Hemophilia is a disorder in which the blood does not clot properly. The two most common types, hemophilia A and hemophilia B, are caused by defective or missing proteins that are part of the clotting system, also called the Coagulation Cascade.In hemophilia B the defective or missing protein is called factor IX. Hemophilia was originally thought to be a disorder that affects primarily males, but recent research shows that a significant number of females are also affected. There are a number of other bleeding disorders, most caused by defects in or absence of other proteins of the clotting system. The most common of these is von Willebrand disease. Most of the others are rare.

Although one might think that the danger for a person with hemophilia would be bleeding to death from even a small injury, that is not usually the problem. The blood of a person with hemophilia clots much more slowly than normal, but the blood clotting system has a lot of redundancy, so it will eventually cause the blood to clot by alternate mechanisms. Most of the danger comes from bleeding internally. For instance, without treatment, many people with severe hemophilia B become crippled from damage caused by recurrent bleeding into their joints. They may also bleed into their muscles and other soft tissues. These bleeding episodes or “bleeds” appear to arise spontaneously, often with no apparent triggering event. Such bleeds can be life threatening if they occur in or around vital organs or block the airway in the throat. The most dangerous event is bleeding into the brain, one of the primary causes of death in hemophilia.

Hemophilia B is usually classified as mild, moderate, or severe. People with less than 1 % of the normal level of factor IX have severe hemophilia B which involves frequent spontaneous bleeding into joints or soft tissue and prolonged bleeding during trauma or surgery. People with 1 – 5 % of normal factor IX levels have moderate hemophilia B with occasional bleeding episodes and excessive bleeding during surgery or trauma. People with factor IX levels more than 5 % of normal have mild hemophilia B. They usually do not have bleeding episodes but may bleed excessively during trauma or surgery. The factor level for people without hemophilia has a wide range: from 50 – 150% of normal.

Hemophilia has an ancient history. The earliest written reference to hemophilia may be that found in the Mishneh Torah, a second century compilation of Jewish law. There it states that if a mother has had two sons circumcised who both died as a result, then a third son must not be circumcised. Although it does not specifically state that the deaths were due to bleeding, other sections of these writings do refer to “loose” blood.

Another early reference is the legend of the Curse of Tenna. In 1769 a judge in the small Swiss village of Tenna condemned an innocent man to death. The legend states that this act led to the inflicting of a curse upon the judge and his family. This curse was believed by the citizens of Tenna to be the cause of a serious bleeding disorder, sometimes leading to bleeding to death, which afflicted the family for generations. This was, in fact, a family with hereditary hemophilia, the oldest and largest such family ever described comprising 3072 members, 55 who had hemophilia. It turns out that the family disease is hemophilia B rather than the more common hemophilia A.

An early medical account published in 1803 correctly described the disease as one which affects males but is transmitted by females. In fact, the early passage from the Jewish Torah goes on to say that additionally, that the sons of the woman’s sister should not be circumcised, but the sons of her brother can be circumcised. Remarkably, it was not until 1865 that Mendel reported the laws of genetic inheritance and not until the early 1900s that such diseases were discovered to be carried by the X chromosome, and thus affect primarily males.

Queen Victoria of England (1837-1901) was a carrier of the disease who passed it on to her son Prince Leopold. Two of her daughters were also carriers who passed the disease on to a number of their descendants in the royal families of Russia, Spain, and Germany.

However, it was not until the early 1950s that hemophilia A and hemophilia B were recognized as separate diseases. Both diseases have very similar symptoms, so it was very difficult to distinguish between them.

Since that time, the history of hemophilia B has followed the development of the factor IX products used to treat the disease. Until the late 1950s serum, and later plasma, were the only treatments available. Then in 1959 the first purified factor IX concentrate derived from plasma was developed in France. This was followed by the development of similar concentrates in Britain and the U.S. The first factor IX product in the U.S. was licensed in 1969.

The early products were known as Factor IX Complex concentrates. The word “complex” in the name refers to the fact that in addition to factor IX, these products also contain several related clotting factors such as factor II, factor X, and in some cases factor VII. Because of the similar properties of these factors, it is difficult to purify factor IX away from the others.

