Hemophilia

Introduction

Hemophilia is a bleeding disorder that occurs almost exclusively among boys and men. Currently hemophilia is not curable, but most cases can now be treated effectively. Although it is an inherited condition that can be detected before a child is born, by determining if the mother is a carrier for the disease or if the father has the disease, hemophilia is usually discovered when a small child who is beginning to crawl suffers exaggerated bruising from what ordinarily would be minor injuries. While most people think of bleeding from open wounds when they think of hemophilia, external injuries do not usually present the most serious problem. Uncontrolled internal bleeding is much more dangerous. . Internal bleeding that is close to the skin?s surface causes bruises and may result in a hematoma, which is when there is a pocket of blood in deeper tissue such as inside a muscle or organ. Individuals with hemophilia not only tend to have more bruises than other individuals, their bruises are usually more severe. Something as simple as a shot that is injected into muscle tissue may cause a large bruise that lasts for several weeks.

In the late 1800s and early 1900s, hemophilia was often referred to as "The Royal Disease", because many members of the English, Russian and Spanish royal families either had it or carried it. Until the 1960's, when clotting factors were identified, the only treatment for hemophilia was blood transfusions. Unfortunately, not enough of the needed clotting factors are present in whole blood or blood plasma to stop serious internal bleeding, so most individuals with severe hemophilia died before reaching adulthood. Others suffered painful and disabling joint damage. Today, because hemophilia can be controlled with clotting factor products, most individuals who have it lead nearly normal lives. Excellent resources, including support groups, are available for individuals with hemophilia and their families. Research, especially in the field of gene therapy, offers hope for better treatment and even a cure in the not-too-distant future.

What is it?

Hemophilia is a disorder of the blood clotting system. Normally, an injury to a blood vessel activates certain proteins in the blood known as ?clotting factors?. A series of 12 natural clotting factors helps to change ordinary blood components into sticky clumps. Platelets, tiny cell particles that circulate in blood, begin attaching to each other and to protein fibers that are also in the blood. Ordinarily, a soft mass of platelets and fibers (a blood clot) forms quickly, bleeding stops, and the wound begins to heal. This process is known as coagulation (pronounced: ?co-ag-u-lay-shun?). Hemophilia results when one or more clotting factors are absent or insufficient. As a result, either blood clots break apart because they are too fragile to withstand blood flow or clots just do not form.

Although a deficiency of any of the 12 clotting factors is possible, the two that appear to be most essential to forming blood clots are factor 8 (designated by the Roman numeral VIII) and factor 9 (IX). A deficiency of factor VIII is also called hemophilia A or classic hemophilia. Approximately 80% of individuals with hemophilia have hemophilia A. Abnormal production of factor IX is called hemophilia B or Christmas Disease (because the first person diagnosed with it was named Stephen Christmas). About 10% to 15% of individuals with hemophilia have hemophilia B. Other inherited bleeding disorders that are results of deficiencies in other clotting factors, such as von Willebrand's disease, are very rare.

von Willebrand?s disease is a bleeding disorder in which an individual?s body has a deficiency of the von Willebrand factor or the factor is not working as it should be. von Willebrand is a protein that aids in the clotting process. It not only helps transport factor VIII, but it acts like a glue to help keep all platelets together when the blood is trying to clot.

Both hemophilia A and hemophilia B are classified by the estimated percentage of factor XIII/IX that are produced by the individual.

  • Mild hemophilia is considered to be 5-30% of normal production
  • Moderate hemophilia is 1% to 5% of normal production
  • Severe hemophilia is 1% or less of normal production

About two-thirds of individuals with hemophilia A and about half with hemophilia B have severe cases. The severity of an individual?s condition often corresponds to the likelihood of physical problems. It may also predict how serious those problems might be and suggest which treatments may be most effective.

Although most bleeding episodes in mild to moderate hemophilia usually result from an injury, individuals with severe hemophilia may experience bleeding with no apparent cause. In severe hemophilia, most bleeding is internal. Bleeding may occur inside joints and muscles, or more seriously, in organs such as the stomach or brain. However, if the appropriate clotting factor is given as quickly as possible following injury, individuals with hemophilia may not have either visible evidence of bleeding or interference with everyday life.

The physical damage that can result from untreated serious bleeding depends on where the bleeding occurs.

