Hemophilia medical therapy
|
Hemophilia Microchapters |
|
Diagnosis |
|---|
|
Treatment |
|
Case Studies |
|
Hemophilia medical therapy On the Web |
|
American Roentgen Ray Society Images of Hemophilia medical therapy |
|
Risk calculators and risk factors for Hemophilia medical therapy |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]
Overview
Medical Therapy
Blood Clotting factor
The main treatment for hemophilia is called replacement therapy. Concentrates of clotting factor VIII (for hemophilia A) or clotting factor IX (for hemophilia B) are slowly dripped or injected into a vein. These infusions help replace the clotting factor that's missing or low. Clotting factor concentrates can be made from human blood. The blood is treated to prevent the spread of diseases, such as hepatitis. With the current methods of screening and treating donated blood, the risk of getting an infectious disease from human clotting factors is very small. To further reduce the risk, you or your child can take clotting factor concentrates that aren't made from human blood. These are called recombinant clotting factors. Clotting factors are easy to store, mix, and use at home—it only takes about 15 minutes to receive the factor. You may have replacement therapy on a regular basis to prevent bleeding. This is called preventive or prophylactic therapy. Or, you may only need replacement therapy to stop bleeding when it occurs. This use of the treatment, on an as-needed basis, is called demand therapy. Demand therapy is less intensive and expensive than preventive therapy. However, there's a risk that bleeding will cause damage before you receive the demand therapy. Though there is no cure for haemophilia, it can be controlled with regular infusions of the deficient clotting factor, i.e. factor VIII in haemophilia A or factor IX in haemophilia B. Some haemophiliacs develop antibodies (inhibitors) against the replacement factors given to them, so the amount of the factor has to be increased or non-human replacement products must be given, such as porcine factor VIII. If a patient becomes refractory to replacement coagulation factor as a result of circulating inhibitors, this may be overcome with recombinant human factor VII (NovoSeven®), which is registered for this indication in many countries.
- 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 concentrates that are made from human plasma proteins are available. All blood and parts of blood, such as plasma, are routinely tested for the viruses. The clotting proteins are separated from other parts of the plasma, purified, and made into a freeze-dried product. This product 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. The concentrate is genetically engineered using DNA technology. Commercially prepared factor concentrates are treated to remove or inactivate bloodborne viruses. In addition, recombinant factors VIII (8) and IX (9) are available that do not contain any plasma or albumin and, therefore, cannot transmit any bloodborne viruses.
The products can be used as needed when a person is bleeding or they can be used on a regular basis to prevent bleeds from occurring. Today, people with hemophilia and their families can learn how to give their own clotting factor at home. Giving factor at home means that bleeds can be treated quicker, resulting in less serious bleeding and fewer side effects.
- Other treatment products:
- DDAVP® (Desmopressin Acetate)-DDAVP® is a chemical that is similar to a hormone that occurs naturally in the body. It releases factor VIII (8) from where it is stored in the body tissues. For people with mild, and some cases of moderate hemophilia, this can work to increase their own factor VIII (8) levels so that they do not have to use clotting factor. This medicine can be given through a vein (DDAVP®) or through nasal spray (Stimate®).
- Amicar® (Epsilon Amino Caproic Acid)-Amicar® is a chemical that can be given in a vein or by mouth (as a pill or a liquid). It prevents clots from breaking down, resulting in a firmer clot. It is often used for bleeding in the mouth or after a tooth has been removed because it blocks an enzyme in the saliva that breaks down clots.
- Cryoprecipitate-Cryoprecipitate is a substance that comes from thawing fresh frozen plasma. It is rich in factor VIII (8) and was commonly used to control serious bleeding in the past. However, because there is no method to kill viruses, such as HIV and hepatitis, in cryoprecipitate it is no longer used as the current standard of treatment in the U.S. It is, however, still used in most developing countries.
In western countries, common standards of care fall into one of two categories: prophylaxis or on-demand. Prophylaxis involves the infusion of clotting factor on a regular schedule in order to keep clotting levels sufficiently high to prevent spontaneous bleeding episodes. On-demand treatment involves treating bleeding episodes once they arise. In 2007, a clinical trial was published in the New England Journal of Medicine comparing on-demand treatment of boys (< 30 months) with Haemophilia A with prophylactic treatment (infusions of 25 IU/kg body weight of Factor VIII every other day) in respect to its effect on the prevention of joint-diseases. When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group had a normal index joint-structure on MRI. [1] Prophylactic treatment, however, resulted in average costs of $300,000 per year. The author of an editorial published in the same issue of the New England Journal of Medicine demands more clinical studies addressing the cost-effectiveness of prophylactic treatment. [2]
As a direct result of the contamination of the blood supply in the late 1970s and early/mid 1980s with viruses such as Hepatitis and HIV, new methods were developed in the production of clotting factor products. The initial response was to heat-treat (pasteurize) plasma-derived factor concentrate, followed by the development of monoclonal factor concentrates, which use a combination of heat treatment and affinity chromatography to inactivate any viral agents in the pooled plasma from which the factor concentrate is derived. The Lindsay Tribunal in Ireland investigated, among other things, the slow adoption of the new methods.