The availability of Factor IX Complex and its effectiveness in treating bleeding episodes significantly improved the health and well-being of hemophilia B patients. The use of Factor IX Complex, however, soon became associated with thromboembolic complications — that is, unwanted, and potentially life-threatening internal clotting. This happened most often when the product was used in large amounts for extended periods of time, for instance in hemophilia B patients undergoing surgery. To eliminate this problem, more highly purified products containing only factor IX were developed with the first one being licensed in the U.S. in 1990.

Another serious complication of the use of factor IX products purified from human plasma is the potential for transmission of infectious diseases. Until the mid-1980s, people receiving factor IX products routinely became infected with hepatitis and other diseases. At the time, it was thought that this was an unfortunate but unavoidable consequence of this valuable therapy. However, then AIDS came along in the early 1980s, and one of the groups most affected was people with hemophilia and their families. This led to the rapid development of a number of methods for inactivating viruses in plasma products. Viral inactivation or removal methods have improved significantly since then to the point that now plasma products have an extremely low risk of disease transmission. Finally, in 1997, the first recombinant factor IX product was licensed in the U.S. Since recombinant products are not made from plasma, they do not carry the same risk of transmission of human diseases.

Today, hemophilia B patients are treated with high-purity plasma-derived or recombinant factor IX concentrates. Advances in treatment methods, such as prophylaxis, have led to essentially almost-normal longevity and a much higher quality of life. Newer recombinant products, new delivery methods, and FDA-approved clinical trials of gene therapy for hemophilia B are under way that may further alter treatment options and improve quality of life.

Hemophilia B is caused by defective or missing factor IX proteins in the blood. Factor IX is one of thirteen clotting factors that were historically identified as substances that affected blood clotting. When the blood clotting system was first being understood, medical researchers did not know exactly what the factors were, so they gave them Roman numerals I through XIII. Now we know that most of the clotting factors are proteins and that there are numerous other substances involved besides the original thirteen. (Actually, two of the numbered factors were later discovered to be the same protein, so there are really only twelve numbered clotting factors.)

The factor IX protein is usually defective or missing because of a defective factor IX gene. A gene tells the body how to make a protein, so a defective gene will result in a defective protein, or if the defect is significant enough, it can result in the body making none of the protein at all. Alternatively, a small defect might result in a protein that still has some activity, which for factor IX could result in a milder form of hemophilia B.

The factor IX gene is located on the X chromosome, which is the reason that the disease mainly affects males. Men have an X and a Y chromosome, so they only have one copy of the factor IX gene. Women have two X chromosomes, which each has a copy of the factor IX gene. Therefore, even if a woman has a defective factor IX gene on one X chromosome, she usually has a normal factor IX gene on the other X chromosome. A woman can have defective factor IX genes on both X chromosomes, , but that is rare.

Even though women with a defective factor IX gene also still have a normal factor IX gene in every cell, more recent research has shown that the body always inactivates one of the two X chromosomes to prevent conflicts between them. This inactivation, called lyonization, is usually random so that 50% of the woman’s cells will have the normal factor IX gene as the active one, but 50% of her cells will have the defective factor IX gene as the active one. That means that a woman who inherits a defective factor IX gene will, on average, only have 50% of the normal level of factor IX. Although 50% is at the bottom level of the normal range, variations in the lyonization process can push a woman’s factor IX level down into the hemophilia range.

Women with a defective factor IX gene are carriers of hemophilia B because if they pass on the X chromosome with the defective gene to a son, the son will have hemophilia B. Men inherit their single X chromosome from their mother and their Y chromosome from their father. A male with hemophilia B cannot pass on the disease to his sons, but he can pass it on to his grandsons. A male with a defective factor IX gene will pass it on to his daughters who then are carriers of the disease. His daughters’ children then have a 50 – 50 chance of inheriting the defective gene, the males having hemophilia and the females being carriers (or women with hemophilia as described above).

Defects in the factor IX gene can also occur spontaneously. During fertilization, the genes in a woman’s egg are combined with the genes in the male’s sperm to produce the set of genes, called the genome, a copy of which will occur in almost every cell of the new child’s body. The single-cell embryo resulting from combining the egg and sperm then starts dividing to produce more cells, copying the genes that were in the single cell to supply genes for the new cells. Whenever genes are combined or copied, there is always the possibility of mistakes (mutations). If a mutation occurs when the factor IX gene is being copied, the child may have hemophilia or be a carrier. Even though the child became afflicted by a spontaneous mutation, it is now part of his or her genetic makeup and can be passed to his or her offspring. About 30% of hemophilia cases are the result of a spontaneous mutation, the rest are passed down through families.