  • Serious bleeding into muscle tissue: Areas of muscle cells around the bleeding may die. The resulting scar tissue contracts as it is formed, potentially leading to decreased ability to bend joints. The scar tissue may also squeeze nerves, causing numbness and tingling.
  • Serious bleeding into joints: knees, elbows, ankles, shoulders, hips, and wrists, are usually affected in that order. Joint bleeding may cause multilayered damage that may result in sever, painful arthritis. This arthritis can eventually led to muscle wasting and if the bones are weakened enough, there could be an increased risk of fractures.
  • Bleeding into the skull or brain: Because bleeding can press on the brain, drowsiness, extreme headaches, nausea, vomiting, and sensitivity to light may result. Scar tissue, which can also be caused by bleeding into the brain, occasionally leads to epilepsy (or seizure disorder).

What causes it?

Hemophilia is a genetic (inherited) disorder, which means that it can be passed from one generation to the next. It is also a sex-linked disorder, which is why it appears mostly in males. A brief review of genetics will help make clear why few females have hemophilia.

Half of each human?s 46 chromosomes are contributed by each parent. Two of these chromosomes, known as X and Y, determine an individual?s gender. Females have two X and no Y chromosomes, while males have one of each. Each chromosome contains hundreds of genes, which determine an individual?s characteristics such as eye color or height. The genes responsible for the production of clotting factors VIII and XI are located on the X chromosome. Since males have only one X chromosome, a defective clotting gene on it means that the individual will have hemophilia. Normal genes for clotting factors dominate defective clotting genes, however. Therefore, because females have two X chromosomes, they have two sets of genes for producing clotting factors VIII and IX. If one set is abnormal, the other set can make up for the deficit. Only a female who has two sets of defective clotting genes will have hemophilia. A woman who has one X chromosome with abnormal activity is said to be a carrier. While all of her children may receive the functioning clotting factor genes from her, she may pass the defective X chromosome to a son, who will have hemophilia. If the daughter of a carrier receives the defective gene, she will also carry it and possibly pass it to her children.

About one-third of patients with hemophilia have no family history of the condition. For these individuals, the cause appears to be a genetic mutation, which means that some event during their pre-birth development altered one or more clotting factor genes.

Who has it?

Both hemophilia A and B are very rare disorders. In the United States, the National Heart, Lung and Blood Institute estimates that about 18,000 males currently have hemophilia, and about 400 babies are diagnosed with hemophilia each year. Approximately one case of hemophilia A occurs for every 5,000 births. Hemophilia B is even less common with only one-fourth the occurrence of hemophilia A. The large majority of cases occur in males, but a small percentage of females may have hemophilia caused by clotting factor defects on both X chromosomes. Females who carry one set of defective genes may have symptoms such as unusually heavy menstrual periods or excessive bleeding after giving birth, dental procedures, or surgery.

What are the risk factors?

About two-thirds of all individuals with hemophilia have inherited it, whereas the other one-third of the cases have no family history of the condition. These individuals are believed to have had a genetic alteration (mutation) during the time their body organs and systems were forming before birth. The exact causes of such mutations are unknown.

If hemophilia is inherited, the likelihood that a child will have hemophilia or be a carrier is well-established.

  • A boy whose mother is a carrier has a 50:50 chance of having hemophilia, whether or not his father has hemophilia.
  • A boy whose mother has hemophilia, but whose father does not, will have hemophilia.
  • A boy whose mother is not a carrier but whose father has hemophilia has no chance of either having hemophilia or being a carrier.
  • A girl whose mother is a carrier and whose father does not have hemophilia has a 50:50 chance of being a carrier.
  • A girl whose father has hemophilia will definitely be a carrier, whether or not her mother is a carrier.
  • A girl whose mother is a carrier and whose father has hemophilia will either be a carrier or have hemophilia.
  • A girl whose mother has hemophilia but whose father does not, will be a carrier.
  • If both parents have hemophilia, all their children will have hemophilia, as well.

What are the symptoms?

The symptoms of major bleeding vary from one individual to another. In general, a superficial bruise that is not associated with the head or a joint usually does not present a problem. In addition, bruises that feel bumpy and move easily when pushed probably do not require treatment. Bruises or bumps that are especially large, that feel tight and hard, or that do not move, however, may indicate bleeding into deep tissues. Treatment should begin immediately.

Most individuals with hemophilia and their caregivers learn to recognize the signs that major bleeding may be starting. Some individuals experience a fizzy or trickling feeling that serves as a warning. Very young children with hemophilia may be irritable. For babies and toddlers, bleeding may be signaled by restricted movement. For example, a child with hemophilia may not want to reach for a toy or a bottle and he may not roll over or crawl as much as other children in the same age group.

