The current, most-used treatment for hemophilia A is factor replacement therapy. This is done by infusing (giving medication into a vein) a FVIII product into the affected person. When you infuse, FVIII concentrate, the FVIII is immediately available in the bloodstream, and your body can use it to stop or prevent the bleeding.
For individuals with mild hemophilia A, Desmopressin (DDAVP) might sometimes be used for short-term support. The way it works is that it promotes the release of stored FVIII and von Willebrand factor from endothelial cells in the lining of your blood vessels. It won’t work if you have moderate or severe hemophilia A because you can’t increase something that isn’t there.
In addition to the above products, bleeding may be successfully treated with amino caproic acid or tranexamic acid, often most useful for mouth bleed. Tranexamic acid is also useful for excessive menstrual bleeding. Both of these medications can be given orally.
When treating on-demand (when you have an active bleed), how much clotting factor you need depends on the following:
- Your weight
- Severity of the bleed
- Severity of your bleeding disorder
- Site of the bleeding/type of bleed
You can learn to administer FVIII concentrates (to yourself or your child) at home at the first signs of a bleed or for preventive care (which we call prophylaxis, or “prophy”). [insert photo of adult infusing self or child peripherally]
Frequency of Infusions for Hemophilia A
How often you or your child need to infuse is based on your bleeding pattern and severity of your hemophilia A. The two types of therapies to consider are prophylaxis (preventive care) and on-demand (also called “episodic” treatment).
Prophylaxis for Hemophilia A
Being on prophylaxis means infusing FVIII on a regular schedule to prevent bleeds from occurring. Prophylaxis is recommended for children with severe hemophilia, but it can also be recommended for those who have frequent bleeds. Prophylaxis may also be used in advance of activities that are likely to cause a bleed. There are two types of prophylaxis:
- Primary – This type of treatment is usually started in young children at or before the first joint bleed to reduce or prevent joint disease and is continued indefinitely.
- Secondary – This type of prophylaxis is started after some joint bleeding has occurred; the patient may even have a target joint. Short-term prophylaxis may be started when a significant bleed has occurred and continues on a regular schedule for a defined period of time, either until the bleed is resolved or for a time after to ensure that the bleed does not occur again. It is also used following surgical procedures.
Possible advantages of prophylaxis include the following:
- Reduced risk of joint damage
- Ability to more safely participate in sports and other physical activities
- Reduced risk of spontaneous bleeding
Possible disadvantages of prophylaxis include the following:
- Frequent infusions
On-Demand Treatment for Hemophilia A
On-demand (also called “episodic”) treatment is used to treat an active bleed. FVIII is infused after an injury has occurred or a bleed has started.
Possible advantages of on-demand treatment include the following:
- Fewer infusions
- Lower cost
Possible disadvantages of on-demand treatment include the following:
- Increased risk of joint damage
- Increased risk of spontaneous bleeds
Infusion Methods for Hemophilia A
All FVIII products need to be infused directly into the bloodstream. There are several ways to infuse FVIII, and each has its advantages and disadvantages. These include peripheral infusion (accessing a vein with a butterfly needle), port-a-catheter (also called a port), a peripherally inserted central catheter (PICC) line, or a BROVIAC® or HICKMAN® catheter.
Peripheral Venous Access for Hemophilia A
Peripheral venous access, where a butterfly needle is inserted directly into a vein and is used to infuse FVIII into the bloodstream, is commonly used by those who infuse at home but do not have a venous access device, such as a port, PICC line, or BROVIAC®. Below are some considerations regarding this type of access:
- Requires a clean technique. Sterile technique is not necessary.
- Low risk of infection when clean technique is used.
- Treatment is completed fairly quickly if the person’s veins are large and easy to find.
- Children’s veins are often small and difficult to find (and children do not like to sit still for infusions).
A port is a device that is surgically implanted under the skin. It has tubing that is inserted into a central vein. In most cases, it is placed on the chest. Below are some considerations regarding this type of access:
- The port can be accessed repeatedly for many years.
- Provides an area where the needle can be placed to infuse factor.
- The port must be accessed using sterile technique to avoid infection.
- Children can participate in water activities, as the port is under the skin.
- Infection: The main risk of a port is the risk of infection.
- Clotting: A clot may form within the catheter.
Peripherally inserted central catheter (PICC)
A PICC line is a catheter inserted into a large vein in the arm that is then connected to an even larger blood vessel in the chest. Part of the catheter stays outside of the arm, and infusions are done through that device. This device is easy to use and does not require a stick through the skin. A sterile dressing is applied over the site where the PICC comes out of the skin, and that dressing must be kept clean and drive. It is generally changed weekly. However, PICC lines only last a few weeks or months.