Hemophilia B is the second most common type of hemophilia and affects approximately 3.7 of every 100,000 males. There are over 7000 people with hemophilia B in the U.S. (based on data from an American study that looked at Hemophilia Treatment Centers). For comparison, hemophilia A, the most common form, affects approximately 12 of every 6100,000 males. Both hemophilias appear to affect all racial and ethnic groups equally.

Inhibitors are antibodies that the immune system develops to attack factor IX because it thinks it is a foreign protein. During very early childhood the immune system learns which proteins are supposed to be in the body. If a person has no factor IX or has a very different form of factor IX, the immune system never learns what normal factor IX looks like. Then when a person with hemophilia B is infused with factor IX concentrate, the immune system may think the normal factor IX molecule is an invading, foreign protein that it needs to fight off. The inhibitor interferes with the function of the factor IX protein keeping it from restoring the clotting ability of the blood.

Now that infectious disease transmission from factor concentrates is no longer a major issue, inhibitor development is the biggest problem in hemophilia treatment. Fortunately, only about 2 – 3 % of hemophilia B patients develop inhibitors. However, for those that do develop an inhibitor, it is a serious consequence. In addition, about 50 % of hemophilia B patients with inhibitors also develop anaphylactic reactions, severe allergic reactions to factor IX, which can be life threatening. If an inhibitor is going to develop, it usually happens early in treatment, during the first few exposures to factor IX, but it can develop in any patient at any time

Patients with low-titer inhibitors, those with smaller amounts of inhibitor in their blood, can be treated by giving them larger amounts of factor IX, enough to overwhelm the inhibitor. However, it is impractical (and expensive) to give enough factor IX to patients with high-titer inhibitors. Bleeding episodes in patients with high-titer inhibitors are usually treated with a plasma-derived concentrate containing activated clotting factors or with a recombinant product containing activated factor VII. (Many of the clotting proteins circulate in the blood in an un-activated form and are then activated when needed for clotting. Factor IX is activated by a reaction that also requires factor VIII, which is why a deficiency of either protein causes diseases with very similar symptoms.) The activated factor concentrates can be thought of as bypassing the step in the clotting process that requires factor IX. Their use has more limitations and side effects than with normal factor IX concentrates, but they work effectively in many inhibitor patients.

Some inhibitors can be eliminated by a method called immune tolerance induction in which daily doses of factor IX are given over an extended period of time. This can lead to complete elimination of the inhibitor in some patients but is only effective in about 30% of hemophilia B inhibitor cases.

Historically, hemophilia patients were only treated when they had bleeding episodes. This is known as on-demand treatment. One of the main reasons on-demand treatment has been used is the high cost and limited supply of factor IX. However, it has become known that treating people who have hemophilia with frequent, periodic factor IX infusions can have significant medical and quality of life benefits. This type of treatment is called prophylactic treatment or prophylaxis. Although prophylactic treatment uses more factor IX, some studies have shown that lifetime medical costs for prophylactic treatment may be equivalent, or sometimes even less, than for on-demand treatment. This is because the patient remains healthier, requiring less additional medical care and fewer hospitalizations.

Prophylaxis, when started at an early age, is the only known treatment that can prevent the joint damage that otherwise afflicts most severe hemophilia patients, as well as many milds and moderates. There is no single method for prophylaxis that is accepted as being the best. A number of different treatment schedules and dosage regimens are being used successfully, but regardless of the method used, the most important factor in preventing joint damage appears to simply be starting early. When started early in children with no joint damage, most never develop joint damage. However, even if prophylaxis is started at a later age, it can often slow or stop further progression of joint damage. In a small number of patients joint condition can actually improve.

For hemophilia B, most prophylaxis patients receive factor infusions every three days or twice a week. The original idea for prophylactic treatment came from the observation that patients with mild or moderate hemophilia, those who have factor levels greater than 1% of normal, bleed only infrequently and generally experience less-severe joint damage. Thus the general goal of prophylaxis is to maintain the factor level above 1%. Since everyone reacts differently, some patients may need a little more and some a little less than 1 %, so many physicians now recommend judging by the patients bleeding behavior rather than just by the factor IX level. More recently, many physicians are recommending higher levels above 12 – 15% to really achieve good protection.