Other signs and symptoms of hemophilia include bleeding in the joints. Bleeding can occur in the knees, ankles, and elbows. Signs to look for include, stiffness of the joint without any pain (first sign), stiffness of the joint with pain, joint becomes very stiff and feels very warm, all movement in the joint is lost due to excessive swelling and is very painful, and the bleeding will actually show after several days.

Other symptoms may include:

  • Blood in the urine
  • Blood in the stool
  • Excessive bleeding after losing a tooth or having surgery
  • Frequent or lengthy nosebleeds without any reason or cause

Bleeding around the brain is typically caused by an injury (eg. a bump on the head). It does not require a very hard bump, so patients with hemophilia need to be very careful. This is very serious if left untreated. The following are major symptoms for which the doctor must be contacted immediately. They include:

  • Long-lasting painful headaches or an increase in the number of headaches
  • Vomiting many times throughout the day
  • Having changes in mood or being very tired throughout the day
  • An arm or leg that suddenly becomes very weak
  • Neck pain or stiffness
  • Double vision
  • Difficulty walking/poor balance
  • Seizures

How is it treated?

The main treatment for hemophilia is replacing the clotting factor that is too low or missing. Clotting factors are given in differing doses according to the weight of the individual and the severity of the bleeding. Clotting factor products are powders that are packaged in sterile glass vials. Many of them require special storage such as refrigeration. When a dose is needed, the powder is dissolved in small amounts of sterile water and the resulting solution is either injected into a vein or mixed with a larger amount of fluid and dripped into a catheter that is inserted into a vein (an IV infusion).

In individuals who have mild forms of hemophilia, replacement therapy is generally not used, unless the individual is going to be participating in sports or is having a dental procedure done. With mild hemophilia, desmopressin (DDAVP) is the agent that is normally used. DDAVP is a synthetic hormone that releases von Willebrand factor which transports factor VIII thus increasing factor VIII levels. DDAVP is not really a clotting factor and is available in two forms: injection and nasal spray.

With moderate forms of hemophilia, clotting factor replacement should begin when bleeding starts, when bleeding is expected (e.g. surgery), and when participating in activities that increase the bleeding risk (e.g. contact sports). For individuals with moderate or severe hemophilia, prompt administration of the missing clotting factor reduces the risk of chronic complications that may result from repeated or prolonged bleeding episodes.

The clotting factors that are used in replacement therapy come from two sources. Many of the clotting factor products that are currently available are produced by recombinant DNA techniques. This process is carried out in sterile production facilities where the clotting factor genes are grown synthetically. Other clotting factor products are derived from human blood plasma. Clotting factors from human blood plasma have a slight chance of being contaminated with viruses such as HIV and hepatitis; therefore, recombinant clotting factors are usually preferred because they do not carry viruses. Manufacturers of human blood plasma-derived factor products include viral inactivation steps in the production process that greatly decrease the risk of viral contamination.

For treating hemophilia A, the following factor VIII products are currently available:

Recombinant Products:

  • Advate
  • Bioclate
  • Helixate FS
  • Kogenate
  • Kogenate FS
  • Recombinate
  • ReFacto

Plasma-derived Products:

  • Alphanate
  • Hemophil M
  • Humate-P
  • Koate DVI
  • Monarc-M
  • Monoclate-P

The following factor IX products are currently available to treat hemophilia B:

Recombinant Product:

  • BeneFIX

Plasma-derived products:

  • AlphaNine SD
  • Mononine
  • Profilnine SD

Antibodies (also called inhibitors) to clotting factors develop in one-fourth to one-third of individuals with severe hemophilia A and 5% to 10% of individuals with severe hemophilia B. Antibodies are parts of the immune system that identify and attack foreign cells such as bacteria. When antibodies attack infused clotting factors, the effectiveness of the clotting factor may be decreased or even eliminated, which can lead to uncontrolled bleeding. Individuals with hemophilia who have antibodies to clotting factors may need to use an anti-inhibitor along with a clotting factor product.