BROVIAC® or HICKMAN® Catheter
BROVIAC® catheters and HICKMAN® catheters (often referred to as “broviacs”) are similar to a PICC line. However, A BROVIAC® catheter is placed directly into a central vein and threaded to a position just above the heart. It is tunneled under the skin and brought out away from the site where it enters the vein to theoretically prevent bacteria from gaining access to the central portion of the catheter. BROVIAC® catheters contain a “cuff” that is under the skin. As the skin grows into this “cuff,” the catheter becomes more stable, reducing the chance of it becoming pulled out. Like the PICC line, his device is easy to use and does not require sticks into the person’s skin. The difference is that these catheters can last for a prolonged period of time. The most common long-term complications of this type of central line are infection, movement that takes the catheter out of the proper position, and damage to the catheter.
Products for Hemophilia A
In the United States, there are two types of FVIII products used to treat hemophilia A today: plasma-derived products and recombinant factor concentrates.
Plasma-Derived Products for Hemophilia A
A plasma-derived product is a factor concentrate made from carefully-screened, donated blood plasma. During the manufacturing process, the proteins extracted from the plasma go through a series of extensive sterilization procedures to eliminate viruses and other contaminants.
Recombinant Factor Concentrates for Hemophilia A
In the early 1980s, the cloning of FVIII and FIX and subsequent expression of functional proteins occurred. This was during the “bad blood” era (when many individuals with hemophilia being treated with plasma-derived clotting factor were infected with HIV and/or HCV). This led to the development and commercialization of recombinant clotting factors. These initial products were manufactured using Chinese hamster ovary cells or baby mouse kidney cells. Manufacturers injected these cells with the factor gene so that large amounts of the factor protein could be produced. Since the proteins are extracted from animal cells, they are not at risk for containing human viruses. Some factor concentrate products are stabilized using human albumin, while others are stabilized using sucrose. This was life-changing for many with hemophilia, allowing for prophylactic (or preventive) treatment. Some companies are now using human embryonic kidney (HEK) cells to grow the factor.
Recombinant factor concentrates can be standard or long-acting. While long-acting factor costs more per IU, you may need to infuse less often.
Your hematologist will determine your FVIII dosage, and it’s based on your weight, the severity of your hemophilia A, and your bleeding pattern. Keeping a log of your bleeding, pain, and infusions is critical in achieving the most effective dosing and treatment. Your dose will likely differ for major, minor, and prophylactic dosing. The dosage will be indicated in units of FVIII. In addition, dosage may be adjusted based on how your body uses the FVIII product, since some people have a longer or shorter half-life with certain products.
FVIII concentrates are measured in international units (IU). One IU is equivalent to the amount of factor activity found in 1 cc or 1 ml of fresh plasma. FVIII products are delivered in glass vials with labels indicating the number of IU per vial. Manufacturing companies produce common size vials, but at times, depending on body weight, a person may need to mix more than one vial to achieve the necessary dosage. Exact dosage vials are usually not available. However, multiple vials can be mixed to add up to the approximate number of units needed.
FVIII dosages are calculated by the amount of factor units needed to raise one kilogram of weight to the desired level of activity. Most FVIII products indicate that 50 units (.5 IU/Kg) are needed to raise one kilogram of weight to normal range activity.
Half-life is how long it takes the body to use up half of the infused dose of factor. The half-life of FVIII products available today is 8 to 12 hours for standard recombinant FVIII products and 12 to 19 hours for long-acting recombinant FVIII products.
Each of us process factor differently, so these times may vary. Your hematologist may adjust your dosage based on your bleeding history and/or factor level testing.
Inhibitors and Hemophilia A
While anyone with a bleeding disorder can develop an inhibitor to clotting factor, those with hemophilia A develop inhibitors more often than the other bleeding disorders. Inhibitors are antibodies that the immune system develops because it perceives the infused FVIII as a foreign substance that needs to be destroyed. Antibodies are proteins that eat up the FVIII before it has time to stop the bleeding.
Up to 30% of people with hemophilia A are affected by inhibitors at some point in their lives. Inhibitors usually occur between the 9th and 50th infusion of factor concentrate, but in rare cases can also be developed later in life.
While people with severe hemophilia are more likely to develop inhibitors, approximately 5–8% of people with mild or moderate hemophilia A also develop inhibitors. The antibodies can destroy not only the factor concentrate infused but also the small percentage of factor protein that the body was producing naturally. So, a person with mild or moderate hemophilia who develops an inhibitor now, in effect, has severe hemophilia (<1% circulating factor).