In addition to preventing joint damage, it is clear from experience in Europe, where prophylactic treatment is more common, that it is highly beneficial to the psychological and social well-being of patients and their families. In general, prophylaxis allows for a more normal lifestyle; the patient and his family have more control over the hemophilia. There is reduced anxiety when leaving children in day care or at school, and participation in a greater variety of physical activities is allowed, although there are still limitations. Children feel less different than their friends and schoolmates. Practically, over the course of his lifetime, the hemophilia patient on prophylaxis experiences fewer days absent from school or work, fewer hospitalizations, and surgical procedures and generally a better quality of life.

A port, also called a portacath, is a surgically-implanted catheter that can make it easier to infuse factor IX into the bloodstream. The most common type is placed completely under the skin, usually in the chest. It has a small round chamber with a septum and a tube leading into a nearby vein. A septum is a rubber disk through which a needle can be inserted. Using a special needle, factor IX is injected through the skin and the septum into the chamber from which it then passes through the tube into the bloodstream.

Ports are more often used in children, but adults who have problems injecting factor IX directly into their veins may also use them. They can be especially useful for prophylaxis because of the required frequent injections. The problem of venous access can be a significant issue. Especially with very young children with small veins, performing an infusion can be a challenge even for experienced medical professionals in a clinic, let alone for a parent at home. However, ports take some care and can be problematic. They can become plugged or infected and may need to be replaced as a child grows. There is also a risk of a misplaced injection into the skin near the port.

Initially, a patient will often start out infusing an average amount based on his weight. The formula for calculating the amount is in the direction leaflet that comes with every vial of factor IX concentrate. However, most patients are not average. All patients vary in the amount of the factor IX infused that ends up in the bloodstream, how long it lasts in the bloodstream, and how effectively it works in their clotting system, among other things. Usually with experience a patient will come to know how much he needs to treat various types of bleeds or to maintain adequate prophylaxis.

Instead of just assuming that everyone is average, physicians are beginning to perform half-life and recovery studies on patients. These are called pharmacokinetic or PK studies. A patient is infused with a known amount of factor IX concentrate and then has blood samples taken periodically over a period of time, often 24 or 48 hours. The amount of factor IX is measured in each of the samples. The first sample is taken as soon as possible after the infusion, and the relative amount of factor IX in it is called the recovery. On average, only about half of the factor IX shows up in the first sample, so an average recovery is about 50 %. Even though the factor IX is injected directly into the bloodstream, about half of it immediately moves to other places in the body.

The later blood samples show how long the factor IX lasts in the bloodstream. Some of the factor IX gets used up in clotting (there is always a little clotting going on somewhere in the body), and some is eliminated by normal body processes. For most blood proteins, the body continuously makes and removes them to keep the amount in the bloodstream at the desired level and to make sure the proteins that are there are fresh and in good shape. For a person with hemophilia B whose body does not produce factor IX, the amount in the bloodstream is highest right after an infusion and then gradually decreases. The amount of time that it takes for half of the protein to disappear is called the half-life. The typical half-life for factor IX is 18 – 24 hours, but there are many patients with half-lives outside that range. Knowing the recovery and half-life gives a physician much of the knowledge needed to more precisely target the amount of factor IX that an individual patient requires. Physicians often use other quantities to describe the lifetime of factor IX in the bloodstream, but all of those quantities are related to the recovery and half-life.

What a recovery study does not tell the physician is how the factor IX behaves in the individual patient’s clotting system. For many patients, a factor IX level that is 1 % of normal is enough to restore the blood’s clotting ability to a point where he has few problems and minimal joint damage. However, 1 % is again an average, and patients can vary considerably. Some patients need much more than 1 % of normal levels for adequate clotting and some need less.

When a patient is treated prophylactically, the amount of factor IX in the bloodstream rises and falls, being highest right after an infusion and lowest right before. The low level right before an infusion is called the trough level. Prophylactic treatment usually aims to keep the trough level above the level that protects from joint damage, often 1 % of normal, but as mentioned above, physicians are more frequently targeting higher trough levels