The following products contain both a clotting factor and an anti-inhibitor:

Plasma-derived combination of anti-inhibitor and factor VIII:

  • Autoplex
  • Feiba VH Immuno

Plasma-derived combination of anti-inhibitor and factors II, VIIa, IX and X:

  • Proplex T

Other combination products available to treat specific types of hemophilia are:

Blood-derived combination of anti-inhibitor and factors II, IX and X:

  • Bebulin VH Immuno

Other products that could be used for hemophilia:

  • Novoseven
  • Hyate: C (porcine VIII)

Other treatments can help aid the clotting factors, so that they work better are agents known as antifibrinolytics (pronounced ?an-tee-fye-bri-noh-lit-iks?). Antifibrinolytics help prevent formed clots from breaking down and include the following agents: Cyklokapron (tranexamic acid) and Amicar (aminocaproic acid). These agents work by blocking the factors that break up clots in the body and are typically used:

  • Before dental procedures
  • For nose bleed treatments
  • For individuals that may be experiencing bleeding in the intestines (blood in the stools)

To learn more about the drugs used to treat hemophilia, click on the Drug Class links below.

Helping Yourself

In addition to treating unusual bleeding as quickly as possible, individuals with hemophilia can follow several simple rules to optimize their health and limit the impact that hemophilia has on their daily lives. Make sure to continue any treatments that you have been prescribed. Taking these medications appropriately will help prevent future complications.

  • Wear a MedicAlert tag and carry treatment information. Because hemophilia is an uncommon condition, it may not be recognized in an accident victim unable to communicate. However, paramedics and other medical providers are trained to look for medical identification. Carrying information on the type of hemophilia factors that may be needed can lead to quicker treatment.
  • Go to the Emergency Room if you experience any bleeding that cannot be stopped. The quicker you get to the hospital, the less chance you have of getting any unwanted complications. You should also go to the ER if you are having symptoms that are indicative of brain bleeding, or you have any limited joint movement or pain. If you go the ER, make sure that you take your medication list.
  • Hemophilia treatment centers. Register with one of these centers that specialize in care for hemophilic patients. These centers are typically located at a University hospitals or medical research centers. They can provide treatment and education which could be very beneficial not only for the patient but the family.
  • Protect Young children. Children need to be protected from objects that could cause them potential harm such as activities that could cause potential bruising or bleeds. Make kids wear helmets along with elbow and knee pads when riding bicycles or tricycles. While traveling in the car, make sure that safety belts are used appropriately. Around the house are many objects that put a child a risk. Be sure to check your furniture for sharp corners that could lead to cuts, place locks on the cabinets to prevent them from being opened, gates around the house to prevent falls down stairs or to keep out of dangerous rooms (furnace, water heater, etc). Other precautions that can be taken include having a ice pack in the freezer in case of bruises or bumps.. Make sure that anyone who watches the child knows about hemophilia and what they should do in case of a bruise or a bleed.
  • Exercise regularly. Early treatment with clotting factor products can help prevent muscle and joint damage, but it cannot restore joint or muscle function. To preserve muscle strength and joint mobility, individuals with hemophilia should incorporate both stretching and active exercises into their daily routines -- especially after a major bleeding episode. High contact sports, such as boxing, football, and wrestling, which may increase the chance of an injury that could cause bleeding, probably should be avoided. However, swimming, biking, golfing, walking, and tennis are excellent ways for individuals with hemophilia to get needed exercise. Individuals with hemophilia will learn which activities work best for them. Appropriate protective gear can help to prevent injury and major bleeding during physical activities. In some cases, prophylactic (preventive) doses of a clotting factor product may be given before exercise.
  • Seek appropriate pain relief. Bleeding episodes are usually associated with some degree of pain. Pain relief can be achieved with or without medication. The use of ice or heat packs often can help relieve pain due to swelling and inflammation. Gentle massage may be helpful if the bleeding has caused a muscle spasm, but care should be taken not to cause bruising by massage that is too rough. Taking acetaminophen (Tylenol) can often relieve pain. However, individuals with hemophilia should avoid aspirin because aspirin reduces the ability of blood components known as platelets to stick together and begin the process of clot formation. Additionally, aspirin may irritate the stomach enough to cause bleeding in the stomach. Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen may be used with caution by individuals with hemophilia. While NSAIDs usually provide good pain relief and reduce inflammation, they also have the potential to cause stomach bleeding. In cases of extreme pain, prescription pain relievers may be helpful but prolonged use should be avoided.
  • Practice good dental hygiene. Good dental care is especially important for individuals with hemophilia because unhealthy gums can lead to bleeding in the mouth .Any oral surgery that is needed by individuals with hemophilia usually should be performed in a hospital. A prophylactic (preventive) dose of a clotting factor product may be administered prior to surgery.
  • Keep up with immunizations. Keeping vaccinations for hepatitis A and hepatitis B current is especially critical for individuals with hemophilia. Although current manufacturing processes filter out viruses, individuals who use blood-derived factor products are at a slightly increased risk for contracting viral infections such as hepatitis through possible contamination of the blood. Vaccinations against other infectious diseases are just as important for individuals with hemophilia.
  • Traveling. Make sure that you take your medicines with you. Also, make sure that you are going to have enough medication for the entire length of the trip. Actually, it?s an even better idea to have an additional supply of medications in case your trip is unexpectantly extended. Have your personal doctor write a letter describing your condition so in an emergency so in an emergency you can pass this letter to the doctors in your travel area. Finally, before leaving town, find out what medical centers are in the area in case an emergency does occur.
  • Get support. Dealing with the symptoms and complications of hemophilia can be overwhelming, especially for parents of children who are newly diagnosed or those with mild hemophilia who have unusual bleeding only occasionally. Help is available from several sources. Many communities have hemophilia clinics, where families can learn about hemophilia and get assistance with giving infusions. In addition, several national organizations maintain websites with helpful information. Among them are:
    • National Hemophilia Foundation (www.hemophilia.org)
    • Hemophilia Galaxy (www.hemophiliagalaxy.com)
    • All About Bleeding (www.allaboutbleeding.com)