Since 1993 (Dr. Mary Nugent), recombinant factor products (which are typically cultured in Chinese hamster ovary (CHO) tissue culture cells and involve little, if any human plasma products) have become available and are widely used in wealthier western countries. While recombinant clotting factor products offer higher purity and safety, they are, like concentrate, extremely expensive, and not generally available in the developing world. In many cases, factor products of any sort are difficult to obtain in developing countries.
It was claimed that Rasputin was successful at treating the Tsarevich Alexei of Russia's haemophilia: however, to this day it is unclear how he accomplished this.
Gene Therapy
Researchers are trying to find ways to correct the faulty genes that cause hemophilia. Gene therapy hasn't yet developed to the point that it's an accepted treatment for hemophilia. However, researchers continue to test gene therapy in clinical trials.For more information, go to the "Clinical Trials" section of this article. On 10 December 2011, a team of British and American investigators reported the successful treatment of haemophilia B using gene therapy. The investigators inserted the F9gene into an adeno-associated virus-8 vector, which has a propensity for the liver, where factor 9 is produced, and remains outside the chromosomes so as not to disrupt other genes. The transduced virus was infused intravenously. To prevent rejection, the people were primed with steroids to suppress their immune response.[18] In October 2013, theRoyal Free London NHS Foundation Trust in London reported that after treating six people with haemophilia in early 2011 with the genetically modified adeno-associated virus, over two years later all were still producing blood plasma clotting factor.Complications of Replacement Therapy
Complications of replacement therapy include
- Developing antibodies (proteins) that attack the clotting factor
- Developing viral infections from human clotting factors
- Damage to joints, muscles, or other parts of the body resulting from delays in treatment
Antibodies to the clotting factor
Antibodies can destroy the clotting factor before it has a chance to work. This is a very serious problem. It prevents the main treatment for hemophilia (replacement therapy) from working.These antibodies, also called inhibitors, develop in about 20–30 percent of people who have severe hemophilia A. Inhibitors develop in 2–5 percent of people who have hemophilia B.When antibodies develop, doctors may use larger doses of clotting factor or try different clotting factor sources. Sometimes the antibodies go away.Researchers are studying new ways to deal with antibodies to clotting factors.
Viruses from human clotting factors
Clotting factors made from human blood can carry the viruses that cause HIV/AIDS and hepatitis. However, the risk of getting an infectious disease from human clotting factors is very small due to:
- Careful screening of blood donors
- Testing of donated blood products
- Treating donated blood products with a detergent and heat to destroy viruses
- Vaccinating people who have hemophilia for hepatitis A and B
Damage to joints, muscles, and other parts of the body
Delays in treatment can cause damage such as:
- Bleeding into a joint. If this happens many times, it can lead to changes in the shape of the joint and impair the joint's function.
- Swelling of the membrane around a joint.
- Pain, swelling, and redness of a joint.
- Pressure on a joint from swelling, which can destroy the joint.
People with hemophilia have a higher quality of life today than ever before, but complications can still occur. Approximately 15-20% of people with hemophilia will develop an antibody-called an inhibitor-to the product used to treat or prevent bleeding episodes. Developing an inhibitor is one of the most serious and costly complications of hemophilia.
About Inhibitors
People with hemophilia use treatment products called factor clotting concentrates. This treatment improves blood clotting and is used to stop or prevent a bleeding episode. Inhibitors develop when the body’s immune system stops accepting the factor (factor VIII for hemophilia A and factor IX for hemophilia B) as a normal part of blood. The body thinks the factor is a foreign substance and tries to destroy it using inhibitors. The inhibitors stop the factor from working. This makes it more difficult to stop a bleeding episode. People with hemophilia who develop an inhibitor do not respond as well to treatment. Inhibitors most often appear during the first year of treatment but they can appear at any time.
Cost of Care
Caring for people with inhibitors poses a special challenge. The health care costs associated with inhibitors can be staggering because of the cost and amount of treatment product required to stop bleeding.1 Also, people with hemophilia who develop an inhibitor are twice as likely to be hospitalized for a bleeding complication.2
Risk Factors and Causes
Scientists do not know exactly what causes inhibitors. Risk factors that have been shown in some studies to possibly play a role include:
- Age
- Race/ethnicity
- Type of hemophilia gene defect
- Frequency and amount of treatment (inhibitors typically occur within the first 50 times factor is used)
- Family history of inhibitors
- Type of factor treatment product
- Presence of other immune disorders
Diagnosis
A blood test is used to diagnose inhibitors. The blood test measures inhibitor levels (called inhibitor titers) in the blood. The amount of inhibitor titers is measured in Bethesda units (BU). The higher the number of Bethesda units, the more inhibitor is present. “Low titer” inhibitor has a very low measurement, usually less than 5 BU. “High titer” inhibitor has a very high measurement, usually much higher than 5 BU.