In addition to the type and severity of hemophilia someone has, there are other risk factors:
- Age/number of exposures to factor product
- Family history of an inhibitor
- Race/ethnicity (people of African American and Hispanic descent are at a higher risk of developing an inhibitor)
- Gene mutation (there are ongoing studies that indicate the type of genetic mutation one has may indicate a higher risk of inhibitor development)
- Intensive factor therapy related to surgery or trauma.
The journal Haemophilia has published the results of a 6-year study called the Hemophilia Inhibitor Research Study (HIRS) that was designed to test the feasibility of conducting national monitoring for inhibitors among people with hemophilia in the United States. In the study, investigators from 17 HTCs located across the United States enrolled 1,163 people with hemophilia and followed them for up to 6 years to learn the best way to determine who was at risk for developing an inhibitor. HIRS investigators and CDC researchers found that people with hemophilia of all ages were at risk for developing an inhibitor and that unless people are regularly tested for an inhibitor, they can have one and not know it until it causes a severe bleeding problem.
What are the symptoms of an inhibitor?
Inhibitors destroy the infused FVIII, as well as the FVIII produced naturally by the body in people with mild and moderate hemophilia. if you are treating a bleeding episode, following your current treatment protocol, and the bleeding is not betting better, or may actually be getting worse, this is a key sign that an inhibitor may have developed. A person who doesn’t have an inhibitor will heal from injuries or feel better after the FVIII is infused or their treatment plan is completed.
How are inhibitors detected?
Anyone with hemophilia A should be tested for inhibitors regularly, at least once per year. A blood test called activated partial thromboplastin time (APTT) is performed soon after factor concentrate is infused to calculate the time it takes for the person’s blood to clot. If clotting time is outside the range expected after an infusion, a second test called a Bethesda assay is performed to confirm the diagnosis and to determine the level of inhibitor that the person has developed. The Bethesda assay determines how many Bethesda Units (BUs) a patient has. Fewer than 5 BUs is considered a low-titer inhibitor, and more than 5 BUs is considered high-titer inhibitor.
Inhibitor testing should be initiated if a patient of any age is responding poorly to treatment. Some HTCs test more frequently in the early days of treatment, and many test before every surgery and at annual comprehensive clinic visits.
If you or your child are diagnosed with an inhibitor, your hematologist will likely want you to not infuse for 48 hours to check your BU assay.
Are all Hemophilia A inhibitors the same?
No. Inhibitors come in different degrees of severity. They are measured in titers (the level of inhibitors present in a person’s blood, which is measured in BUs).
Here is some terminology associated with inhibitors:
- Titer: The inhibitor titer is measured in Bethesda Units (BUs). This number represents the level of inhibitors in a person’s body. Inhibitors are classified as follows:
- Low Titer: When the inhibitor level in the blood is lower than 5 BU. The number, and therefore strength, of the inhibitor is low. People with low-titer inhibitors can sometimes continue to use FVIII products to treat bleeds; they just need a lot more of it. Low-titer inhibitors can sometimes resolve on their own.
- High Titer: When the level of inhibitors found in the blood is greater than 5 BU. The number, and therefore strength of the inhibitor, is high. People with a high titer inhibitor get no benefit from FVIII, no matter how much they infuse.
- Anamnestic Response: Once an inhibitor is present, the strength with which the body reacts to further exposure of factor concentrate, also called immune response or immunologic response, can further classify the inhibitor type.
- Low Responder: When people with low-responding inhibitors receive FVIII, the inhibitor titer does not rise. Because the titer stays low, they may be able to control bleeding by using larger quantities of FVIII concentrates.
- High Responder: When people with high-responding inhibitors are exposed to FVIII, the immune system quickly triggers even more inhibitor development.
Personal Stories about Living with An Inhibitor
CDC’s National Center on Birth Defects and Developmental Disabilities (NCBDDD) hosts a Flickr Album featuring the stories of people with hemophilia who have also experienced the added challenge of an inhibitor. This Flickr Album provides powerful, personal testimonials on what it’s like to live with hemophilia and an inhibitor. It is aimed at raising awareness of this serious bleeding disorder complication, the need for continued inhibitor research, and the importance of routine inhibitor screening.
For more information about inhibitors
- Center for Disease Control and Prevention (CDC) website, including results of the CDC’s 6-year, Hemophilia Inhibitor Research Study (HIRS), which tested the feasibility of conducting national monitoring for inhibitors amongst people with hemophilia in the United States.
- World Federation of Hemophilia Inhibitor Primer
- Canadian Hemophilia Society Inhibitor Guide
- Managing Your Child’s Inhibitor: A Practical Guide for Parents, by Laureen A. Kelley
- CLINICAL TRIALS – There may be some current clinical trials in hemophilia with inhibitors. Click here for more information on clinical trials.