What is on the horizon?

A major focus of research in hemophilia centers on gene therapy. Because only one defective gene is involved, replacing that gene effectively will cure hemophilia. In multiple studies, normal clotting factor genes have been introduced in laboratory animals such as mice and dogs that had hemophilia. In some of the studies, increased production of clotting factors has lasted for more than a year. Only small amounts of clotting factor production was seen in some of the test animals, however, and many developed antibodies that limited clotting factor production. Genetic studies in humans with hemophilia are not yet feasible. Although gene therapy may eventually replace treatment for individuals with hemophilia, it will not eliminate defective genes in carriers, who could still pass hemophilia to their children. Currently studies are being conducted for type B hemophilia to determine the safety of the gene transfers.

A less well-studied, but potentially more useful way of producing clotting factor products for treating hemophilia may be breeding herds of ?transgenic? animals. These animals, such as goats or pigs, have been modified genetically to produce human clotting factors in their milk. Drinking milk fortified with clotting factors may supplement or even replace injections of clotting factors, as well as help to prevent inhibitors. It would also extend treatment options for individuals with hemophilia who live in remote areas of the world.

References

Baz R, Mekhail T. Clotting Factor Deficiencies. The Cleveland Clinic. Reviewed July 15, 2004. Available at: https://www.clevelandclinicmeded.com/diseasemanagement/hematology/ clotting/clotting.htm. Accessed August 19, 2004 and June 20, 2007.

Bicker B, Kwiatkowski JL. Coagulation disorders. In: Dipiro JT, Talbert RL, Yee GC, et al. (eds.). Pharmacotherapy: a Pathophysiologic Approach. 6th ed. New York: McGraw Hill; 2005.

Giangrande J. New transgenic developments. World Federation of Hemophilia. Available at: http://www.wfh.org/ShowDoc.asp?Rubrique=22&Document=317&Contentid=606. Accessed August 24, 2004 and June 20, 2007.

Jones P. Living with Haemophilia [sic]. 5th ed. New York: Oxford University Press; 2002.

National Heart, Lung, and Blood Institute. Hemophilia. Available at: http://www.nhlbi.nih.gov/health/dci/Diseases/hemophilia/hemophilia_what.html. Accessed September 12, 2006 and June 20, 2007.

Nation Heart, Lung, and Blood Institute. von Willebrand. Available at: http://www.nhlbi.nih.gov/health/dci/Diseases/vWD/vWD_WhatIs.html. Accessed June 20, 2007.

National Hemophilia Foundation Medical and Scientific Advisory Council (MASAC) Recommendations concerning the treatment of hemophilia and other bleeding disorders. March 2003. Available at: http://www.hemophilia.org/research/masac/masac151.htm Accessed Dec. 3, 2003 and June 20, 2007.

National Institutes of Health. Research on complications of hemophilia. No date given. Available at: http://www.nhlbi.nih.gov/health/prof/blood/other/hemophilia/hemophil.htm. Accessed August 18, 2004.

Canadian Hemophilia Society. Available at: http://www.hemophilia.ca/en/2.1.php. Accessed August 18, 2004 and June 20, 2007.

Hemophilia Health Condition Last Updated: June 2007

Note: The above information is intended to supplement, not substitute for, the expertise and judgment of your physician, pharmacist, or other healthcare professional. It is not intended to diagnose a health condition, but it can be used as a guide to help you decide if you should seek professional treatment or to help you learn more about your condition once it has been diagnosed.

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