Inhibitors are also labeled “low responding” or “high responding” based on how strongly a person’s immune system reacts or responds to repeated exposure to factor concentrate. When people with high-responding inhibitors receive factor concentrates, the inhibitor titer measurement increases quickly. The increased inhibitor titer prevents the factor clotting concentrates from stopping or preventing a bleeding episode. Repeated exposure to factor clotting concentrates will cause more inhibitors to develop.
When people with low-responding inhibitors receive factor concentrates, the inhibitor titers do not rise. Therefore, people with low-responding inhibitors can usually still use factor clotting concentrates to stop or prevent a bleeding episode.
Treatment
Treating people who have inhibitors is complex and remains one of the biggest challenges in hemophilia care today. If possible, a person with inhibitors should be cared for at a hemophilia treatment center (HTC). HTCs are specialized health care centers that bring together a team of doctors, nurses, and other health professionals experienced in treating people with hemophilia.
Some treatments for people with inhibitors include the following:
- High-Dose Clotting Factor Concentrates: People who have low responding inhibitors may be treated with higher amounts of factor concentrate to overcome the inhibitor and yet have enough left over to form a clot. It is important to test the blood and measure the factor level after this new treatment schedule is established to see if the inhibitor is gone.
- Bypassing Agents: Special blood products are used to treat bleeding in people with high titer inhibitors. They are called bypassing agents. Instead of replacing the missing factor, they go around (or bypass) the factors that are blocked by the inhibitor to help the body form a normal clot. People taking bypassing agents should be monitored closely to make sure the blood is not clotting too much or clotting in the wrong place in the body.
- Immune Tolerance Induction (ITI) Therapy: The goal of ITI therapy is to stop the inhibitor reaction from happening in the blood and to teach the body to accept clotting factor concentrate treatments. With ITI therapy, people receive large amounts of clotting factor concentrates every day for many weeks or months.
ITI therapy requires specialized medical expertise, is costly, and may take a long time to work. In many cases, ITI gets rid of the inhibitor. However, patients may need to continue taking frequent, large amounts of factor concentrates for many years to keep the inhibitor from coming back. HTCs can serve a vital role in supporting patients who undergo a treatment regimen as intensive as ITI.
Treatment of a Specific Bleeding Site
Pain medicines, steroids, and physical therapy may be used to reduce pain and swelling in an affected joint. Talk with your doctor or pharmacist about which medicines are safe for you to take.
Which Treatment Is Best for You?
The type of treatment you or your child receives depends on several things, including how severe the hemophilia is, the activities you'll be doing, and the dental or medical procedures you'll be having.
- Mild hemophilia—Replacement therapy usually isn't needed for mild hemophilia. Sometimes, though, DDAVP is given to raise the body's level of factor VIII.
- Moderate hemophilia—You may need replacement therapy only when bleeding occurs or to prevent bleeding that could occur when doing certain activities. Your doctor also may recommend DDAVP prior to having a procedure or doing an activity that increases the risk of bleeding.
- Severe hemophilia—You usually need replacement therapy to prevent bleeding that could damage your joints, muscles, or other parts of your body. Typically, replacement therapy is given at home two or three times a week. This preventive therapy usually is started in patients at a young age and may need to continue for life.
For both types of hemophilia, getting quick treatment for bleeding is important. Quick treatment can limit damage to your body. If you or your child has hemophilia, learn to recognize signs of bleeding.
Other family members also should learn to watch for signs of bleeding in a child who has hemophilia. Children sometimes ignore signs of bleeding because they want to avoid the discomfort of treatment.''''
References
- ↑ Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, Ingram JD, Manco-Johnson ML, Funk S, Jacobson L, Valentino LA, Hoots WK, Buchanan GR, DiMichele D, Recht M, Brown D, Leissinger C, Bleak S, Cohen A, Mathew P, Matsunaga A, Medeiros D, Nugent D, Thomas GA, Thompson AA, McRedmond K, Soucie JM, Austin H, Evatt BL. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe haemophilia. N Engl J Med. 2007 Aug 9;357(6):535-44. PMID 17687129
- ↑ Roosendaal G, Lafeber F. Prophylactic treatment for prevention of joint disease in haemophilia--cost versus benefit. N Engl J Med. 2007 Aug 9;357(6):603-5. PMID 17687136