitor. Inhibitors make it more difficult to stop a bleeding episode because they prevent the treatment from working.
Other Treatment Products
Hemlibra® works by replacing the function of factor VIII (8), rather than replacing the missing clotting factor VIII directly. It can be used to either prevent or reduce the frequency of bleeding episodes in people with hemophilia A. This treatment product can be given by injection under the skin. Patients who use Hemlibra® for prophylaxis and use clotting factor concentrates to treat breakthrough bleeds, can still develop an inhibitor. Traditional laboratory inhibitor testing methods do not work when testing for inhibitors in patients on Hemlibra®; as such, a specialized testing method called the chromogenic Bethesda assay is needed.
- DDAVP® or Stimate® (Desmopressin Acetate)
DDAVP® and Stimate® are medications that are similar to a hormone that occurs naturally in the body. The medications release factor VIII (8) from where it is stored in the body tissues. For people with mild, as we11 as some cases of moderate, hemophilia, this can work to increase the persons own factor VIII (8) levels so that they do not have to use clotting factors to stop bleeding episodes. DDAVP® can be given through a vein and Stimate®.via a nasal spray.
- Amicar® (Epsilon Amino Caproic Acid)
Amicar® is a medication that can be given through a vein or by mouth (as a pill or a liquid). It prevents blood clots from breaking down, resulting in a firmer clot, and is often used for bleeding in the mouth or after a tooth has been removed because it blocks a substance found in the saliva (spit) that breaks down clots.
At this time there is no cure for hemophilia. There is, however, great hope in a treatment known as gene therapy. Several types of gene therapy are being tested. In general, gene therapy involves taking normal genes (the ones that tell the body to make clotting factor) and putting them into the body of a person with hemophilia. The new genes should cause the clotting factor level in the blood to rise. People who had successful gene therapy would no longer need to take factor. They would be cured of hemophilia. It is possible that the genes would only provide a partial cure. People with severe hemophilia might be raised to the level of mild hemophilia. They would need to take factor less often.
In a small number of people with hemophilia who have had liver transplants, their hemophilia has been cured. This is because clotting factor is made in the liver. The new livers they received made normal amounts of factor for them. Transplants are too risky to use as a cure for hemophilia. Liver transplants are done only to save someone's life when the liver has stopped working.
Complications may arise with the onset of a bleeding episode. There are four main types of complications: life threatening bleeds, arthropathy, inhibitors and infectious complications.
Life Threatening Bleeds
The five major sites of serious bleeding are:
- Intracranial or spinal cord
- Intra-abdominal areas
- Limb compartments, such as thigh, calf, forearm, or upper arm
All of these bleeding episodes are characterized by:
- bleeding into an enclosed space
- compression of vital tissue
- potential loss of life, limb or function
Serious bleeding requires immediate assessment and intervention. Patients with severe or moderate hemophilia are at greater risk for spontaneous serious bleeding. Trained intervention, communication, reassurance, and support are essential elements in helping patients and families through these crises. These bleeding episodes often cause great anxiety and fear of the outcome in patients and their families. The uncommon nature of bleeding disorders, and especially these life-threatening bleeding episodes, only re-emphasizes the importance of involving the hemophilia treatment center staff in each episode. Statistics from the Centers for Disease Control and Prevention show that patients with bleeding disorders not treated or followed at hemophilia treatment centers suffer a 60 percent increase in mortality rates.
Joint damage (hemophilia arthropathy) is the most common complication of bleeding in hemophilia. Prophylaxis has been shown to reduce joint bleeding and prevent joint damage. Early treatment of each joint bleed reduces the risk of chronic joint disease, functional impairment, and disability. Factor concentrates, home treatment, physical therapy, and orthopedic surgery have contributed to decreased frequency and severity of joint disease among people with hemophilia during the past 25 years. Prevention remains the focus of hemophilia treatment centers.
The frequency of joint disease has been further reduced as increasing numbers of individuals with severe hemophilia have participated in prophylactic programs. Unfortunately, most of these patients still develop at least one chronic joint in their lifetimes.
Complications can also arise from inhibitors in the body. Factor VIII and factor IX inhibitors are circulating antibodies that actively destroy factor VIII or factor IX. These inhibitors are currently measured in Bethesda units (BU). One BU inhibitor is defined as the amount of inhibitor needed to neutralize half the factor VIII or factor IX in two hours in an equal mix of patient and normal plasma.
The most widely used incidence rate of inhibitors among patients with severe factor VIII deficiency is 10% to 30%.
Until 1992, all factor replacement materials were derived from human plasma. Freeze-dried concentrates, which consisted of pooled blood from many donors, were introduced in the late 1960s and resulted in serious complications for many hemophilia patients. Many patients were at high risk for hepatitis or HIV/AIDS infection.